Endopeptidases that are specific for AMYLOID PROTEIN PRECURSOR. Three secretase subtypes referred to as alpha, beta, and gamma have been identified based upon the region of amyloid protein precursor they cleave.
A single-pass type I membrane protein. It is cleaved by AMYLOID PRECURSOR PROTEIN SECRETASES to produce peptides of varying amino acid lengths. A 39-42 amino acid peptide, AMYLOID BETA-PEPTIDES is a principal component of the extracellular amyloid in SENILE PLAQUES.
A sub-subclass of endopeptidases that depend on an ASPARTIC ACID residue for their activity.
Peptides generated from AMYLOID BETA-PEPTIDES PRECURSOR. An amyloid fibrillar form of these peptides is the major component of amyloid plaques found in individuals with Alzheimer's disease and in aged individuals with trisomy 21 (DOWN SYNDROME). The peptide is found predominantly in the nervous system, but there have been reports of its presence in non-neural tissue.
A degenerative disease of the BRAIN characterized by the insidious onset of DEMENTIA. Impairment of MEMORY, judgment, attention span, and problem solving skills are followed by severe APRAXIAS and a global loss of cognitive abilities. The condition primarily occurs after age 60, and is marked pathologically by severe cortical atrophy and the triad of SENILE PLAQUES; NEUROFIBRILLARY TANGLES; and NEUROPIL THREADS. (From Adams et al., Principles of Neurology, 6th ed, pp1049-57)
A fibrous protein complex that consists of proteins folded into a specific cross beta-pleated sheet structure. This fibrillar structure has been found as an alternative folding pattern for a variety of functional proteins. Deposits of amyloid in the form of AMYLOID PLAQUES are associated with a variety of degenerative diseases. The amyloid structure has also been found in a number of functional proteins that are unrelated to disease.
A subclass of PEPTIDE HYDROLASES that catalyze the internal cleavage of PEPTIDES or PROTEINS.
Integral membrane protein of Golgi and endoplasmic reticulum. Its homodimer is an essential component of the gamma-secretase complex that catalyzes the cleavage of membrane proteins such as NOTCH RECEPTORS and AMYLOID BETA-PEPTIDES precursors. PSEN1 mutations cause early-onset ALZHEIMER DISEASE type 3 that may occur as early as 30 years of age in humans.
Accumulations of extracellularly deposited AMYLOID FIBRILS within tissues.
Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN.
Extracellular protease inhibitors that are secreted from FIBROBLASTS. They form a covalent complex with SERINE PROTEASES and can mediate their cellular internalization and degradation.
An ACUTE PHASE REACTION protein present in low concentrations in normal sera, but found at higher concentrations in sera of older persons and in patients with AMYLOIDOSIS. It is the circulating precusor of amyloid A protein, which is found deposited in AA type AMYLOID FIBRILS.
Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques.
The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.
Integral membrane protein of Golgi and endoplasmic reticulum. Its homodimer is an essential component of the gamma-secretase complex that catalyzes the cleavage of membrane proteins such as NOTCH RECEPTORS and AMYLOID BETA-PEPTIDES precursors. PSEN2 mutations cause ALZHEIMER DISEASE type 4.
The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM.
Any of various enzymatically catalyzed post-translational modifications of PEPTIDES or PROTEINS in the cell of origin. These modifications include carboxylation; HYDROXYLATION; ACETYLATION; PHOSPHORYLATION; METHYLATION; GLYCOSYLATION; ubiquitination; oxidation; proteolysis; and crosslinking and result in changes in molecular weight and electrophoretic motility.
A group of sporadic, familial and/or inherited, degenerative, and infectious disease processes, linked by the common theme of abnormal protein folding and deposition of AMYLOID. As the amyloid deposits enlarge they displace normal tissue structures, causing disruption of function. Various signs and symptoms depend on the location and size of the deposits.
A heterogeneous group of sporadic or familial disorders characterized by AMYLOID deposits in the walls of small and medium sized blood vessels of CEREBRAL CORTEX and MENINGES. Clinical features include multiple, small lobar CEREBRAL HEMORRHAGE; cerebral ischemia (BRAIN ISCHEMIA); and CEREBRAL INFARCTION. Cerebral amyloid angiopathy is unrelated to generalized AMYLOIDOSIS. Amyloidogenic peptides in this condition are nearly always the same ones found in ALZHEIMER DISEASE. (from Kumar: Robbins and Cotran: Pathologic Basis of Disease, 7th ed., 2005)
Integral membrane proteins and essential components of the gamma-secretase complex that catalyzes the cleavage of membrane proteins such as NOTCH RECEPTORS and AMYLOID BETA-PEPTIDES precursors. Mutations of presenilins lead to presenile ALZHEIMER DISEASE with onset before age 65 years.
Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.
The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.
Microtubule-associated proteins that are mainly expressed in neurons. Tau proteins constitute several isoforms and play an important role in the assembly of tubulin monomers into microtubules and in maintaining the cytoskeleton and axonal transport. Aggregation of specific sets of tau proteins in filamentous inclusions is the common feature of intraneuronal and glial fibrillar lesions (NEUROFIBRILLARY TANGLES; NEUROPIL THREADS) in numerous neurodegenerative disorders (ALZHEIMER DISEASE; TAUOPATHIES).
The level of protein structure in which combinations of secondary protein structures (alpha helices, beta sheets, loop regions, and motifs) pack together to form folded shapes called domains. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Small proteins usually consist of only one domain but larger proteins may contain a number of domains connected by segments of polypeptide chain which lack regular secondary structure.
Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors.
Proteins that form the core of amyloid fibrils. For example, the core of amyloid A is formed from amyloid A protein, also known as serum amyloid A protein or SAA protein.
Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.
Naturally occurring or experimentally induced animal diseases with pathological processes sufficiently similar to those of human diseases. They are used as study models for human diseases.
Disorders of the peripheral nervous system associated with the deposition of AMYLOID in nerve tissue. Familial, primary (nonfamilial), and secondary forms have been described. Some familial subtypes demonstrate an autosomal dominant pattern of inheritance. Clinical manifestations include sensory loss, mild weakness, autonomic dysfunction, and CARPAL TUNNEL SYNDROME. (Adams et al., Principles of Neurology, 6th ed, p1349)
A curved elevation of GRAY MATTER extending the entire length of the floor of the TEMPORAL HORN of the LATERAL VENTRICLE (see also TEMPORAL LOBE). The hippocampus proper, subiculum, and DENTATE GYRUS constitute the hippocampal formation. Sometimes authors include the ENTORHINAL CORTEX in the hippocampal formation.
Established cell cultures that have the potential to propagate indefinitely.
Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.
A pancreatic beta-cell hormone that is co-secreted with INSULIN. It displays an anorectic effect on nutrient metabolism by inhibiting gastric acid secretion, gastric emptying and postprandial GLUCAGON secretion. Islet amyloid polypeptide can fold into AMYLOID FIBRILS that have been found as a major constituent of pancreatic AMYLOID DEPOSITS.
The thin layer of GRAY MATTER on the surface of the CEREBRAL HEMISPHERES that develops from the TELENCEPHALON and folds into gyri and sulchi. It reaches its highest development in humans and is responsible for intellectual faculties and higher mental functions.
A family of proteins that share sequence similarity with the low density lipoprotein receptor (RECEPTORS, LDL).
The process of moving proteins from one cellular compartment (including extracellular) to another by various sorting and transport mechanisms such as gated transport, protein translocation, and vesicular transport.
The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.
The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.
Learning the correct route through a maze to obtain reinforcement. It is used for human or animal populations. (Thesaurus of Psychological Index Terms, 6th ed)
Cleavage of proteins into smaller peptides or amino acids either by PROTEASES or non-enzymatically (e.g., Hydrolysis). It does not include Protein Processing, Post-Translational.
Histochemical localization of immunoreactive substances using labeled antibodies as reagents.
CELL LINE derived from the ovary of the Chinese hamster, Cricetulus griseus (CRICETULUS). The species is a favorite for cytogenetic studies because of its small chromosome number. The cell line has provided model systems for the study of genetic alterations in cultured mammalian cells.
Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes.
A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.
Abnormal structures located in various parts of the brain and composed of dense arrays of paired helical filaments (neurofilaments and microtubules). These double helical stacks of transverse subunits are twisted into left-handed ribbon-like filaments that likely incorporate the following proteins: (1) the intermediate filaments: medium- and high-molecular-weight neurofilaments; (2) the microtubule-associated proteins map-2 and tau; (3) actin; and (4) UBIQUITINS. As one of the hallmarks of ALZHEIMER DISEASE, the neurofibrillary tangles eventually occupy the whole of the cytoplasm in certain classes of cell in the neocortex, hippocampus, brain stem, and diencephalon. The number of these tangles, as seen in post mortem histology, correlates with the degree of dementia during life. Some studies suggest that tangle antigens leak into the systemic circulation both in the course of normal aging and in cases of Alzheimer disease.
The directed transport of ORGANELLES and molecules along nerve cell AXONS. Transport can be anterograde (from the cell body) or retrograde (toward the cell body). (Alberts et al., Molecular Biology of the Cell, 3d ed, pG3)
The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.
A CELL LINE derived from a PHEOCHROMOCYTOMA of the rat ADRENAL MEDULLA. PC12 cells stop dividing and undergo terminal differentiation when treated with NERVE GROWTH FACTOR, making the line a useful model system for NERVE CELL differentiation.
A family of membrane-anchored glycoproteins that contain a disintegrin and metalloprotease domain. They are responsible for the proteolytic cleavage of many transmembrane proteins and the release of their extracellular domain.
Loss of functional activity and trophic degeneration of nerve axons and their terminal arborizations following the destruction of their cells of origin or interruption of their continuity with these cells. The pathology is characteristic of neurodegenerative diseases. Often the process of nerve degeneration is studied in research on neuroanatomical localization and correlation of the neurophysiology of neural pathways.
Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation.
Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes.
A plant genus of the family CONVOLVULACEAE. The common name of morning glory also refers to IPOMOEA. The common name of bindweed also refers to IPOMOEA; CALYSTEGIA; or POLYGONUM.
Proteins prepared by recombinant DNA technology.
Amyloid P component is a small, non-fibrillar glycoprotein found in normal serum and in all amyloid deposits. It has a pentagonal (pentaxin) structure. It is an acute phase protein, modulates immunologic responses, inhibits ELASTASE, and has been suggested as an indicator of LIVER DISEASE.
Small proteinaceous infectious particles which resist inactivation by procedures that modify NUCLEIC ACIDS and contain an abnormal isoform of a cellular protein which is a major and necessary component. The abnormal (scrapie) isoform is PrPSc (PRPSC PROTEINS) and the cellular isoform PrPC (PRPC PROTEINS). The primary amino acid sequence of the two isoforms is identical. Human diseases caused by prions include CREUTZFELDT-JAKOB SYNDROME; GERSTMANN-STRAUSSLER SYNDROME; and INSOMNIA, FATAL FAMILIAL.
A common neoplasm of early childhood arising from neural crest cells in the sympathetic nervous system, and characterized by diverse clinical behavior, ranging from spontaneous remission to rapid metastatic progression and death. This tumor is the most common intraabdominal malignancy of childhood, but it may also arise from thorax, neck, or rarely occur in the central nervous system. Histologic features include uniform round cells with hyperchromatic nuclei arranged in nests and separated by fibrovascular septa. Neuroblastomas may be associated with the opsoclonus-myoclonus syndrome. (From DeVita et al., Cancer: Principles and Practice of Oncology, 5th ed, pp2099-2101; Curr Opin Oncol 1998 Jan;10(1):43-51)
An enzyme the catalyzes the degradation of insulin, glucagon and other polypeptides. It is inhibited by bacitracin, chelating agents EDTA and 1,10-phenanthroline, and by thiol-blocking reagents such as N-ethylmaleimide, but not phosphoramidon. (Eur J Biochem 1994;223:1-5) EC 3.4.24.56.
Compounds which inhibit or antagonize biosynthesis or actions of proteases (ENDOPEPTIDASES).
A family of conserved cell surface receptors that contain EPIDERMAL GROWTH FACTOR repeats in their extracellular domain and ANKYRIN repeats in their cytoplasmic domains. The cytoplasmic domain of notch receptors is released upon ligand binding and translocates to the CELL NUCLEUS where it acts as transcription factor.
In tissue culture, hairlike projections of neurons stimulated by growth factors and other molecules. These projections may go on to form a branched tree of dendrites or a single axon or they may be reabsorbed at a later stage of development. "Neurite" may refer to any filamentous or pointed outgrowth of an embryonal or tissue-culture neural cell.
An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed.
Changes in the amounts of various chemicals (neurotransmitters, receptors, enzymes, and other metabolites) specific to the area of the central nervous system contained within the head. These are monitored over time, during sensory stimulation, or under different disease states.
RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.
The gradual irreversible changes in structure and function of an organism that occur as a result of the passage of time.
An acid dye used in testing for hydrochloric acid in gastric contents. It is also used histologically to test for AMYLOIDOSIS.
The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells.
A genus of the family Muridae consisting of eleven species. C. migratorius, the grey or Armenian hamster, and C. griseus, the Chinese hamster, are the two species used in biomedical research.
Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body.
Enzyme that is a major constituent of kidney brush-border membranes and is also present to a lesser degree in the brain and other tissues. It preferentially catalyzes cleavage at the amino group of hydrophobic residues of the B-chain of insulin as well as opioid peptides and other biologically active peptides. The enzyme is inhibited primarily by EDTA, phosphoramidon, and thiorphan and is reactivated by zinc. Neprilysin is identical to common acute lymphoblastic leukemia antigen (CALLA Antigen), an important marker in the diagnosis of human acute lymphocytic leukemia. There is no relationship with CALLA PLANT.
Cytoplasmic vesicles formed when COATED VESICLES shed their CLATHRIN coat. Endosomes internalize macromolecules bound by receptors on the cell surface.
Disturbances in registering an impression, in the retention of an acquired impression, or in the recall of an impression. Memory impairments are associated with DEMENTIA; CRANIOCEREBRAL TRAUMA; ENCEPHALITIS; ALCOHOLISM (see also ALCOHOL AMNESTIC DISORDER); SCHIZOPHRENIA; and other conditions.
Recombinant proteins produced by the GENETIC TRANSLATION of fused genes formed by the combination of NUCLEIC ACID REGULATORY SEQUENCES of one or more genes with the protein coding sequences of one or more genes.
A cell line derived from cultured tumor cells.
The production of a dense fibrous network of neuroglia; includes astrocytosis, which is a proliferation of astrocytes in the area of a degenerative lesion.
Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.
The aggregation of soluble ANTIGENS with ANTIBODIES, alone or with antibody binding factors such as ANTI-ANTIBODIES or STAPHYLOCOCCAL PROTEIN A, into complexes large enough to fall out of solution.
The third type of glial cell, along with astrocytes and oligodendrocytes (which together form the macroglia). Microglia vary in appearance depending on developmental stage, functional state, and anatomical location; subtype terms include ramified, perivascular, ameboid, resting, and activated. Microglia clearly are capable of phagocytosis and play an important role in a wide spectrum of neuropathologies. They have also been suggested to act in several other roles including in secretion (e.g., of cytokines and neural growth factors), in immunological processing (e.g., antigen presentation), and in central nervous system development and remodeling.
The parts of a macromolecule that directly participate in its specific combination with another molecule.
Members of the class of compounds composed of AMINO ACIDS joined together by peptide bonds between adjacent amino acids into linear, branched or cyclical structures. OLIGOPEPTIDES are composed of approximately 2-12 amino acids. Polypeptides are composed of approximately 13 or more amino acids. PROTEINS are linear polypeptides that are normally synthesized on RIBOSOMES.
CELL LINES derived from the CV-1 cell line by transformation with a replication origin defective mutant of SV40 VIRUS, which codes for wild type large T antigen (ANTIGENS, POLYOMAVIRUS TRANSFORMING). They are used for transfection and cloning. (The CV-1 cell line was derived from the kidney of an adult male African green monkey (CERCOPITHECUS AETHIOPS).)
A cell line generated from human embryonic kidney cells that were transformed with human adenovirus type 5.
Peptides composed of two amino acid units.
A potentially neurotoxic 8-hydroxyquinoline derivative long used as a topical anti-infective, intestinal antiamebic, and vaginal trichomonacide. The oral preparation has been shown to cause subacute myelo-optic neuropathy and has been banned worldwide.
A class of large neuroglial (macroglial) cells in the central nervous system - the largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the BLOOD-BRAIN BARRIER. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with MICROGLIA) respond to injury.
The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.
The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.
Vaccines or candidate vaccines used to prevent or treat ALZHEIMER DISEASE.
A class of protein components which can be found in several lipoproteins including HIGH-DENSITY LIPOPROTEINS; VERY-LOW-DENSITY LIPOPROTEINS; and CHYLOMICRONS. Synthesized in most organs, Apo E is important in the global transport of lipids and cholesterol throughout the body. Apo E is also a ligand for LDL receptors (RECEPTORS, LDL) that mediates the binding, internalization, and catabolism of lipoprotein particles in cells. There are several allelic isoforms (such as E2, E3, and E4). Deficiency or defects in Apo E are causes of HYPERLIPOPROTEINEMIA TYPE III.
The period of history from 1451 through 1600 of the common era.
The rate dynamics in chemical or physical systems.
Physiologically inactive substances that can be converted to active enzymes.
Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures.
Incorporation of biotinyl groups into molecules.
A MARVEL domain-containing protein found in the presynaptic vesicles of NEURONS and NEUROENDOCRINE CELLS. It is commonly used as an immunocytochemical marker for neuroendocrine differentiation.
Elements of limited time intervals, contributing to particular results or situations.
A tetrameric protein, molecular weight between 50,000 and 70,000, consisting of 4 equal chains, and migrating on electrophoresis in 3 fractions more mobile than serum albumin. Its concentration ranges from 7 to 33 per cent in the serum, but levels decrease in liver disease.
The insertion of recombinant DNA molecules from prokaryotic and/or eukaryotic sources into a replicating vehicle, such as a plasmid or virus vector, and the introduction of the resultant hybrid molecules into recipient cells without altering the viability of those cells.
The assembly of the QUATERNARY PROTEIN STRUCTURE of multimeric proteins (MULTIPROTEIN COMPLEXES) from their composite PROTEIN SUBUNITS.
Compound used for therapy of thiamine deficiency. It has also been suggested for several non-deficiency disorders but has not yet proven useful.
Culture media containing biologically active components obtained from previously cultured cells or tissues that have released into the media substances affecting certain cell functions (e.g., growth, lysis).
A stack of flattened vesicles that functions in posttranslational processing and sorting of proteins, receiving them from the rough ENDOPLASMIC RETICULUM and directing them to secretory vesicles, LYSOSOMES, or the CELL MEMBRANE. The movement of proteins takes place by transfer vesicles that bud off from the rough endoplasmic reticulum or Golgi apparatus and fuse with the Golgi, lysosomes or cell membrane. (From Glick, Glossary of Biochemistry and Molecular Biology, 1990)
Different forms of a protein that may be produced from different GENES, or from the same gene by ALTERNATIVE SPLICING.
A short pro-domain caspase that plays an effector role in APOPTOSIS. It is activated by INITIATOR CASPASES such as CASPASE 7; CASPASE 8; and CASPASE 10. Isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.
A chromosome disorder associated either with an extra chromosome 21 or an effective trisomy for chromosome 21. Clinical manifestations include hypotonia, short stature, brachycephaly, upslanting palpebral fissures, epicanthus, Brushfield spots on the iris, protruding tongue, small ears, short, broad hands, fifth finger clinodactyly, Simian crease, and moderate to severe INTELLECTUAL DISABILITY. Cardiac and gastrointestinal malformations, a marked increase in the incidence of LEUKEMIA, and the early onset of ALZHEIMER DISEASE are also associated with this condition. Pathologic features include the development of NEUROFIBRILLARY TANGLES in neurons and the deposition of AMYLOID BETA-PROTEIN, similar to the pathology of ALZHEIMER DISEASE. (Menkes, Textbook of Child Neurology, 5th ed, p213)
Immunologic method used for detecting or quantifying immunoreactive substances. The substance is identified by first immobilizing it by blotting onto a membrane and then tagging it with labeled antibodies.
Serologic tests in which a positive reaction manifested by visible CHEMICAL PRECIPITATION occurs when a soluble ANTIGEN reacts with its precipitins, i.e., ANTIBODIES that can form a precipitate.
Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed)
The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.
Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. ENDOSOMES play a central role in endocytosis.
Cell surface proteins that bind signalling molecules external to the cell with high affinity and convert this extracellular event into one or more intracellular signals that alter the behavior of the target cell (From Alberts, Molecular Biology of the Cell, 2nd ed, pp693-5). Cell surface receptors, unlike enzymes, do not chemically alter their ligands.
Abnormal structures located chiefly in distal dendrites and, along with NEUROFIBRILLARY TANGLES and SENILE PLAQUES, constitute the three morphological hallmarks of ALZHEIMER DISEASE. Neuropil threads are made up of straight and paired helical filaments which consist of abnormally phosphorylated microtubule-associated tau proteins. It has been suggested that the threads have a major role in the cognitive impairment seen in Alzheimer disease.

Mechanism of the cleavage specificity of Alzheimer's disease gamma-secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein. (1/1874)

Proteolytic processing of the amyloid precursor protein by beta-secretase yields A4CT (C99), which is cleaved further by the as yet unknown gamma-secretase, yielding the beta-amyloid (Abeta) peptide with 40 (Abeta40) or 42 residues (Abeta42). Because the position of gamma-secretase cleavage is crucial for the pathogenesis of Alzheimer's disease, we individually replaced all membrane-domain residues of A4CT outside the Abeta domain with phenylalanine, stably transfected the constructs in COS7 cells, and determined the effect of these mutations on the cleavage specificity of gamma-secretase (Abeta42/Abeta40 ratio). Compared with wild-type A4CT, mutations at Val-44, Ile-47, and Val-50 led to decreased Abeta42/Abeta40 ratios, whereas mutations at Thr-43, Ile-45, Val-46, Leu-49, and Met-51 led to increased Abeta42/Abeta40 ratios. A massive effect was observed for I45F (34-fold increase) making this construct important for the generation of animal models for Alzheimer's disease. Unlike the other mutations, A4CT-V44F was processed mainly to Abeta38, as determined by mass spectrometry. Our data provide a detailed model for the active site of gamma-secretase: gamma-secretase interacts with A4CT by binding to one side of the alpha-helical transmembrane domain of A4CT. Mutations in the transmembrane domain of A4CT interfere with the interaction between gamma-secretase and A4CT and, thus, alter the cleavage specificity of gamma-secretase.  (+info)

Calpain inhibitor I increases beta-amyloid peptide production by inhibiting the degradation of the substrate of gamma-secretase. Evidence that substrate availability limits beta-amyloid peptide production. (2/1874)

The calpain inhibitor N-acetyl-leucyl-leucyl-norleucinal (ALLN) has been reported to have complex effects on the production of the beta-amyloid peptide (Abeta). In this study, the effects of ALLN on the processing of the amyloid precursor protein (APP) to Abeta were examined in 293 cells expressing APP or the C-terminal 100 amino acids of APP (C100). In cells expressing APP or low levels of C100, ALLN increased Abeta40 and Abeta42 secretion at low concentrations, decreased Abeta40 and Abeta42 secretion at high concentrations, and increased cellular levels of C100 in a concentration-dependent manner by inhibiting C100 degradation. Low concentrations of ALLN increased Abeta42 secretion more dramatically than Abeta40 secretion. ALLN treatment of cells expressing high levels of C100 did not alter cellular C100 levels and inhibited Abeta40 and Abeta42 secretion with similar IC50 values. These results suggest that C100 can be processed both by gamma-secretase and by a degradation pathway that is inhibited by low concentrations of ALLN. The data are consistent with inhibition of gamma-secretase by high concentrations of ALLN but do not support previous assertions that ALLN is a selective inhibitor of the gamma-secretase producing Abeta40. Rather, Abeta42 secretion may be more dependent on C100 substrate concentration than Abeta40 secretion.  (+info)

Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. (3/1874)

Amyloid beta peptide (Abeta), the principal proteinaceous component of amyloid plaques in brains of Alzheimer's disease patients, is derived by proteolytic cleavage of the amyloid precursor protein (APP). Proteolytic cleavage of APP by a putative alpha-secretase within the Abeta sequence precludes the formation of the amyloidogenic peptides and leads to the release of soluble APPsalpha into the medium. By overexpression of a disintegrin and metalloprotease (ADAM), classified as ADAM 10, in HEK 293 cells, basal and protein kinase C-stimulated alpha-secretase activity was increased severalfold. The proteolytically activated form of ADAM 10 was localized by cell surface biotinylation in the plasma membrane, but the majority of the proenzyme was found in the Golgi. These results support the view that APP is cleaved both at the cell surface and along the secretory pathway. Endogenous alpha-secretase activity was inhibited by a dominant negative form of ADAM 10 with a point mutation in the zinc binding site. Studies with purified ADAM 10 and Abeta fragments confirm the correct alpha-secretase cleavage site and demonstrate a dependence on the substrate's conformation. Our results provide evidence that ADAM 10 has alpha-secretase activity and many properties expected for the proteolytic processing of APP. Increases of its expression and activity might be beneficial for the treatment of Alzheimer's disease.  (+info)

Protein kinase C and amyloid precursor protein processing in skin fibroblasts from sporadic and familial Alzheimer's disease cases. (4/1874)

Non-amyloidogenic alpha-secretase processing of amyloid precursor protein (APP) is stimulated by protein kinase C (PKC). Levels and activity of PKC are decreased in sporadic Alzheimer's disease skin fibroblasts. We investigated whether alterations in PKC and PKC-mediated APP processing occur also in fibroblasts established from individuals with familial Alzheimer's disease APP KM670/671NL, PS1 M146V and H163Y mutations. These pathogenic mutations are known to alter APP metabolism to increase Abeta. PKC activities, but not levels, were decreased by 50% in soluble fractions from sporadic Alzheimer's disease cases. In contrast, familial Alzheimer's disease fibroblasts showed no significant changes in PKC enzyme activity. Fibroblasts bearing the APP KM670/671NL mutation showed no significant differences in either PKC levels or PKC-mediated soluble APP (APPs) secretion, compared to controls. Fibroblasts bearing PS1 M146V and H163Y mutations showed a 30% increase in soluble PKC levels and a 40% decrease in PKC-mediated APPs secretion. These results indicate that PKC deficits are unlikely to contribute to increased Abeta seen with APP and PS1 mutations, and also that PS1 mutations decrease alpha-secretase derived APPs production independently of altered PKC activity.  (+info)

Effect of protein kinase A inhibitors on the production of Abeta40 and Abeta42 by human cells expressing normal and Alzheimer's disease-linked mutated betaAPP and presenilin 1. (5/1874)

1. We previously established that the formation of both alpha- and beta/gamma-secretase-derived products generated by human embryonic kidney 293 cells (HEK293) expressing either wild type or mutant betaAPP could be stimulated by agonists of the cyclic AMP/protein kinase A pathways. This cyclic AMP-dependent effect modulates post-translational events since it is not prevented by actinomycin D or cycloheximide. 2. We show here that two protein kinase A inhibitors, H89 and PKI, both trigger dose-dependent inhibition of the basal constitutive production of Abeta40 and Abeta42 by HEK293 cells expressing wild type betaAPP751. 3. H89 also potently inhibits the total Abeta produced by the neocortical neuronal cell line TSM1. 4. These two inhibitors also drastically reduce the recovery of Abeta40 and Abeta42 produced by HEK293 cells expressing the Swedish (Sw) betaAPP and M146V-presenilin 1 (PS1) mutations responsible for cases of the early-onset forms of Familial Alzheimer's disease (FAD). 5. By contrast, H89 and PKI do not significantly affect the recovery of the physiological alpha-secretase-derived fragment APPalpha. 6. Our study indicates that protein kinase A inhibitors selectively lower the formation of Abeta40 and Abeta42 in human cells expressing normal and mutant betaAPP and PS1 without affecting the physiological alpha-secretase pathway in these cells. Selective inhibitors of protein kinase A may be of therapeutic value in both sporadic and Familial Alzheimer's disease, since they may decrease the production of Abeta that is thought to be responsible for the neurodegenerative process.  (+info)

gamma-Secretase, evidence for multiple proteolytic activities and influence of membrane positioning of substrate on generation of amyloid beta peptides of varying length. (6/1874)

gamma-Secretase activity is the final cleavage event that releases the amyloid beta peptide (Abeta) from the beta-secretase cleaved carboxyl-terminal fragment of the amyloid beta protein precursor (APP). No protease responsible for this highly unusual, purportedly intramembranous, cleavage has been definitively identified. We examined the substrate specificity of gamma-secretase by mutating various residues within or adjacent to the transmembrane domain of the APP and then analyzing Abeta production from cells transfected with these mutant APPs by enzyme-linked immunosorbent assay and mass spectrometry. Abeta production was also analyzed from a subset of transmembrane domain APP mutants that showed dramatic shifts in gamma-secretase cleavage in the presence or absence of pepstatin, an inhibitor of gamma-secretase activity. These studies demonstrate that gamma-secretase's cleavage specificity is primarily determined by location of the gamma-secretase cleavage site of APP with respect to the membrane, and that gamma-secretase activity is due to the action of multiple proteases exhibiting both a pepstatin- sensitive activity and a pepstatin-insensitive activity. Given that gamma-secretase is a major therapeutic target in Alzheimer's disease these studies provide important information with respect to the mechanism of Abeta production that will direct efforts to isolate the gamma-secretases and potentially to develop effective therapeutic inhibitors of pathologically relevant gamma-secretase activities.  (+info)

Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation. (7/1874)

The amyloid-beta precursor protein (APP) is directly and efficiently cleaved by caspases during apoptosis, resulting in elevated amyloid-beta (A beta) peptide formation. The predominant site of caspase-mediated proteolysis is within the cytoplasmic tail of APP, and cleavage at this site occurs in hippocampal neurons in vivo following acute excitotoxic or ischemic brain injury. Caspase-3 is the predominant caspase involved in APP cleavage, consistent with its marked elevation in dying neurons of Alzheimer's disease brains and colocalization of its APP cleavage product with A beta in senile plaques. Caspases thus appear to play a dual role in proteolytic processing of APP and the resulting propensity for A beta peptide formation, as well as in the ultimate apoptotic death of neurons in Alzheimer's disease.  (+info)

Thimet oligopeptidase cleaves the full-length Alzheimer amyloid precursor protein at a beta-secretase cleavage site in COS cells. (8/1874)

We developed an assay method using a novel quenched fluorescent substrate (QFS) flanking the beta-cleavage site of amyloid precursor protein (APP), and purified a candidate beta-secretase from bovine brain. N-terminal amino acid analysis showed the candidate to be thimet oligopeptidase (TOP). The cDNA for human TOP was cloned from a human brain cDNA library and expressed in COS cells. The enzyme was further purified on a Ni2+-agarose column. TOP cleaved the Swedish Alzheimer's substrate (SEVNLDAEFR) as well as the normal substrate (SEVKMDAEFR). We then coexpressed TOP with APP695 in COS cells, collected transfected cells and conditioned media, and analyzed them by immunoblotting. The antibody against the specific secreted APP cleaved by beta-secretase (sAPPbeta) detected the secretion of sAPPbeta only from APP/hTOP-overexpressing cells, and not from cells overexpressing of antisense hTOP cDNA. Finally, we analyzed the immunolocalization of overexpressed hTOP in COS cells. Most hTOP was localized in the nuclei, but a small amount was localized in the Golgi or other organelles around the nuclei. These results suggest that TOP has a beta-secretase-like activity responsible for the processing of APP.  (+info)

Amyloid Precursor Protein Secretases: Endopeptidases that are specific for AMYLOID PROTEIN PRECURSOR. Three secretase subtypes referred to as alpha, beta, and gamma have been identified based upon the region of amyloid protein precursor they cleave.
The intramembrane aspartyl protease gamma-secretase plays a fundamental role in several signaling pathways involved in cellular differentiation and has been linked with a variety of human diseases, including Alzheimers disease. Here, we describe a transgenic Drosophila model for in vivo-reconstituted gamma-secretase, based on expression of epitope-tagged versions of the four core gamma-secretase components, Presenilin, Nicastrin, Aph-1, and Pen-2. In agreement with previous cell culture and yeast studies, coexpression of these four components promotes the efficient assembly of mature, proteolytically active gamma-secretase. We demonstrate that in vivo-reconstituted gamma-secretase has biochemical properties and a subcellular distribution resembling those of endogenous gamma-secretase. However, analysis of the cleavage of alternative substrates in transgenic-fly assays revealed unexpected functional differences in the activity of reconstituted gamma-secretase toward different substrates, ...
The insidious progression of AD (Alzheimers disease) is believed to be linked closely to the production, accumulation and aggregation of the ∼4.5 kDa protein fragment called Aβ (amyloid β-peptide). Aβ is produced by sequential cleavage of the amyloid precursor protein by two enzymes referred to as β- and γ-secretase. β-Secretase is of central importance, as it catalyses the rate-limiting step in the production of Aβ and was identified 7 years ago as BACE1 (β-site APP-cleaving enzyme 1). Soon afterwards, its homologue BACE2 was discovered, and both proteins represent a new subclass of the aspartyl protease family. Studies examining the regulation and function of β-secretase in the normal and AD brain are central to the understanding of excessive production of Aβ in AD, and in targeting and normalizing this β-secretase process if it has gone awry in the disease. Several reports indicate this, showing increased β-secretase activity in AD, with recent findings by our group showing ...
TY - JOUR. T1 - APH1, PEN2, and Nicastrin increase Aβ levels and γ-secretase activity. AU - Marlow, Laura. AU - Canet, Rosa M.. AU - Haugabook, Sharie J.. AU - Hardy, John A.. AU - Lahiri, Debomoy K.. AU - Sambamurti, Kumar. PY - 2003/6/6. Y1 - 2003/6/6. N2 - A major component of the amyloid plaque core in Alzheimers disease (AD) is the 40-42-residue amyloid β peptide (Aβ). Mutations linked to AD such as those in presenilins 1 (PS1) and 2 (PS2) invariably increase the longer Aβ42 species that forms neurotoxic oligomers. It is believed that PS1/2 constitute the catalytic subunit of the γ-secretase responsible for the final step in Aβ biogenesis. Recent genetic studies have identified a number of additional genes encoding APH1a, APH1b, PEN2, and Nicastrin proteins, which are part of the γ-secretase complex with PS1. Further, knockout studies using RNAi showed that these components are essential for γ-secretase activity. However, the nature of γ-secretase and how the aforementioned ...
TY - JOUR. T1 - Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor. AU - Gillman, K.W.. AU - Starrett, J.E.. AU - Parker, M.F.. AU - Xie, K.. AU - Bronson, J.J.. AU - Marcin, L.R.. AU - McElhone, K.E.. AU - Bergstrom, C.P.. AU - Mate, R.A.. AU - Williams, Richard. AU - Meredith, J.E.. AU - Burton, C.R.. AU - Barten, D.M.. AU - Toyn, J.H.. AU - Roberts, S.B.. AU - Lentz, K.A.. AU - Houston, J.G.. AU - Zaczek, R.. AU - Albright, C.F.. AU - Decicco, C.P.. AU - Macor, J.E.. AU - Olson, R.E.. PY - 2010/6/10. Y1 - 2010/6/10. N2 - During the course of our research efforts to develop a potent and selective gamma-secretase inhibitor for the treatment of Alzheimers disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-beta precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of gamma-secretase ...
Beta Secretase 1 (Aspartyl Protease 2 or Beta Site Amyloid Precursor Protein Cleaving Enzyme 1 or Memapsin 2 or Membrane Associated Aspartic Protease 2 or BACE1 or EC 3.4.23.46) - Pipeline Review, H2 2018
Alzheimers disease (AD) is characterized by extracellular accumulation of amyloid-β peptide (Aβ), generated by proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretase. Aβ generation is inhibited when the initial ectodomain shedding is caused by α-secretase, cleaving APP within the Aβ domain. Therefore, an increase in α-secretase activity is an attractive therapeutic target for AD treatment. APP and the APP-cleaving secretases are all transmembrane proteins, thus local membrane lipid composition is proposed to influence APP processing. Although several studies have focused on γ-secretase, the effect of the membrane lipid microenvironment on α-secretase is poorly understood. In the present study, we systematically investigated the effect of fatty acid (FA) acyl chain length (10:0, 12:0, 14:0, 16:0, 18:0, 20:0, 22:0, 24:0), membrane polar lipid headgroup (phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine), saturation grade and the FA double-bond
Gamma-secretase activity is vital for the transmembrane cleavage of Notch receptors and the subsequent migration of their intracellular domains to the nucleus. Notch overexpression has been associated with breast, colon, cervical and prostate cancers. We tested the effect of three different gamma-secretase inhibitors (GSIs) in breast cancer cells. One inhibitor (GSI1) was lethal to breast cancer cell lines at concentrations of 2 muM and above but had a minimal effect on the non-malignant breast lines. GSI1 was also cytotoxic for a wide variety of cancer cell lines in the NCI60 cell screen. GSI1 treatment resulted in a marked decrease in gamma-secretase activity and downregulation of the Notch signalling pathway with no effects on expression of the gamma-secretase components or ligands. Flow cytometric and western blot analyses indicated that GSI1 induces a G2/M arrest leading to apoptosis, through downregulation of Bcl-2, Bax and Bcl-XL. GSI1 also inhibited proteasome activity. Thus, the ...
Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:12522139, PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable). PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity (PubMed:12522139, PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111).
Coffee made from the roasted seeds of the genus Coffee, belonging to the family Rubiaceae native to southern Arabia. Coffee may consist certain substances, effecting the risk of Alzheimers disease. AD mice given caffeine in their drinking water from young adulthood into older age showed to inhibit memory and cognitive impairment and lower brain levels of amyloid-beta; Abeta)(24)(25). In mice with Alzheimers disease caused by dysregulated endoplasmic reticulum (ER) calcium (Ca 2+), induced deletion of RyanR3, showed the enhancement of coffee in activation of RyanRs which protected AD neurons from synaptic and network dysfunction(26). Intake of 5 cups of coffee per day(moderate caffeine intake) found to protect against the development of certain cognitive impairment and decreased hippocampal amyloid-beta (Abeta) levels through suppression of both beta-secretase (BACE1), a beta-site amyloid precursor protein cleaving enzyme 1 and presenilin 1 (PS1)/gamma-secretase expression(mutations in the ...
cansSAR 3D Structure of 2OHR | X-RAY CRYSTAL STRUCTURE OF BETA SECRETASE COMPLEXED WITH COMPOUND 6A | 2OHR_A | Beta-secretase 1 - Also known as BACE1_HUMAN, BACE1, BACE, KIAA1149. Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase (PubMed:10656250, PubMed:10677483, PubMed:20354142). Cleaves CHL1 (By similarity). Monomer. Interacts (via DXXLL motif) with GGA1, GGA2 and GGA3 (via their VHS domain); the interaction highly increases when BACE1 is phosphorylated at Ser-498 (PubMed:14567678, PubMed:15886016). Interacts with RTN3 and RTN4 (PubMed:15286784, PubMed:16965550, PubMed:16979658). Interacts with SNX6 (PubMed:20354142). Interacts with PCSK9 (PubMed:18660751). Interacts with NAT8 and NAT8B (PubMed
β-Secretase (BACE) is a membrane-bound aspartyl protease that cleaves the amyloid precursor protein and is consequently an excellent target for anti-amyloid therapy in the treatment of Alzheimers disease. Finding inhibitors of β-secretase is one of the major goals of Alzheimers disease drug development. PromoKines β-Secretase Fluorometric Assay Kit provides a convenient, non-radioactive system for detecting β-Secretase activity in biological samples. The kit provides active β-Secretase as positive control, β-Secretase inhibitor as negative control, optimized peptide substrate (conjugated to two reporter molecules), and buffers for convenient measurement of β-Secretase activity in mammalian samples. β-Secretase inhibitors are also available separately. ...
We have used the confocal microscope to analyze the subcellular distribution of the APH-1 protein in early embryos of C. elegans. APH-1 is one of four protein members of the gamma-secretase complex, which achieves intramembranous cleavage of a variety of target membrane proteins. Although the effect in protein cleavage is clear, the site of gamma-secretase assembly and function within the cell remains elusive. We use the early C. elegans embryo as the context in which to analyze protein localization because the cells are relatively large, and because the four-cell embryo is the site of a well-defined event of Notch signaling that has been shown to be entirely dependent on gamma-secretase activity. Our analysis of wild type C. elegans embryos shows that the APH-1 protein is present at the plasma membrane in early embryos. This location is consistent with the role of gamma-secretase in targeting the Notch receptor after it has interacted with its ligand on an adjacent cell, and is also consistent ...
Hoffman LM, Fouladi M, Olson J, Daryani VM, Stewart CF, Wetmore C, Kocak M, Onar-Thomas A, Wagner L, Gururangan S, Packer RJ, Blaney SM, Gajjar A, Kun LE, Boyett JM, Gilbertson RJ. Phase I trial of weekly MK-0752 in children with refractory central nervous system malignancies: a pediatric brain tumor consortium study. Childs Nerv Syst. 2015 Aug; 31(8):1283-9 ...
Theres a new kid on the Alzheimers block, and it may explain why the huge sums thrown at beta-secretase inhibitors by big pharma has been such an abject failure. First, a lot of technical background. The APP (for amyloid precursor protein) contains anywhere from 563 to 770 amino acids in 5 distinct transcripts made by…
Alzheimer`s disease is the most common cause of progressive cognitive decline in the aged population. Pathologically Alzheimer`s disease is characterized by the invariant accumulation of senile plaques. Senile plaques are predominantly composed of the amyloid beta-peptide (A-beta), which is derived from the membrane bound beta-amyloid precursor protein (beta-APP) by sequential proteolytic cleavage. The recently identified beta-secretase (BACE) is responsible for the cleavage at the N-terminus of the A-beta domain. This cleavage generates membrane-bound beta-APP-Cterminal fragments (beta-APP-CTF) which are the immediate precursor for gamma-secretase cleavage and therefore for liberation of A-beta. The present work shows that BACE moves along the secretory pathway, while it undergoes post-translational modifications, which can be monitored by a significant increase in the molecular mass and cleavage of its pro-peptide. BACE becomes N-glycosylated within the ER and the increase in molecular mass is ...
Alzheimer`s disease is the most common cause of progressive cognitive decline in the aged population. Pathologically Alzheimer`s disease is characterized by the invariant accumulation of senile plaques. Senile plaques are predominantly composed of the amyloid beta-peptide (A-beta), which is derived from the membrane bound beta-amyloid precursor protein (beta-APP) by sequential proteolytic cleavage. The recently identified beta-secretase (BACE) is responsible for the cleavage at the N-terminus of the A-beta domain. This cleavage generates membrane-bound beta-APP-Cterminal fragments (beta-APP-CTF) which are the immediate precursor for gamma-secretase cleavage and therefore for liberation of A-beta. The present work shows that BACE moves along the secretory pathway, while it undergoes post-translational modifications, which can be monitored by a significant increase in the molecular mass and cleavage of its pro-peptide. BACE becomes N-glycosylated within the ER and the increase in molecular mass is ...
This project focuses on ultimately defining the structure of a soluble gamma-secretase modulator (SGSM)-bound gamma-secretase enzyme complex at high resolution. Defining the structure of this complex will provide critical information towards elucidating the mechanism of action of this promising ...
3UQR: Cyanobacterial Peptides as a Prototype for the Design of Potent beta-Secretase Inhibitors and the Development of Selective Chemical Probes for Other Aspartic Proteases
3UQP: Cyanobacterial Peptides as a Prototype for the Design of Potent beta-Secretase Inhibitors and the Development of Selective Chemical Probes for Other Aspartic Proteases
9.B.47 The γ-Secretase (γ-Secretase) Family. γ-secretase is an unusual membrane-embedded protease, which cleaves the transmembrane domains (TMSs) of type I membrane proteins, including amyloid-beta precursor protein and Notch receptor. A hydrophilic pore is formed by TMS6 and TMS7 of presenilin 1 (PS1), the catalytic subunit of γ-secretase. TMS8, TMS9 and the C-terminus of PS1, which encompass the conserved PAL motif and the hydrophobic C-terminal tip, are critical for the catalytic activity and the formation of the γ-secretase complex. The amino acid residues around the PAL motif and the extracellular/luminal portion of TMS9 are highly water accessible and located in proximity to the catalytic pore (Sato et al., 2008). Furthermore, the region starting from the luminal end of TMS9 toward the C terminus forms an amphipathic alpha-helix-like structure that extends along the interface between the membrane and the extracellular milieu. Competition analysis using γ-secretase inhibitors revealed ...
The results of this study demonstrate that Aβ metabolism in the rhesus monkey is similar to healthy humans (Bateman et al., 2006), which is expected because there are no significant amyloid plaques present in the rhesus monkey brain at this age (Struble et al., 1985). In conjunction with in vivo stable-isotope-labeling, new generation of CNS Aβ was significantly reduced in response to γ-secretase inhibition. However, in contrast to the periphery, production of CNS Aβ did not rebound above baseline after cessation of inhibition. Defining the metabolic fate of APP in the CNS is critically important for the development of γ-secretase inhibitors to treat AD, as a substrate build-up of APP fragments could potentially lead to an overshoot in neurotoxic amyloid peptides. The lack of Aβ rebound in the CNS could be attributed to the shunting of APP (possibly β C-terminal fragments, e.g., C99) to γ-secretase independent degradation. In support of this alternative, noncanonical processing, ...
Nicastrin is a Type I transmembrane glycoprotein. Along with presenilin, APH-1, PEN-2, it comprises the multimeric gamma-secretase complex. The gamma-secretase complex can cleave the beta-amyloid (A4) precursor protein and yields amyloid beta peptide, the main component of the neuritic plaque a...
Although there has been controversy about the relative importance of plaques versus tangles in the development of Alzheimers disease, there is increasing evidence that altered metabolism of Aβ peptides and amyloid deposition in neuritic plaques causes Alzheimers disease by triggering a complex pathological cascade that produces dementia. The Aβ peptides Aβ1-40 and Aβ1-42, the two major species of Aβ, are generated from APP by sequential proteolytic cleavage by β- and γ- secretases. These enzymes are not the only ones involved in the breakdown of APP: α-secretase cleaves the full-length APP, producing soluble sAPP and, subsequently, p3. Because processing by α-secretase precludes production of full-length Aβ peptides, it is anti-amyloidogenic (Younkin, 1998).. Several lines of evidence suggest that deposition of Aβ-42 is an important initial step in the pathogenesis of Alzheimers disease. Aβ1-42 aggregates more rapidly and is deposited earlier in Alzheimers disease plaques than ...
Hansson CA, Frykman S, Farmery MR, Tjernberg LO, Nilsberth C, Pursglove SE, Ito A, Winblad B, Cowburn RF, Thyberg J, Ankarcrona M. Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria ...
|p|Alzheimer's disease is characterized by the accumulation of aggregated Aß peptides in senile plaques and vascular deposits. Aß peptides are derived from amyloid precursor proteins (APP) through sequential proteolytic cleavage of APP by ß- and ?-secretases generating diverse Aß species. Aß can agg
Inhibition of the γ-secretase enzyme that snips amyloid precursor protein (APP) to form Aβ has long been seen as a therapeutic option for Alzheimer disease, but finding a safe, effective inhibitor has proved frustrating. The risk of side effects from γ-secretase inhibition is high, in part because this secretase also cuts Notch, an essential protein for numerous biological functions. The recent cancellation of a high-profile γ-secretase inhibitor clinical trial (see ARF related news story) is the latest disappointment for approaches targeting this secretase. A paper in yesterdays Nature online offers a new tack for this field by reporting the discovery of a γ-secretase activating protein (GSAP) that acts specifically to promote the binding of γ-secretase to APP, but not to Notch. Researchers led by Paul Greengard at the Rockefeller University in New York show that inhibition of GSAP reduces the production of Aβ by 40 to 50 percent both in vitro and in AD model mice, while having no ...
Presenilin enhancer protein 2 (PEN2) is a 101-amino acid protein that traverses the membrane twice and it is the regulatory component of the multimeric gamma-secretase complex which also consists of presenilin, APH-1 and Nicastrin. The gamma-secretase complex catalyzes the cleavage of a number of...
Regulated intramembrane proteolysis is certainly a central mobile practice included in sign membrane layer and transduction proteins turnover. condition of MHCII-containing endosomes, highlighting SPPL2a as a possible medicinal focus on for using up and/or modulating T cells. The concept of intramembrane proteases (I-CLIPs) cleaving within the phospholipid bilayer was originally place forwards structured on digesting of the sterol regulatory elementCbinding proteins (SREBP; Goldstein and Brown, 1997; Kopan and Wolfe, 2004). Generally, I-CLIPs operate as component of a proteolytic series known to as governed intramembrane proteolysis (Split; Lichtenthaler et al., 2011). Intracellular websites (ICDs) of many Split substrates function as signaling elements after their proteolytic discharge as exemplified by the Level path (De Strooper et al., 1999; Freeman and Urban, 2002). Structured on their catalytic middle, serine, metallo, or aspartyl I-CLIPs (Wolfe, 2009) can end up being differentiated. The ...
The pathogenesis of Alzheimers disease (AD) is only partially understood. β-amyloid (Aβ) is physiologically generated by sequential cleavage of its precursor protein by the β- and the γ-secretase and it is normally disposed of. In Alzheimers disease, Aβ is excessively produced or less dismissed, but the hypothesis on its physiological and pathological role are heterogeneous and often discordant. It has been described a positive feedback loop from the γ- to the β-secretase cleavages of Aβ precursor protein, which is activated by mutations of Presenilin 1 (PS1), the catalytic core of the γ-secretase. These findings show that Aβ precursor protein as well the activity of the γ-secretase are required to obtain the up-regulation of β-secretase which is induced by Presenilin 1 mutations. Then, Aβ 1-42 is the Aβ precursor protein derivative that up-regulates the expression of β-secretase, and c-jun N-terminal kinase (JNK)/c-Jun and ERK1/2 are involved. Here, we describe the activation ...
Beta Secretase Substrate Functional Assay Kits datasheet (ab101160). Abcam offers quality products including antibodies, assays and other reagents.
Gamma-secretase is a key enzyme in the development of Alzheimer pathology. It performs the final step in the production of beta-amyloid by cutting beta-amyloid from its parent molecule. Beta-amyloid then goes on to aggregate into amyloid plaques, which are a characteristic feature of Alzheimer pathology. Gamma-secretase also produces other molecules that are important for the normal function of nerve cells.. Like most enzymes, gamma-secretase is localized to specific compartments (microdomains) within cells. Such localization affects the enzymes function by restricting its access to include only proteins that are found in the same compartments. In the case of gamma-secretase, localization is achieved by the attachment of specific fatty acids to different components of the enzyme, thereby determining where those components reside within the cell.. Gopal Thinakaran, Ph.D., and colleagues are studying how localization of gamma-secretase within nerve cells affects the ability of those cells to ...
Reactome is pathway database which provides intuitive bioinformatics tools for the visualisation, interpretation and analysis of pathway knowledge.
Liu et al. describe a previously unrecognized cellular complex (∼5 MD) containing β- and γ-secretases that generates a full array of Aβ peptides with physiological Aβ42/40 ratios by sequential cleavages of holo-APP. Such coordinated substrate processing also occurs with the α- and γ-secretases in the RIP mechanism.. ...
The β/γ Secretase Antibody Sampler Kit offers flexibility for sampling and detection of β- and γ-secretase proteases that are essential components in the processing of amyloid precursor protein and generation of amyloid beta peptide.
APOBEC3 proteins catalyze deamination of cytidines in single-stranded DNA (ssDNA), providing innate protection against retroviral replication by inducing deleterious dC dU hypermutation of replication intermediates. DSB repair, inhibition of APOBEC3G appearance or deaminase activity led to deficient DSB fix, whereas reconstitution of APOBEC3G appearance in leukemia cells improved DSB fix. APOBEC3G activity included digesting of DNA flanking a DSB within an integrated reporter cassette. Atomic power microscopy indicated that APOBEC3G multimers keep company with ssDNA termini, triggering multimer disassembly to multiple catalytic products. These results recognize APOBEC3G being a prosurvival element in lymphoma cells, marking APOBEC3G being a potential focus on for sensitizing lymphoma to rays therapy. Launch Ionizing rays and nearly all anticancer agencies inflict deleterious DNA harm on tumor cells, mostly DNA double-strand breaks (DSBs) and covalent DNA crosslinks. DNA DSBs are extremely ...
BioAssay record AID 71721 submitted by ChEMBL: Inhibition of A-beta-42 production by inhibiting Gamma-secretase proteolytic pathway in HEK293 cell stably transfected with a double mutant form of human APP(K595N/M596L).
Compare Beta-Secretase 1 ELISA Kits from leading suppliers on Biocompare. View specifications, prices, citations, reviews, and more.
Complete information for NOMO1 gene (Protein Coding), NODAL Modulator 1, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
Cell Lines, Hydrogen, Lead, Amyloid, Disease, Electronic, Evaluation, Inhibition, Mutation, Secretase, Secretases, At 10, Breast, Breast Cancer, Cancer, Cancers, Cell, Cell Viabilities, Cell Viability, Cells
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Maximum-tolerated Dose of Gamma-secretase Inhibitor RO4929097, Defined as the Dose Level Where no More Than 1 Out of 6 Patients Experience DLT at the Highest Dose Level Below the MAD, Graded According to NCI-CTCAE Version 4.0 (Phase Ib ...
Supplementary MaterialsFigure S1: Kinetic parameter distribution of SNs before evolution. pone.0050905.s003.tif (81K) GUID:?270C2747-8D2C-40C2-A1ED-52BFDFB4C35A Abstract Transmission transduction is the process of routing information inside cells when receiving stimuli from their environment that modulate the behavior and function. In such natural procedures, the receptors, after getting the corresponding indicators, switch on several biomolecules which transduce the sign […]. ...
Supplementary MaterialsVideo 1 Time-lapse imaging cells expressing both mt-roGFP and Smac mCherry treated with cisplatin stably. with an indicated medication with 10?nm of TMRM. Live cell imaging was TMP 269 biological activity completed as defined. mmc6.mp4 (20M) GUID:?20E6FE9E-0743-40DF-9A25-5E8A9CEF2F51 TMP 269 biological activity Video 7 EGCG: U2Operating-system cells stably expressing mt-roGFP were stained with TMRM to […]. ...
Meredith, J.E.; Thompson, L.A.; Toyn, J.H.; Marcin, L.; Barten, D.M.; Marcinkeviciene, J.; Kopcho, L.; Kim, Y.; Lin, A.; Guss, V.; Burton, C.; Iben, L.; Polson, C.; Cantone, J.; Ford, M.; Drexler, D.; Fiedler, T.; Lentz, K.A.; Grace, J.E.; Kolb, J.; Corsa, J.; Pierdomenico, M.; Jones, K.; Olson, R.E.; Macor, J.E.; Albright, C.F., 2008: P-glycoprotein efflux and other factors limit brain amyloid beta reduction by beta-site amyloid precursor protein-cleaving enzyme 1 inhibitors in mice
TY - JOUR. T1 - The Rat Central Nervous System Expresses Alzheimers Amyloid Precursor Protein APP695, but Not APP677 (L‐APP Form). AU - Ohgami, Tetsuya. AU - Kitamoto, Tetsuyuki. AU - Tateishi, Jun. PY - 1993/10. Y1 - 1993/10. N2 - Abstract: A novel splicing form of βA4 amyloid precursor protein (APP) lacking exon 15, corresponding to 18 residues, was first reported in leukocytes and then in ubiquitous organs. To determine which APP molecules (APP695, APP751, or APP770) either with (N‐APP) or without (L‐APP; leukocytederived APP) exon 15 were expressed in various organs, we investigated the alternative splicing at exon 15 in the rat brain, kidney, heart, and testis by a PCR analysis of reverse‐transcribed RNA and Southern blot analysis. Regarding APP695 without exons 7 and 8, L‐APP was either seldom or never expressed in the brain, whereas both N‐ and L‐APP were expressed in other organs. On the other hand, regarding APP751/770 containing exon 7, which codes for the Kunitz‐type ...
TY - JOUR. T1 - Purification and aggregation of the amyloid precursor protein intracellular domain. AU - El Ayadi, Amina. AU - Stieren, Emily S.. AU - Barral, José M.. AU - Oberhauser, Andres F.. AU - Boehning, Darren. PY - 2012/8/28. Y1 - 2012/8/28. N2 - Amyloid precursor protein (APP) is a type I transmembrane protein associated with the pathogenesis of Alzheimers disease (AD). APP is characterized by a large extracellular domain and a short cytosolic domain termed the APP intracellular domain (AICD). During maturation through the secretory pathway, APP can be cleaved by proteases termed α, β, and γ-secretases1. Sequential proteolytic cleavage of APP with β and γ-secretases leads to the production of a small proteolytic peptide, termed Aβ, which is amyloidogenic and the core constituent of senile plaques. The AICD is also liberated from the membrane after secretase processing, and through interactions with Fe65 and Tip60, can translocate to the nucleus to participate in transcription ...
Background Icaritin (ICT) is a prenylflavonoid derivative from Epimedium brevicornum Maxim. ICT has been shown to have neuroprotective effects. We investigate how ICT affects secretion of amyloid precursor protein (APP). Methods We exposed APP-PS1-HEK293 cells to ICT to investigate its effect on beta-site amyloid cleaving enzyme (BACE)1. Cell viability was evaluated by MTT and lactate dehydrogenase (LDH) assays. The half-maximal inhibitory concentration (IC50) of ICT for BACE1 was measured using fluorescence resonance energy transfer. Effects of ICT on the mRNA expression of APP were assessed by quantitative polymerase chain reaction, and protein expression was measured by western blotting and immunofluorescence. Results Icaritin inhibited BACE1 activity and IC50 was 5.70 ± 1.09 μM. Compared with the control group, at ICT concentrations of 5 μM and 10 μM, the viability increased and LDH leakage decreased in APP-PS1-293 cells. Also, mRNA expression of A disintegrin and metalloproteinase domain
To address the substrate requirements of BACE-IgG, we designed three peptide substrates, each containing 30 amino acids, extending from P21 to P9 to span the β-secretase cleavage site. These peptides represent: (i) APPwt; (ii) APPsw; and (iii) the MV substitution (P1 changed from Met → Val). In intact cells, endogenous β-secretase cleaves APPsw much better than APPwt, but the MV mutant is not cleaved (22). Pure BACE-IgG cleaves the pure wt peptide with a specific activity of approximately 9 nmol/min/mg, demonstrating that BACE acts as a protease (Fig. 8B). We detect only one cleavage and this is at the correct Asp1 site (24). As expected for β-secretase, the specific activity of BACE-IgG for the Swedish substrate is much higher than for the wt substrate, whereas cleavage of the MV mutant is not detectable at all (Fig. 8B).. Experiments with intact cells suggest that β-secretase has an acidic pH optimum (14, 15). Indeed, a pH titration of BACE activity shows an optimum at pH 4.5 for both ...
APP (Amyloid Precursor Protein), eFluor 570, clone: 22C11, eBioscience™ 100μg; eFluor 570 APP (Amyloid Precursor Protein), eFluor 570, clone: 22C11,...
This paper focuses deals with the cleavage of NaVβ2 via BACE-1 (Beta-site APP-cleaving enzyme 1), leading to increased NaV1.1 levels, which do not translocate to the cell plasma membrane. Reinforcing that decreased NaV1.1 levels are involved in AD development/progression. This work cites the use of Alomone Labs Anti-SCN1A (NaV1.1) Antibody (#ASC-001) and Anti-NaVβ2 Antibody (#ASC-007).. The early stages of Alzheimers disease (AD), an incurable neurological affliction with adverse effects on memory and cognition, are often accompanied by aberrant neuronal activity and epileptic seizures - events which are increasingly seen as having a direct influence on ADs progression. Cortical accumulation of amyloid β (Aβ), a peptide derived from amyloid precursor protein (APP), seems to play a prominent role on the onset of AD. Beta-site APP-cleaving enzyme 1 (BACE1) - the rate-determining factor in Aβ synthesis - is significantly high in both AD patients and APP mice (transgenic line with ...
How could the entry of the Notch receptor into endosomes promote efficient signaling? Because signaling depends on intramembrane cleavage of Notch by γ-secretase, we asked whether altered Notch endosomal transport might affect its cleavage. We directly measured the amount of Notch in endocytic mutant tissue that can be cleaved by γ-secretase by using an assay that induces ligand-independent Notch cleavage in tissue extracts (see Materials and methods). Notch cleavage efficiency ex vivo is measured in Western blots by quantifying the amount of the lower band (corresponding to the γ-secretase cleavage product NICD) relative to the upper band (corresponding to its immediate precursor, the membrane-anchored γ-secretase substrate NEXT) of the ∼120-kD doublet recognized by an antibody against an NICD epitope. As expected, generation of free NICD in this assay is completely blocked by treatment with the γ-secretase inhibitor N-(N-[3,5-difluorophenacetyl-l-alanyl])-S-phenylglycine t-butyl ester ...
Recombinant Human BACE1 His tagged best suppliers; Recombinant Human BACE1 His tagged best sources; Recombinant Human BACE1 His tagged best vendors; Recombinant Human BACE1 His tagged protocol; Recombinant Human BACE1 His tagged citations; Recombinant Human BACE1 His tagged publications; Recombinant Human BACE1 His tagged papers - Labshake
Authors: Moussavi Nik, Seyyed Hani , Wilson, Lachlan , Newman, Morgan , Croft, Kevin , Mori, Trevor A. , Musgrave, Ian , Lardelli, Michael Article Type: Research Article Abstract: Oxygen homeostasis is essential for the development and normal physiology of an organism. Hypoxia causes the mitochondrial electron transport chain to generate higher levels of reactive oxygen species resulting in oxidative stress. Hypoxia can be a direct consequence of hypoperfusion, a common vascular component among Alzheimers disease (AD) risk factors, and may play an important role in AD pathogenesis. Beta-site amyloid-β A4 precursor protein-cleaving enzyme 1 (BACE1) is responsible, with γ-secretase, for cleavage of the amyloid-β protein precursor (AβPP) to produce amyloid-β (Aβ) peptide. A recent study observed that oxidative stress increases BACE1 expression via a regulatory pathway dependent on …γ-secretase cleavage of AβPP and this increases Aβ peptide production. Zebrafish embryos represent normal ...
TY - JOUR. T1 - Galectin 3- binding protein suppresses amyloid-β production by modulating β-cleavage of amyloid precursor protein. AU - Seki, Tsuneyoshi. AU - Kanagawa, Motoi. AU - Kobayashi, Kazuhiro. AU - Kowa, Hisatomo. AU - Yahata, Naoki. AU - Maruyama, Kei. AU - Iwata, Nobuhisa. AU - Inoue, Haruhisa. AU - Toda, Tatsushi. N1 - Funding Information: This work was supported by Japan Society for the Promotion of Science (JSPS) Grant 17H06421 (to M. K.) and by CREST (to H. I., N. I., and T. T.). The authors declare that they have no conflicts of interest with the contents of this article. Publisher Copyright: © 2020 Seki et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.. PY - 2020/3/13. Y1 - 2020/3/13. N2 - Alzheimers disease (AD) is the most common type of dementia, and its pathogenesis is associated with accumulation of β-amyloid (Aβ) peptides. Aβ is produced from amyloid precursor protein (APP) that is sequentially cleaved by β- and γ-secretases. ...
Background: Amyloid- neurotoxicity depends on the specificity of the proteolytic cleavage of the amyloid precursor protein (APP) transmembrane domain. Results: The APP transmembrane -helix is straight in a biological membrane bilayer. Conclusion: The flexibility of APP is key for adapting to the lipid environment and modulating proteolytic processing by -secretase. Significance: The dynamic characterization of APP is expected to rationalize the design of -secretase modulators. The amyloid precursor protein (APP) is a widely expressed type I transmembrane (TM) glycoprotein present at the neuronal synapse. The proteolytic cleavage by -secretase of its C-terminal fragment produces amyloid- (A) peptides of different lengths, the deposition of which is an early indicator of Alzheimer disease. At present, there is no consensus on the conformation of the APP-TM domain at the biological membrane. Although structures have been determined by NMR in detergent micelles, their conformation is markedly ...
The Laboratory for Neurodegenerative Disease Research focuses on the generation of Amyloid ß-peptide (Aß) as the major constituent of neurotoxic amyloid plaques in Alzheimers Disease (AD). Proteolytic processing of an amyloid precursor protein (βAPP) by β- and γ-secretases leads to Aß, whereas βAPP cleavage by α-secretases prevents Aß formation. In order to identify cellular mechanisms involved in the physiological and pathophysiological regulation of AD secretases, the group of Dr. Willem studies the function, expression, subcellular localization and the influence of trafficking and sorting of β- secretase (BACE1) by using transgenic mouse models. Some key topics addressed in the lab regarding the understanding of BACE1 function in physiological and pathophysiological conditions, especially in AD, are:. - Biochemical identification of new proteolytic substrates of the beta-Secretase BACE1. - Immunohistological subcellular localization of compartments in which BACE1 cleaves the ...
Background-The single spanning transmembrane amyloid precursor protein (APP) and its proteolytic product, amyloid-beta (Aβ) peptide, have been intensely studied due to their role in the pathogenesis of Alzheimers disease. However, the biological role of the secreted ectodomain of APP, which is also generated by proteolytic cleavage, is less well understood. Here, we report Tol2 red fluorescent protein (RFP) transposon gene trap integrations in the zebrafish amyloid precursor protein a (appa) and amyloid precursor-like protein 2 (aplp2) genes. The transposon integrations are predicted to disrupt the appa and aplp2 genes to primarily produce secreted ectodomains of the corresponding proteins that are fused to RFP. Results-Our results indicate the Appa-RFP and Aplp2 fusion proteins are likely secreted from the central nervous system and accumulate in the embryonic veins independent of blood flow. Conclusions-The zebrafish appa and aplp2 transposon insertion alleles will be useful for investigating the
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The amyloid precursor protein (APP) plays a central role in the pathophysiology of Alzheimers disease in large part due to the sequential proteolytic cleavages that result in the generation of β-amyloid peptides (Aβ). Not surprisingly, the biological properties of APP have also been the subject of great interest and intense investigations. Since our 2006 review, the body of literature on APP continues to expand, thereby offering further insights into the biochemical, cellular and functional properties of this interesting molecule. Sophisticated mouse models have been created to allow in vivo examination of cell type-specific functions of APP together with the many functional domains. This review provides an overview and update on our current understanding of the pathobiology of APP.
TY - JOUR. T1 - Ubiquilin-1 regulates amyloid precursor protein maturation and degradation by stimulating K63-linked polyubiquitination of lysine 688. AU - Ayadi, Amina El. AU - Stieren, Emily S.. AU - Barral, José M.. AU - Boehning, Darren. PY - 2012/8/14. Y1 - 2012/8/14. N2 - The pathogenesis of Alzheimers disease (AD) is associated with proteolytic processing of the amyloid precursor protein (APP) to an amyloidogenic peptide termed Aβ. Although mutations in APP and the secretase enzymes that mediate its processing are known to result in familial forms of AD, the mechanisms underlying the more common sporadic forms of the disease are still unclear. Evidence suggests that the susceptibility of APP to amyloidogenic processing is related to its intracellular localization, and that secretase-independent degradation may prevent the formation of cytotoxic peptide fragments. Recently, single nucleotide polymorphisms in the UBQLN1 gene have been linked to late-onset AD, and its protein product, ...
AICD, the C-terminal tail generated from the proteolytic cleavage of the Amyloid Precursor Protein (APP), has been generating interest for its transcriptional modulatory roles. AICD has been hypothesized to have such a function as it is generated by a gamma-secretase-mediated regulated intramembrane proteolysis step, analogous to the generation of Notch intracellular domain (NICD), a well-known transcriptional regulator, from Notch. The AICD/Fe65/Tip60 ternary complex has been proposed as the working transcriptional regulatory complex and some of its target genes have been reported. However, our knowledge of the functions of AICD is still limited due to difficulties in detecting and manipulating the rapidly degraded peptide. Looking at AICD transcription modulation targets from a genome-wide perspective will aid our understanding of the role of AICD tremendously. To this end, AICD chromatin binding sites were investigated from a genome-wide perspective by performing Chromatin Immunoprecipitation ...
The invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof: wherein X is CH2, O or S. The compounds inhibit gamma secretase without affecting Notch signalling, and hence find use in the treatment or prevention of Alzheimers disease.
Growth factors are substances that are capable of stimulating cellular proliferation, differentiation, as well as growth. Another probable hypothesis is that the membrane-bound APP may be involved in cell signaling, which is the complex communication system used by cells to govern basic cellular activities and actions. Molecules of APP that are not cleaved by α-secretase are capable of forming internalized endocytic compartments, which in turn are subsequently cleaved by β- and γ- secretases (6). γ- secretase carries out proteolytic modification further by processing the membrane-bound peptide into the amyloid beta (Aβ) peptide form (7). Generation of the Aβ peptide is borne solely from the cleavage of APP in which the amyloid precursor protein intracellular domain (AICD) is released and deposited in aggregated fibrils in senile plaques. Other APP protein family members do not form the Aβ peptide deposits on cleavage (6). It is important to restate that the physiological function of ...
TY - JOUR. T1 - Enhancement of activation of caspases by presenilin 1 gene mutations and its inhibition by secretase inhibitors. AU - Miyoshi, Katsue. AU - Ohyagi, Yasumasa. AU - Sakae, Nobutaka. AU - Motomura, Kyoko. AU - Ma, Linqing. AU - Taniwaki, Takayuki. AU - Furuya, Hirokazu. AU - Tabira, Takeshi. AU - Kira, Jun Ichi. PY - 2009. Y1 - 2009. N2 - Presenilin 1 (PS1) gene mutations are the major causes of early-onset familial Alzheimers disease. Acceleration of apoptosis is one of the major pathogenic mechanisms of PS1 mutants, and PS1 mutants have also been reported to induce overproduction of amyloid-β protein 42. Here, we investigated aberrancy in activation of initiator caspases related to two PS1 gene mutations, I143T and G384A. Acceleration of apoptosis, elevation of caspase-3/7 activity, and significant increases in caspase-4, -8 and -9 activities during apoptosis induced by several agents were found in these mutant PS1-transfected cells. Interestingly, thapsigargin treatment ...
Amyloid-β-protein (Aβ), the key component of senile plaques in Alzheimers disease (AD) brain, is produced from amyloid precursor protein (APP) by cleavage of β-secretase and then γ-secretase. APP adaptor proteins with phosphotyrosine-binding (PTB) domains, including Dab (gene: DAB) and Numb (gene: NUMB), can bind to and interact with the conserved YENPTY-motif in the APP C-terminus. Here we describe, for the first time, the effects of RNAi knock-down of Dab and Numb expression on APP processing and Aβ production. RNAi knock-down of Dab and Numb in H4 human neuroglioma cells stably transfected to express either FL-APP (H4-FL-APP cells) or APP-C99 (H4-APP-C99 cells) increased levels of APP-C-terminal fragments (APP-CTFs) and lowered Aβ levels in both cell lines by inhibiting γ-secretase cleavage of APP. Finally, RNAi knock-down of APP also reduced levels of Numb in H4-APP cells. These findings suggest that pharmacologically blocking interaction of APP with Dab and Numb may provide novel
Increased amyloid-β (Aβ) load in the brain, neurite degeneration, neuronal loss, and decreased levels of several neurotrophins are among the characteristics of Alzheimers disease (AD). Generation of Aβ occurs when the amyloid precursor protein (APP) is proteolytically processed by β- and γ-secretases in the amyloidogenic pathway. However, Aβ formation is prevented if APP is cleaved by α- and γ- secretases in the non-amyloidogenic pathway. The normal function of APP is still not fully known. It seems clear that the different fragments that are produced during proteolytic processing have different bioactive properties. APP and its metabolites have been implicated in neurite outgrowth, synaptogenesis, cell adhesion, neuroprotection and apoptosis.. The aim of this thesis was to investigate how neurotrophic factors affect the synthesis and processing of APP and its two mammalian paralogues the APP-like protein-1 and-2 (APLP1 and APLP2). We also wanted to determine how the expression levels ...
0034] Memapsin 2 (BACE1, β-secretase) is a membrane anchored aspartic protease. Although this enzyme is ubiquitously present in many mammalian organs, its functions in the brain are best studied. One of the most important physiological functions of memapsin 2 is the cleavage of a brain membrane protein β-amyloid precursor protein (APP). The hydrolytic product of APP C-terminal fragment is cleaved again by an intramembrane protease γ-secretase to generate a 40- or 42-residue β-amyloid peptide (Ar). Aβ has been shown to feedback down regulate the synaptic activity in neurons (Kamenetz et al., 2003; Lauren et al., 2009). Also, memapsin 2 produced APP N-terminal fragment is involved in the trimming of neurons and axons in the brain (Nikolaev et al., 2009). However, since excess levels of brain Aβ are intimately related to the pathogenesis of Alzheimers disease (Selkoe, 1999), there has been intensive effort to develop inhibitor drugs against memapsin 2 (Ghosh et al., 2008). Important to such ...
Sequential proteolysis of the amyloid precursor protein (APP) and amyloid-beta petide (Abeta) release is an upstream event in Alzheimers disease (AD) pathogenesis. The function of APP in neuronal physiology is still, however, poorly understood. Along with its paralog APP-like Proteins 1 and 2 (APLP1-2), APP is involved in neurite formation and synaptic function by mechanisms that are not elucidated. APP is a single-pass transmembrane protein expressed at high levels in the brain that resembles a cell adhesion molecule or a membrane receptor, suggesting that its function relies on cell interaction processes and/or activation of intracellular pathways of signal transduction. Along this line, the APP intracellular domain (AICD) was reported to act as a transcriptional factor for targeted gene activation that mediates physiological APP functions. Here, we used an unbiased transcriptome-based approach to identify the genes transcriptionally regulated by APP in the rodent embryonic cortex and upon ...
The present study was designed to determine the effects of senescence and angiotensin II (Ang II) on expression and processing of amyloid precursor protein (APP) in human brain microvascular endothelial cells (BMECs). Senescence caused a decrease in APP expression thereby resulting in reduced secretion of soluble APPα (sAPPα). In contrast, β-site APP cleaving enzyme (BACE1) expression and production of amyloid β (Aβ)40 were increased in senescent endothelium. Importantly, in senescent human BMECs, treatment with BACE1 inhibitor IV inhibited Aβ generation and increased sAPPα production by enhancing a disintegrin and metalloprotease (ADAM)10 expression. Furthermore, Ang II impaired expression of ADAM10 and significantly reduced generation of sAPPα in senescent human BMECs. This inhibitory effect of Ang II was prevented by treatment with BACE1 inhibitor IV. Our results suggest that impairment of α-processing and shift to amyloidogenic pathway of APP contribute to endothelial dysfunction induced by
Dementia-Linked Presenilin Mutation Causes Abnormal Splicing. Hirotaka Watanabe, Dan Xia, Takahisa Kanekiyo, Raymond J. Kelleher III, and Jie Shen. (see pages 5085-5096). Presenilin is part of the γ-secretase complex that cleaves amyloid precursor protein (APP) to form β-amyloid (Aβ). Mutations in presenilin cause familial Alzheimers disease (AD) and frontotemporal dementia (FTD), but how such mutations affect γ-secretase function is unclear. Accumulation of Aβ suggests that γ-secretase is overactive in AD, but some presenilin mutations produce FTD without amyloid plaques, suggesting γ-secretase function is diminished. Furthermore, γ-secretase has targets besides APP, notably the signaling molecule Notch, and preventing cleavage of these products-either by reducing γ-secretase activity or by increasing its APP load-might contribute to cognitive impairment in AD and FTD. To address this question, Watanabe et al. created knock-in mice harboring the presenilin mutation c.548G,T, which ...
Alzheimers disease (AD) is a progressive neurodegenerative disorder, neuropathologically characterized by neurofibrillay tangles and deposition of amyloid-β (Aβ) peptides. Several mutations in the gene for amyloid precursor protein (APP) cause familial AD and affect APP processing leading to increased levels of Aβ42. However, the Arctic Alzheimer mutation (APP E693G) reduces Aβ levels. Instead, the increased tendency of Arctic Aβ peptides to form Aβ protofibrils is thought to contribute to the pathogenesis.. In this thesis, the pathogenic mechanisms of the Arctic mutation were further investigated, specifically addressing if and how the mutation affects APP processing. Evidence of a shift towards β-secretase cleavage of Arctic APP was demonstrated. Arctic APP did not appear to be an inferior substrate for α-secretase, but the availability of Arctic APP for α-secretase cleavage was reduced, with diminished levels of cell surface APP in Arctic cells. Interestingly, administration of the ...
The as yet unfinished story of MPN pathogenesis begun RO4929097 with all the discovery of the JAK2 mutation; afterwards countless other mutations are found in chronic and blast phase of MPN, some involving JAKSTAT signaling activation, many others chromatin remodeling and many others leukemic transformation. Mutations by using a obtain of perform of JAK2, MPL, CBL and these by using a reduction of perform of LNK and NF1 activate the JAKSTAT pathway main to a last phenotype of MPN with alteration of immune response, irritation, angiogenesis, proliferation and resistance to apoptosis. This pathway will be the target of new JAK2 inhibitors. JAK2 mutation, taking place inside of exon 14 of JAK2 and found on 9p24 is the most frequent mutation in MPN, ranging from roughly 96% in PV to 65% in ET and PMF. This mutation has an effect on the auto-inhibitory domain of JAK2 major to constitutive activation of JAK2 and JAK/STAT signaling. In retroviral mouse designs JAK2 confers a PV-like phenotype using a ...
Mô tả: Membrane-type 5-matrix metalloproteinase (MT5-MMP) is a proteinase mainly expressed in the nervous system with emerging roles in brain pathophysiology. The implication of MT5-MMP in Alzheimers disease (AD), notably its interplay with the amyloidogenic process, remains elusive. Accordingly, we crossed the genetically engineered 5xFAD mouse model of AD with MT5-MMP-deficient mice and examined the impact of MT5-MMP deficiency in bigenic 5xFAD/MT5-MMP(-/-) mice. At early stages (4 months) of the pathology, the levels of amyloid beta peptide (Aβ) and its amyloid precursor protein (APP) C-terminal fragment C99 were largely reduced in the cortex and hippocampus of 5xFAD/MT5-MMP(-/-), compared to 5xFAD mice. Reduced amyloidosis in bigenic mice was concomitant with decreased glial reactivity and interleukin-1β (IL-1β) levels, and the preservation of long-term potentiation (LTP) and spatial learning, without changes in the activity of α-, β- and γ-secretases. The positive impact of... ...
The amyloid precursor protein (APP) protein has been in the limelight of research on Alzheimer´s disease (AD) pathogenesis because its proteolytic processing gives rise to the neurotoxic amyloid β (Aβ) peptide, the main constituent of amyloid plaques in the brains of AD patients. APP is sequentially processed by at least three different proteases termed α-, β-, and γ-secretases. The proteolytic processing of APP can be divided into two different pathways, the non-amyloidogenic and the amyloidogenic. Whether APP is processed by the non-amyloidogenic or the amyloidogenic pathway is highly dependent on co-localization of APP with the different processing enzymes. Hence, understanding the mechanism underlying regulation of APP trafficking and its related secretases is of great importance in our understanding of AD and AD pathogenesis. The aim of this thesis was to study the processing and trafficking of APP, how it may be regulated by the interaction with the adaptor protein, Fe65, and by a ...
LY-411575 is a potent γ-secretase inhibitor with IC50 of 0.078 nM/0.082 nM (membrane/cell-based), and also inhibits Notch S3 cleavage with IC50 of 0.39 nM. - Mechanism of Action & Protocol.
Identification of heparin-binding domains in the amyloid precursor protein of Alzheimers disease by deletion mutagenesis and peptide mapping
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BACE1 - BACE1 (untagged)-Human beta-site APP-cleaving enzyme 1 (BACE1), transcript variant a available for purchase from OriGene - Your Gene Company.
Anti-Notch 2 Antibody recognizes Notch 2 that is synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase (S1 cleavage) in the trans-golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form. Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved (S2 cleavage) by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called Notch extracellular truncation (NEXT). This fragment is then cleaved by presenilin-dependent gamma-secretase (S3 cleavage) to release the intracellular domain (NICD) from the membrane.
Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (By similarity). Responsible for the proteolytic release of several other cell-surface proteins, including heparin-binding epidermal growth-like factor, ephrin-A2, CD44, CDH2 and for constitutive and regulated alpha-secretase cleavage of amyloid precursor protein (APP) (PubMed:10097139). Contributes to the normal cleavage of the cellular prion protein (By similarity). Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity (By similarity). Controls also the proteolytic processing of Notch and mediates lateral inhibition during neurogenesis (By similarity). Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form (By similarity). Also cleaves the ectodomain of the
Proceedings of the International Symposium, EXON, VladivostokVladivostok, Russia, 1 Oct 2012 - 6 Oct 20122012-10-012012-10-06 New Jersey : WORLD SCIENTIFIC 263 - 272 (2013) [10.1142/9789814508865_0036]2013 BibTeX , EndNote: XML, Text , RIS http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Journal Article Kienle, P. (Gefeierter) ; Bosch, F. (Corresponding author)GSI* ; Bühler, P. ; Faestermann, T. ; Litvinov, Y.GSI* ; Winckler, N.GSI* ; Sanjari, M. S.GSI* ; Shubina, D.GSI* ; Atanasov, D.GSI* ; Geissel, H.GSI* ; Ivanova, V.GSI* ; Yan, X. L. ; Boutin, D.GSI* ; Brandau, C.GSI* ; Dillmann, I.GSI* ; Dimopoulou, C.GSI* ; Heß, R.GSI* ; Hillenbrand, P.-M.GSI* ; Izumikawa, T. ; Knöbel, R.GSI* ; Kurcewicz, J.GSI* ; Kuzminchuk, N. ; Lestinsky, M.GSI* ; Litvinov, S.GSI* ; Ma, X. W. ; Maier, L. ; Mazzocco, M.GSI* ; Mukha, I.GSI* ; Nociforo, C.GSI* ; Nolden, F.GSI* ; Scheidenberger, C.GSI* ; Spillmann, U.GSI* ; Steck, M.GSI* ; Stöhlker, T.GSI* ; Sun, B. H. ; Suzaki, F. ; Torilov, S. Y. ...
cansSAR 3D Structure of 5HDX | BACE-1 IN COMPLEX WITH (7AR)-7A-(5-CYANOTHIOPHEN-2-YL)-6-(4-ETHOXY-5- FLUORO-6-METHYLPYRIMIDIN-2-YL)-3-METHYL-4-OXOOCTAHYDRO-2H-PYRROLO[3, 4-D]PYRIMIDIN-2-IMINIUM | 5HDX_A | Beta-secretase 1 - Also known as BACE1_HUMAN, BACE1, BACE, KIAA1149. Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase (PubMed:10656250, PubMed:10677483, PubMed:20354142). Cleaves CHL1 (By similarity). Monomer. Interacts (via DXXLL motif) with GGA1, GGA2 and GGA3 (via their VHS domain); the interaction highly increases when BACE1 is phosphorylated at Ser-498 (PubMed:14567678, PubMed:15886016). Interacts with RTN3 and RTN4 (PubMed:15286784, PubMed:16965550, PubMed:16979658). Interacts with SNX6 (PubMed
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While predisposition to AD has been linked to mutations of several genes, including those of presenilins and apolipoprotein E, mainly two protein components are present in the two types of AD aggregates (reviewed in Hardy and Selkoe, 2002). Plaques are generated by deposition of the amyloid peptides (Aβ), which are degradation products of the amyloid precursor protein (APP). APP is a transmembrane cell surface glycoprotein, expressed in five isoforms, with APP(695) being the dominant isoform in brain. APP can be cleaved by three different proteases, called α, β and γ secretases. When APP is concomitantly hydrolysed by β‐secretase at the N‐terminus of Aβ and by the γ‐secretase within the membrane (Lichtenthaler et al., 2002), the two main products, Aβ(1-40) and Aβ(1-42), migrate outside the cell and give rise to fibrils. When APP is cut by α‐secretase, the resulting soluble peptides are generally considered non‐toxic, although a recent report shows that the p3 peptide derived ...
Presenilin 1 (PS1) is a transmembrane protein localized to internal cell membranes and is involved in processing amyloid β precursor protein to produce Aβ (a protein implicated in Alzheimers disease) and processing of Notch (a signaling protein involved in development). Kim et al. show that overexpression of PS1 in embryonic kidney cells or neuroblastoma cells inhibits activation of the stress-activated protein kinase (SAPK) pathway and suppresses peroxide-induced apoptosis. Experiments in which PS1 and constitutively active mutants of the proteins in the SAPK pathway were coexpressed indicate that PS1 exerts its inhibitory effect upstream of the guanosine triphosphatase Rac1 or via a Rac1-independent pathway. PS1-deficient mouse embryo fibroblasts exhibited enhanced SAPK activity under resting conditions and increased apoptosis upon treatment with peroxide. The γ-secretase activity of PS1 was determined to be essential for the inhibition of SAPK signaling based on analysis of various PS1 ...
Disclosed are various forms of an active, isolated β-secretase enzyme in purified and recombinant form. This enzyme is implicated in the production of amyloid plaque components which accumulate in the
The aggregation of the amyloid-β (Aβ; see Drosophila Appl) peptide into fibrillar deposits has long been considered the key neuropathological hallmark of Alzheimers disease (AD). Aβ peptides are generated from proteolytic processing of the transmembrane Aβ precursor protein (AβPP) via sequential proteolysis through the β-secretase activity of β-site AβPP-cleaving enzyme (BACE1) and by the intramembranous enzyme γ-secretase. For over a decade, Drosophila melanogaster has been used as a model organism to study AD, and two different approaches have been developed to investigate the toxicity caused by AD-associated gene products in vivo. In one model, the Aβ peptide is directly over-expressed fused to a signal peptide, allowing secretion of the peptide into the extracellular space. In the other model, human AβPP is co-expressed with human BACE1, resulting in production of the Aβ peptide through the processing of AβPP by BACE1 and by endogenous fly γ-secretase. This study consisted of ...
Fig. 3. Dictyostelium has PS-dependent γ-secretase activity that processes human APP to release Aβ peptides. (A) Diagrams of human APP α, β and γ proteolytic cleavage sites, and processed fragments; shown are FL (full-length), ΔN (N-terminal deletion), α- and β-CTFs, Aβ40 peptide, and AICD regions. (B) Media conditioned by growing WT and ps1-null cells that express ΔN-APP (a truncated human APP) were analyzed for levels of Aβ40 and Aβ42 peptides by quantitative ELISA. Fresh media and media conditioned by native WT cells were used as negative controls. Bars indicate standard errors that are derived from two independent experiments, each with two replicates. (C)Protein samples were collected from growing native WT Dictyostelium, or WT and ps1-null Dictyostelium that express ΔN-APP. ΔN-APP expression and processed fragments (arrows) were determined by immunoblot assay using α-APP C-terminus. (D) Protein samples were collected from native and APP-expressing CHO cells untreated or ...
The best-characterized gamma-secretase substrates are the Notch receptor and amyloid precursor protein (APP). Presenilins' role ... protein. To form Aβ, APP must be cut by two enzymes, beta secretases and gamma secretase. Presenilin is the sub-component of ... or the amyloid precursor protein (APP) can be found. The majority of these cases carry mutant presenilin genes. An important ... January 1997). "Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both ...
Alpha secretases are a family of proteolytic enzymes that cleave amyloid precursor protein (APP) in its transmembrane region. ... "Protein kinase C-dependent alpha-secretase competes with beta-secretase for cleavage of amyloid-beta precursor protein in the ... De Strooper, B; Annaert, W (2000). "Proteolytic processing and cell biological functions of the amyloid precursor protein". J ... "The neuropeptide PACAP promotes the alpha-secretase pathway for processing the Alzheimer amyloid precursor protein". FASEB J. ...
His research interest are the secretases, proteases which cleave the amyloid precursor protein (APP), resulting in amyloid ... "Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein". Nature. 391 (6665): 387-90. doi:10.1038/ ... The amyloid peptide is the main constituent of the plaques in the brain of people with Alzheimer's disease. Together with ...
Aβ42 is generated by the enzymatic cleavage of the β-amyloid precursor protein (βΑPP) through β- and γ- secretases. Like other ... while up-regulating the α-secretase ADAM10 and the secreted amyloid precursor protein-α (sAPPα). Overall, the above mechanism ... Specifically, PD1 regulates this protein family by promoting the dephosphorylation of Bcl-xL by protein phosphatase 2A (PP2A) ... the release of Aβ42 down-regulates the anti-apoptotic proteins Bcl-2 and Bcl-xL and up-regulates the pro-apoptotic proteins Bax ...
The amyloid precursor protein (APP) is constutively transported from the ER after its synthesis to the plasma membrane via the ... The amyloidogenic pathway leads to APP processement by γ-secretases and β-secretases such as BACE1, resulting in production of ... are involved in protein-protein interactions. The SNX8 protein, even though is very similar to the other sorting nexins, ... SNX8 protein regulates cholesterol levels as an activator of the SREBPs (Sterol Regulatory Element Binding Proteins), which is ...
... protein is a membrane-associated glycoprotein that is cleaved by secretases in a manner similar to amyloid beta A4 precursor ... Li Q, Südhof TC (2004). "Cleavage of amyloid-beta precursor protein and amyloid-beta precursor-like protein by BACE 1". J. Biol ... 1998). "Immunohistochemical and in situ analysis of amyloid precursor-like protein-1 and amyloid precursor-like protein-2 ... precursor-like protein 1". Wasco W, Brook JD, Tanzi RE (January 1993). "The amyloid precursor-like protein (APLP) gene maps to ...
... amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo". Proceedings of the National Academy ... by proteases referred to as the β and γ secretases. The physiological role of this processing is unclear, though it may play a ... Aβ is a byproduct generated as the result of proteolytic processing of the amyloid precursor protein (APP) ... Kerr ML, Small DH (April 2005). "Cytoplasmic domain of the beta-amyloid protein precursor of Alzheimer's disease: function, ...
... and β-amyloid precursor protein secretases and therefore inhibits formation of the beta amyloid peptide that forms amyloid ... however it has been demonstrated that expression of TMEM59 protein inhibits Golgi glycosylation of amyloid precursor protein ( ... Transmembrane protein 59 is a protein that in humans is encoded by the TMEM59 gene. TMEM59 is a membrane bound protein that is ... and secretion of the amyloid precursor protein". The Journal of Biological Chemistry. 285 (27): 20664-74. doi:10.1074/jbc. ...
... generates from the 17-40 or 17-42 sequence of the amyloid precursor protein (APP), which is a type I integral ... Under normal physiological conditions, APP is processed with three different proteolytic enzymes: α-, β- and γ-secretases. At ... and γ-secretase cleavage from the amyloid precursor protein (APP). It is known to be the major constituent of diffuse plaques ... That is why p3 peptide represents the benign form of amyloid. Energy plays a very important role in p3 peptides. While Aβ ...
... and β-secretases which generate Aβ from its precursor protein, APP (amyloid precursor protein). Aβ circulates in plasma, ... Hiltunen M, van Groen T, Jolkkonen J (2009). "Functional roles of amyloid-beta protein precursor and amyloid-beta peptides: ... December 2014). "Amyloidprecursor protein promotes cell proliferation and motility of advanced breast cancer". BMC Cancer. ... The peptides derive from the amyloid precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield A ...
The amyloidprecursor protein (AβPP), and all associated secretases, are expressed early in development and play a key role ... Amyloid-beta precursor protein is an ancient and highly conserved protein. In humans, the gene APP is located on chromosome 21 ... Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses ... Mutations in critical regions of amyloid precursor protein, including the region that generates amyloid beta (Aβ), cause ...
Among other roles in the cell, secretases act on the amyloid-beta precursor protein (APP) to cleave the protein into three ... Secretases are enzymes that "snip" pieces off a longer protein that is embedded in the cell membrane. ... BACE is a transmembrane protein with an extracellular aspartic acid protease domain. γ-secretase is actually a protein complex ... no amyloid beta is formed because α-secretase recognizes a target protein sequence closer to the cell surface than BACE. The ...
Selkoe, DJ (1999). "Chapter 19: Biology of β-amyloid precursor protein and the mechanism of Alzheimer disease". In Terry, RD; ... The sequential actions of these secretases results in Aβ protein fragments that are released into the extracellular space The ... Amyloid beta (Aβ) is a small protein, most often 40 or 42 amino acids in length, that is released from a longer parent protein ... Suh YH; Checler F (September 2002). "Amyloid precursor protein, presenilins, and alpha-synuclein: molecular pathogenesis and ...
Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor ... A delicate balance of the enzymes secretases regulate the amyloid-beta accumulation. Alpha Secretase can render a non- ... 2006). "The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production". Nature. 440 ( ... is a short peptide that is a proteolytic byproduct of the transmembrane protein amyloid precursor protein (APP), whose function ...
Hiltunen M, van Groen T, Jolkkonen J (2009). "Functional roles of amyloid-beta protein precursor and amyloid-beta peptides: ... e γ-secretases son moi procurados polos investigadores. Para iniciar a inhibición parcial da β- e γ-secretases, necesítase un ... "Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE". Science 286 ( ... "The Alzheimer's Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide". PLoS ONE 5 (3): e9505. Bibcode:2010PLoSO... ...
Endopeptidases that are specific for AMYLOID PROTEIN PRECURSOR. Three secretase subtypes referred to as alpha, beta, and gamma ... have been identified based upon the region of amyloid protein precursor they cleave. ... Amyloid Precursor Protein Secretases (beta-Secretase). Subscribe to New Research on Amyloid Precursor Protein Secretases ... beta-Secretase; alpha-Secretase; gamma-Secretase; Secretase; APP Secretase; Amyloid Precursor Protein Secretase; Secretases; ...
"Amyloid Precursor Protein Secretases" by people in this website by year, and whether "Amyloid Precursor Protein Secretases" was ... "Amyloid Precursor Protein Secretases" is a descriptor in the National Library of Medicines controlled vocabulary thesaurus, ... Below are the most recent publications written about "Amyloid Precursor Protein Secretases" by people in Profiles. ... Below are MeSH descriptors whose meaning is more general than "Amyloid Precursor Protein Secretases". ...
Amyloid Precursor Protein Secretases / genetics * Amyloid Precursor Protein Secretases / metabolism* * Anthracenes / ... activity by JNK inhibitor SP600125 repressed PS1 transcription and PS1 protein expression by augmenting p53 protein level in SK ... p53, ZNF237 and Chromodomain helicase DNA-binding protein 3 which are repressors of PS1 transcription, also reduced Ca²⁺ leak ... Therefore, p53, ZNF237, and Chromodomain helicase DNA-binding protein 3 inhibit the function ER Ca²⁺ leak channels to regulate ...
Amyloid Precursor Protein Secretases / metabolism * Amyloid beta-Peptides / analysis * Amyloid beta-Peptides / metabolism* ... and various proteins in the beta-amyloid precursor protein (APP) processing pathway. The strongest and most consistent effects ... Synergistic effects of long-term antioxidant diet and behavioral enrichment on beta-amyloid load and non-amyloidogenic ... We evaluate the hypothesis that antioxidants, enrichment, or the combination intervention reduces age-related beta-amyloid ( ...
Phosphorylation of APP has also been implicated in neuronal differentiation (Ando et al., 1999), APP processing by secretases ( ... King GD, Turner RS (2004) Adaptor protein interactions: modulators of amyloid precursor protein metabolism and Alzheimers ... interacting protein-1b/islet-brain-1 scaffolds Alzheimers amyloid precursor protein with JNK. J Neurosci 21: 6597-6607. ... Amyloid beta protein precursor is phosphorylated by JNK-1 independent of, yet facilitated by, JNK-interacting protein (JIP)-1. ...
Amyloid Precursor Protein Secretases); EC 3.4.23.- (Aspartic Acid Endopeptidases); EC 3.4.23.46 (BACE1 protein, human). ... Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A -Site Amyloid Precursor Protein ... 0 (Amyloid beta-Protein Precursor); 0 (Cyclic S-Oxides); 0 (Thiadiazines); 0 (verubecestat). ... site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the ...
Amyloid Precursor Protein Secretases. *Intercellular Signaling Peptides and Proteins. *Membrane Proteins. *Down-Regulation ... positive regulation of tyrosine phosphorylation of Stat3 protein - protein binding - protein complex assembly - protein ... The protein has a particular type of basic domain that contains a helix interrupting protein that binds to the N-box rather ... BACKGROUND: PTOV1 is an adaptor protein with functions in diverse processes, including gene transcription and protein ...
Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury.. Loane DJ, Pocivavsek A, Moussa CE, ... Inhibition of amyloid precursor protein secretases reduces recovery after spinal cord injury. ... Cholesterol distribution, not total levels, correlate with altered amyloid precursor protein processing in statin-treated mice. ... The metalloprotease inhibitor TIMP-3 regulates amyloid precursor protein and apolipoprotein E receptor proteolysis. ...
This article briefly explains the production of Aß from amyloid precursor protein (APP). ... Alzheimers disease is characterized by the presence of neurotoxic beta amyloid (Aß) deposits in the brain. ... Allinson TM, Parkin ET, Turner AJ, Hooper NM (2003). ADAMs family members as amyloid precursor protein α‐secretases. J Neurosci ... Aβ peptides are produced by the proteolytic cleavage of the transmembrane protein amyloid precursor protein (APP) by enzyme ...
2003) ADAMs family members as amyloid precursor protein alpha-secretases. J Neurosci Res 74:342-352. ... 2000) Protein kinase C-dependent alpha-secretase competes with beta-secretase for cleavage of amyloid-beta precursor protein in ... amyloid precursor protein (APP) (Hooper and Turner, 2002; Asai et al., 2003; Postina et al., 2004), prion protein (Vincent, ... 1996) Activation of K+ channels and suppression of neuronal activity by secreted beta-amyloid-precursor protein. Nature 379:74- ...
1 regulates the processing of beta-amyloid precursor protein C-terminal fragments and the generation of amyloid beta-protein in ... Dominguez, D. I., De S. and Annaert, W. (2001). Secretases as therapeutic targets for the treatment of Alzheimers disease. ... Beta-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications ... Heyn, S. N. and Vulliet, P. R. (2001). Presenilin 1 mutations increase amyloid precursor protein production and proteolysis in ...
Among other roles in the cell, secretases act on the amyloid-beta precursor protein (APP) to cleave the protein into three ... Secretases are enzymes that "snip" pieces off a longer protein that is embedded in the cell membrane. ... BACE is a transmembrane protein with an extracellular aspartic acid protease domain. γ-secretase is actually a protein complex ... no amyloid beta is formed because α-secretase recognizes a target protein sequence closer to the cell surface than BACE. The ...
ADAMs family members as amyloid precursor protein alpha-secretases. J Neurosci Res. 2003 Nov 1;74(3):342-52. PubMed. ... Its interesting that amyloidprecursor protein forms a transcriptionally active complex with the chromatin remodeling enzyme ... Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. J Cell Biol. 2003 Jan 6;160(1 ... Metabolite-initiated protein misfolding may trigger Alzheimers disease. Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4752-7. ...
Localization and Trafficking of AmyloidProtein Precursor and Secretases: Impact on Alzheimers Disease ... Keywords: Alzheimers disease, amyloid-β, amyloidprotein precursor, protein phosphatases, protein phosphorylation, tau ... Keywords: Alzheimers disease, amyloidprotein, beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1), estrogen ... The amyloidprotein precursor (AβPP) itself appears to be hyperphosphorylated at different residues in AD brains, including ...
Healthy . 1) Loss of neurons (cortical degeneration). 3. Prevents tubulin . 2. Amyloid Precursor Protein (APP) 10 different ... Amyloid Precursor Protein. The enzymes that cut these are called Secretases (specific proteases) ... Healthy . 1) Loss of neurons (cortical degeneration). 3. Prevents tubulin . 2. Amyloid Precursor Protein (APP) 10 different ... Binds to ß-amyloid protein after it is made but prevents it from aggregating into plaques. ...
Beta-secretase, one of the enzymes that slices the amyloid precursor protein, cuts the protein into a piece that is insoluble, ... Enzymes called secretases split the protein in pieces, forming smaller beta-amyloid fragments. ... Their main component is beta-amyloid, a protein fragment that breaks off from a larger molecule called the amyloid precursor ... Amyloid precursor protein is part of the cell membrane that encases every nerve cell. When nerve cells die, this large molecule ...
Amyloid Precursor Protein Secretases, antagonists & inhibitors. UNII. KK8645V7LE. CAS number. 847925-91-1. Weight. Average: ... Protein binding. Not Available. Metabolism. Not Available. Route of elimination. Not Available. Half life. Not Available. ...
Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury. Nat Med. 2009 Apr;15(4):377-9. PubMed. ... Interaction of reelin with amyloid precursor protein promotes neurite outgrowth. J Neurosci. 2009 Jun 10;29(23):7459-73. PubMed ... Mitochondrial γ-secretase participates in the metabolism of mitochondria-associated amyloid precursor protein. FASEB J. 2011 ...
... activity of acetyl cholinesterase and expressions of amyloid precursor protein, amyloid beta , beta and gamma secretases, glial ... 0 (Aluminum Compounds); 0 (Amyloid); 0 (Amyloid beta-Peptides); 0 (Amyloid beta-Protein Precursor); 0 (Chlorides); 0 ( ... Amyloids are protein fibrils with a characteristic spatial structure. Amyloids were long perceived as the pathogens involved in ... Microbial proteins or metabolites may influence neurodegeneration through the promotion of amyloid formation by human proteins ...
... which are generated from enzymatic cleavage of the amyloid precursor protein (APP) by ?- and ?-secretases. In the present work ... CLONING, SEQUENCING AND EXPRESSION IN THE DOG OF THE MAIN AMYLOID PRECURSOR PROTEIN ISOFORMS AND SOME OF THE ENZYMES RELATED ... Using fusion proteins of matrin 3 (MATR3) to yellow fluorescent protein (YFP), we recently observed that deletion of the second ... We identified ~123 proteins that bound MATR3, with proteins associated with stress granules and RNA processing/splicing being ...
Amyloid Precursor Protein Secretases (beta-Secretase)IBA 04/2015. 1. Vitamin B 12 (Cyanocobalamin)FDA LinkGeneric 01/2015. ...
Amyloid-beta is generated from amyloid precursor protein (APP) by proteolytic processing by beta and gamma secretases. Since ... The amyloid-beta peptide is the major component of such plaques and is considered to be the major culprit in the pathogenesis ... Thus in patients, it is anticipated that inhibitors blocking BACE1 could prevent the build up of amyloid-beta plaques and help ... The inhibition of BACE - an enzyme involved in the formation of amyloid-beta plaques which accumulate in the brains of patients ...
Amyloid Precursor Protein Secretases. *Animals. *Aspartic Acid Endopeptidases. *Axin Protein. *Cyclin D1 ... In addition to its documented role in the proteolytic processing of Notch-1 and the beta-amyloid precursor protein, presenilin ... In addition to its documented role in the proteolytic processing of Notch-1 and the beta-amyloid precursor protein, presenilin ... beta-catenin levels can be separated from its roles in facilitating gamma-secretase cleavage of beta-amyloid precursor protein ...
... generated by proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretase. Aβ generation is inhibited ... APP and the APP-cleaving secretases are all transmembrane proteins, thus local membrane lipid composition is proposed to ... is characterized by extracellular accumulation of amyloid-β peptide (Aβ), ... Allinson, T.M.; Parkin, E.T.; Turner, A.J.; Hooper, N.M. ADAMs family members as amyloid precursor protein alpha-secretases. J ...
Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury. Loane DJ, Pocivavsek A, Moussa CE, ... Modulation of ABCA1 by an LXR agonist reduces beta-amyloid levels and improves outcome after traumatic brain injury. Loane DJ, ... Delayed Inflammatory mRNA and protein expression after spinal chord injury. Byrnes KR, Washington PM, Knoblach SM, Hoffman E, ... The p53 tumor suppressor protein protects against chemotherapeutic stress and apoptosis in human medulloblastoma cells. Waye S ...
Angiotensin-converting enzyme and the amyloid precursor protein secretases N. M. Hooper, S. Parvathy, E. H. Karran, A. J. ... Angiotensin-converting enzyme and the amyloid precursor protein secretases N. M. Hooper, S. Parvathy, E. H. Karran, A. J. ... Angiotensin-converting enzyme and the amyloid precursor protein secretases N. M. Hooper, S. Parvathy, E. H. Karran, A. J. ... Angiotensin-converting enzyme and the amyloid precursor protein secretases N. M. Hooper, S. Parvathy, E. H. Karran, A. J. ...
Angiotensin-converting enzyme and the amyloid precursor protein secretases N. M. Hooper, S. Parvathy, E. H. Karran, A. J. ... Role for ADAM-family proteinases as membrane protein secretases Anthony J. Turner, Nigel M. Hooper ... Diversity in the signalling and regulation of G-protein-coupled receptors G. Milligan, D. A. Groarke, A. McLean, R. Ward, C. W. ... Protein antibiotics and their inhibitors C. Kleanthous, R. James, A. M. Hemmings, G. R. Moore ...
Angiotensin-converting enzyme and the amyloid precursor protein secretases. Biochem. Soc. Trans. 27,229 -234. ... Structure-activity relationship of hydroxamate-based inhibitors on the secretases that cleave the amyloid precursor protein, ... Muscarine enhances soluble amyloid precursor protein secretion in human neuroblastoma SH-SY5Y by a pathway dependent on protein ... Parkin, E. T., Hussain, I., Turner, A. J. and Hooper, N. M. (1997). The amyloid precursor protein is not enriched in caveolae- ...
Amyloid peptides are derived from the amyloid precursor protein (APP) by sequential proteolytic cleavages by - and -secretases ... β-amyloid precursor protein in familial Alzheimers disease increases β-protein production," Nature, vol. 360, no. 6405, pp. ... "Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimers disease," Nature, vol. 349, ... "Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain," Journal ...
Both result from the cleavage of Amyloid Precursor Protein (APP) by secretases. The mAb 4G8 reacts to the abnormally processed ... Biochemical analysis of the amyloid peptides isolated from Alzheimer s disease brain indicates that Beta-Amyloid (1-42) is the ... principal species associated with senile plaque amyloids, while Beta-Amyloid (1-40) is more abundant in cerebrovascular amyloid ... This antibody is reactive to residues 17-24 of Beta-Amyloid. The epitope lies within amino acids 18-22 of Beta-Amyloid (VFFAE ...
  • Aβ peptides are produced by the proteolytic cleavage of the transmembrane protein amyloid precursor protein (APP) by enzyme complexes a, β and γ-secretases. (news-medical.net)
  • These are subsequently cleaved by γ-secretase at multiple sites in the transmembrane region, releasing small peptides, Aβ 1-40 and Aβ 1-42 , the major components of AD-associated amyloid fibrils. (biologists.org)
  • One of the neuropathological features of AD is the presence of extracellular amyloid plaques, which are mainly composed of amyloid-β (Aβ) peptides. (iospress.com)
  • These peptides derive from the amyloidogenic proteolytic processing of the amyloid-β protein precursor (AβPP), through the sequential action of β- and γ-secretases. (iospress.com)
  • Here, we report that amyloids composed of short peptides can direct the sequence-selective, regioselective and stereoselective condensation of amino acids. (bireme.br)
  • Firstly, from the "concrete" deposits of amyloid plaques to less well-defined soluble or pseudosoluble oligomers of the amyloid peptides, ranging from dimers to dodecamers and even larger aggregates. (hindawi.com)
  • Moreover, the precise molecular actions of the amyloid peptides and their aggregates remain unknown and enigmatic, largely because their molecular targets, or their specific receptors remain undefined. (hindawi.com)
  • For one, while the proteolytic enzymes and their mechanisms responsible for the generation of the amyloid peptides become well-known and understood at the molecular level, the eventual physiological function of the peptides is still questioned-and remains questionable. (hindawi.com)
  • Biochemical analysis of the amyloid peptides isolated from Alzheimer s disease brain indicates that Beta-Amyloid (1-42) is the principal species associated with senile plaque amyloids, while Beta-Amyloid (1-40) is more abundant in cerebrovascular amyloid deposits. (anaspec.com)
  • The 4-subunit intramembrane protease complex γ-secretase cleaves many substrates including fragments of the β-amyloid precursor protein (APP), leading to formation of Aβ peptides, and Notch. (dtu.dk)
  • Cleavage of APP by β- and γ-secretases generates insoluble Aβ peptides. (sciencemag.org)
  • A 30-d course of oral administration of a semipurified extract of the root of Withania somnifera consisting predominantly of withanolides and withanosides reversed behavioral deficits, plaque pathology, accumulation of β-amyloid peptides (Aβ) and oligomers in the brains of middle-aged and old APP/PS1 Alzheimer's disease transgenic mice. (pnas.org)
  • Distinct sites of intracellular production of Alzheimer's disease A beta 40/42 amyloid peptides. (nature.com)
  • Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by a number of neuropathological features, including extracellular deposits composed primarily of amyloid- (A ) peptides. (dissertations.se)
  • The amyloid precursor protein gene (APP) and its derivative peptides have important functions in the central nervous system. (scirp.org)
  • P. Panegyres and E. Atkins, "The Functions of the Amyloid Precursor Protein Gene and Its Derivative Peptides: I Molecular Biology and Metabolic Processing," Neuroscience and Medicine , Vol. 2 No. 2, 2011, pp. 120-131. (scirp.org)
  • The process, controlled by - and -secretases, leads to the formation of -amyloid and a few smaller peptides (A-40 and A-42). (termedia.pl)
  • Expression of amyloid β peptides in APP-PS1-HEK293 cells was lower in ICT-treated groups compared with that in the control group. (peerj.com)
  • Amyloid-β peptides (AβPs) are generated through sequential cleavage of amyloid precursor protein (APP) by beta-site amyloid cleaving enzyme (BACE)1 and γ-secretase (presenilin-1 (PS1)), which play pivotal roles in AD pathogenesis ( Querfurth & LaFerla, 2010 ). (peerj.com)
  • AD is characterized by formation and aggregation of extracellular plaques of abnormal amyloid-beta (A[beta]) peptides, as well as presence of intracellular aggregates of hyperphosphorylated tau protein, known as neurofibrillary tangles (NFT) [11, 12]. (thefreelibrary.com)
  • A[beta] peptides promote intracellular tau phosphorylation, with hyperphosphorylated tau protein posteriorly aggregating into NFT [11, 14]. (thefreelibrary.com)
  • A gene on chromosome 21q21.3 that encodes a cell surface receptor and transmembrane precursor protein which is cleaved by secretases to form various peptides. (thefreedictionary.com)
  • β -secretase 1 (BACE1) or beta-site APP cleaving enzyme 1 is responsible for the generation of the 40-42 amino acid-long fibrillar amyloid-β peptides that form aggregates/plaques in the brain of Alzheimer's patients. (biovision.com)
  • Endpoints are APP and BACE1 mRNA & proteins, and Aß peptides, which we predict to change with miRNA. (elsevier.com)
  • In an article published January 10, 2005, in the journal Public Library of Science Medicine, Sam Gandy's group of Thomas Jefferson University, Philadelphia, with colleagues elsewhere, report evidence suggesting that statin drugs can boost α-secretase cleavage of AβPP via the Rho/ROCK1 protein phosphorylation pathway. (alzforum.org)
  • Since beta-secretase (beta-site APP cleaving enzyme 1, or BACE1) cleavage is rate limiting for the production of amyloid-beta, inhibition of this enzyme represents an attractive strategy to ameliorate amyloid-beta plaque deposition in Alzheimer's disease. (biospace.com)
  • In contrast, PS1Deltacat restores Notch-1 proteolytic cleavage and Abeta generation in PS1-deficient cells, indicating that PS1 function in modulating beta-catenin levels can be separated from its roles in facilitating gamma-secretase cleavage of beta-amyloid precursor protein and in Notch-1 signaling. (nih.gov)
  • Sequential proteolytic cleavage of APP with β and γ-secretases leads to the production of a small proteolytic peptide, termed Aβ, which is amyloidogenic and the core constituent of senile plaques. (jove.com)
  • Angiotensin-converting enzyme (ACE), a type I integral membrane protein that plays a major role in vasoactive peptide metabolism, is shed from the plasma membrane by proteolytic cleavage within the juxtamembrane stalk. (biologists.org)
  • Both result from the cleavage of Amyloid Precursor Protein (APP) by secretases. (anaspec.com)
  • We find that the plasma membrane enzyme glycerophosphodiester phosphodiesterase 2 (GDE2) stimulates ADAM10 APP cleavage by shedding and inactivating reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a glycosylphosphatidylinositol (GPI)-anchored inhibitor of ADAM10. (sciencemag.org)
  • 4 Amyloid Beta ( Aβ) is formed through cleavage of the APP, generating a peptide 36-43 amino acids long. (google.com)
  • The cleavage is performed by α, β, and γ secretases in the brain. (google.com)
  • This disease is characterized by intraneuronal tangles and extracellular plaques, and the amyloid beta-peptide (Aβ), which is derived from APP upon cleavage by β- and γ-secretases, is the major component of the plaques. (biologists.org)
  • β-amyloid is generated by cleavage of the amyloid precursor protein (APP) by the β- and γ-secretases in a two-step process. (sciencemag.org)
  • Alternate cleavage of APP by α-secretase (encoded by the ADAM10 gene) and γ-secretase, on the other hand, prevents β-amyloid accumulation. (sciencemag.org)
  • In this regard, the gamma-secretase complex is responsible for the final cleavage event in the processing of beta-amyloid precursor protein (betaAPP), resulting in Abeta generation. (jove.com)
  • The molecular culprit in AD is the amyloid β peptide (Aβ), which derives from the amyloid precursor protein (APP) through sequential cleavage by the two proteases β- and γ-secretase. (eurekaselect.com)
  • Protein kinase C and mitogen-activated protein kinase constitute central signaling hubs for the regulation of α-secretase cleavage. (eurekaselect.com)
  • Additionally, recent studies increasingly demonstrate that the correct spatial and temporal localization of the two membrane proteins APP and α-secretase is essential for efficient α-secretase cleavage of APP. (eurekaselect.com)
  • This review highlights the role of signaling pathways and protein trafficking in the control of APP α-secretase cleavage. (eurekaselect.com)
  • HP-β-CD lowered levels of Aβ42 in part by reducing β cleavage of the APP protein, and it also up-regulated the expression of genes involved in cholesterol transport and Aβ clearance. (rupress.org)
  • The presence of these proteins, which all contribute to the generation of Aβ, indicates that the DIG fraction is probably where the intra-membranous cleavage of APP occurs. (nature.com)
  • Sorting nexin-4 regulates β-amyloid production by modulating β-site-activating cleavage enzyme-1. (sigmaaldrich.com)
  • Functions as a protease inhibitor by blocking access of secretases to APP cleavage sites. (uniprot.org)
  • Proteolytic cleavage, or 'shedding', of the ectodomains (extracellular regions) at a juxta-membrane site on transmembrane proteins has emerged as one such mechanism. (portlandpress.com)
  • The deposits are composed of products of the amyloid precursor protein cleavage. (termedia.pl)
  • The consequences of the PS/g-secretase-mediated cleavage on the function of many of these proteins are largely unknown. (j-alz.com)
  • Finally, we recapitulate the current knowledge on the possible physiological function of PS/g-secretase-mediated cleavage of specific substrate proteins. (j-alz.com)
  • So instead of generating the toxic A-beta fragment, cleavage with alpha-secretase produces a protein fragment that has been reported to protect and stimulate the generation of neurons in brain. (seniorjournal.com)
  • Jaehong Suh, PhD, of the MGH-MIND Genetics and Aging Research Unit, lead author of the Neuron article, says, 'Our current study shows that reducing ADAM10 activity by these AD-associated mutations delivers a 'one-two punch' to the brain one, decreasing neuroprotective alpha-secretase cleavage products and two, increasing neurotoxic A-beta protein accumulation. (seniorjournal.com)
  • Sequential cleavage by beta-secretase 1 (BACE) and gamma-secretase (γ-secretase) produces the amyloid-beta peptide fragment that aggregates into clumps called amyloid plaques in the brains affected by Alzheimer's disease. (wikipedia.org)
  • Presenilins undergo cleavage in an alpha helical region of one of the cytoplasmic loops to produce a large N-terminal and a smaller C-terminal fragment that together form part of the functional protein. (wikipedia.org)
  • Amyloid-beta is generated from amyloid precursor protein (APP) by proteolytic processing by beta and gamma secretases. (biospace.com)
  • In addition to its documented role in the proteolytic processing of Notch-1 and the beta-amyloid precursor protein, presenilin 1 (PS1) associates with beta-catenin. (nih.gov)
  • Alzheimer's disease (AD) is characterized by extracellular accumulation of amyloid-β peptide (Aβ), generated by proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretase. (mdpi.com)
  • Aβ is generated by sequential proteolytic processing of the amyloid precursor protein (APP), a large type-I transmembrane protein [ 3 ]. (mdpi.com)
  • The deacetylase SIRT1 suppresses the production of Alzheimer's disease-associated β-amyloid by activating a gene encoding a key proteolytic enzyme. (sciencemag.org)
  • The main constituent of Alzheimer's amyloid plaques is a peptide, named Aβ, generated through the proteolytic processing of the precursor protein APP ( De Strooper and Annaert, 2000 ). (biologists.org)
  • These proteolytic events control the generation of the pathogenic amyloid-β (Aβ) peptide, which excessively accumulates in the brains of individuals afflicted by AD. (j-alz.com)
  • That enzyme has been targeted for a long time now, since it's thought to be involved in the proteolytic processing that generates beta-amyloid, a hallmark of Alzheimer's. (sciencemag.org)
  • Familial AD (FAD), on the other hand, is associated with mutations in amyloid precursor protein (APP) on chromosome 21, apolipoprotein E gene on chromosome 19, presenilin-1 (PS1) on chromosome 14 (14q24.3) and presenilin-2 (PS2) on chromosome 1. (biologists.org)
  • Presenilin 1 negatively regulates beta-catenin/T cell factor/lymphoid enhancer factor-1 signaling independently of beta-amyloid precursor protein and notch processing. (nih.gov)
  • To study the properties of this mutation, the authors of the work added the mutated gene of presenilin 1 to the cultures of neurons along with a gene coding a fluorescent protein. (medicalxpress.com)
  • The mutated gene and the gene of the fluorescent protein were added simultaneously, and therefore each fluorescent neuron expressed the mutated presenilin 1 gene. (medicalxpress.com)
  • The small fraction of familial cases are caused primarily by mutations in three genes: amyloid precursor protein (APP), presenilin1 (PS1), and presenilin 2 (PS2). (pnas.org)
  • The best characterized function of PRESENILIN (PSEN) proteins is in γ-secretase enzyme activity. (iospress.com)
  • The Alzheimer's disease (AD)-associated amyloid-β protein precursor (AβPP) is cleaved by α-, b-, and presenilin (PS)/g-secretases through sequential regulated proteolysis. (j-alz.com)
  • Also, mRNA expression of A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) increased, while that of BACE1 and presenilin-1 (PS1) decreased, upon ICT treatment. (peerj.com)
  • Early Contextual Fear Memory Deficits in a Double-Transgenic Amyloid-[beta] Precursor Protein/Presenilin 2 Mouse Model of Alzheimer's Disease. (thefreelibrary.com)
  • Consistent with reports that presenilins are the elusive γ-secretases, subcellular fractionation studies showed that presenilin-1, CTFα, and CTFβ are enriched in the CTFγ-generating fractions. (elsevier.com)
  • Recent findings suggest that Presenilin 1 (PS1) mutations play a major role in the development of Alzheimer's disease (AD) by increasing the production of the beta amyloid peptide (Aβ). (elsevier.com)
  • Heyn, SN & Vulliet, PR 2001, ' Presenilin 1 mutations increase amyloid precursor protein production and proteolysis in Xenopus laevis oocytes ', Brain Research , vol. 904, no. 2, pp. 189-198. (elsevier.com)
  • When it was learned that gamma-secretase, as part of a complex called presenilin , also processes the Notch protein , a lot of people were understandably worried about what an inhibitor might do on the side). (sciencemag.org)
  • γ-secretase is actually a protein complex containing presenilin, nicastrin, APH-1, and PEN-2. (wikipedia.org)
  • Presenilins are the catalytic component of the gamma secretase intramembrane protease, a four-member protein complex consisting of presenilin, nicastrin, APH-1, and PEN-2. (wikipedia.org)
  • We show that JNK-interacting protein-3 (JIP-3), a JNK scaffolding protein that does not bind APP, selectively increases APP phosphorylation, accumulation of pAPP into processes, and stimulates process extension in both neurons and COS-1 cells. (jneurosci.org)
  • Amylopathy is a term that describes abnormal synthesis and accumulation of amyloid beta (Aβ) in tissues with time. (jove.com)
  • Intracellular accumulation of insoluble amyloid β peptide (Aβ) oligomers is a major pathogenic event in Alzheimer's disease (AD). (sciencemag.org)
  • Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Aβ) accumulation, which is associated with Alzheimer disease, results in synaptic loss and impaired neurotransmission. (pubmedcentralcanada.ca)
  • From a histological viewpoint, the progression of AD is associated with 3 cardinal neuropathological features: the accumulation of extracellular senile plaques which is mediated by amyloid-beta (Aβ), intracellular neurofibrillary tangles (NFT) and synaptic degeneration (fig. 1 ) [ 13 , 14 ]. (karger.com)
  • Intracellular generation and accumulation of amyloid β-peptide terminating at amino acid 42. (nature.com)
  • Further provided are methods of screening a test compound for the ability to inhibit amyloid-beta peptide accumulation in a mammalian cell or biological fluid. (patents.com)
  • In the report from Massachusetts General Hospital (MGH), which will appear in the October 16 issue of Neuron and has been released online, the investigators from the MassGeneral Institute for Neurodegenerative disease (MGH-MIND) describe how the two mutations in ADAM10 increase generation and accumulation of the toxic amyloid beta (A-beta) protein in the brains of a mouse model of AD. (seniorjournal.com)
  • The early-onset form of AD is linked to genetic mutations, and accumulation of a protein called amyloid-β occurs in many patients with both early- and late-onset AD. (sciencemag.org)
  • Alzheimer's disease (AD) is a progressive dementia disorder characterized by synaptic degeneration and amyloid-β (Aβ) accumulation in the brain. (sciencemag.org)
  • Drugs or inhibitors to block this enzyme could prevent the accumulation of beta-amyloid and may help slow or stop Alzheimers disease. (biovision.com)
  • Aβ is a hallmark of Alzheimer's disease (AD) and is found in Lewy body dementia, inclusion body myositis and cerebral amyloid angiopathy 1-4 . (jove.com)
  • Cerebral amyloid angiopathy-related inflammation (CAARI), a relatively recently recognized disease entity, occurs in patients affected by cerebral amyloid angiopathy (CAA) [6,7], also referred to as congophilic amyloid angiopathy. (termedia.pl)
  • With an aging population, clinicians are more frequently encountering patients with atrial fibrillation who are also at risk of intracerebral hemorrhage due to cerebral amyloid angiopathy, the result of β-amyloid deposition in cerebral vessels. (onlinejacc.org)
  • Cerebral amyloid angiopathy is common among elderly patients, and is associated with an increased risk of intracerebral bleeding, especially with the use of anticoagulation. (onlinejacc.org)
  • Determining the presence and burden of cerebral amyloid angiopathy is particularly important when planning to start or restart anticoagulation after an intracerebral hemorrhage. (onlinejacc.org)
  • The HAS-BLED score (4) is used to estimate bleeding risk with anticoagulation, but does not adequately account for cerebral amyloid angiopathy (CAA), a prevalent risk factor for ICH in the elderly. (onlinejacc.org)
  • APP mutations are implicated in autosomal dominant Alzheimer's disease and cerebroarterial amyloidosis (cerebral amyloid angiopathy). (thefreedictionary.com)
  • APP and the APP-cleaving secretases are all transmembrane proteins, thus local membrane lipid composition is proposed to influence APP processing. (mdpi.com)
  • ADAM10 regulates over 40 other transmembrane proteins and acts as a 'molecular scissor' by removing their extracellular regions. (portlandpress.com)
  • The tetraspanins are a superfamily of 33 four-transmembrane proteins in mammals which interact with and regulate specific partner proteins within membrane nanodomains. (portlandpress.com)
  • Similarly to AβPP, most of these proteins are type-I transmembrane proteins involved in vital signaling functions regulating cell fate, adhesion, migration, neurite outgrowth, or synaptogenesis. (j-alz.com)
  • γ-Secretases are multi-subunit protease complexes within the membrane that cleave single-pass transmembrane proteins at residues within the transmembrane domain. (biovision.com)
  • Although BACE cleaves the extracellular domains of several transmembrane proteins, its physiological function remains unknown. (wikipedia.org)
  • Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. (wikipedia.org)
  • Presenilins are transmembrane proteins with nine alpha helices. (wikipedia.org)
  • 8 Presenilins are a set of proteins that are part of the gamma secretase complex, which helps cleave APP to form Aβ. (google.com)
  • Many people had assumed that such mutations somehow turned gamma-secretase loose to do its amyloid-forming work earlier and more thoroughly, but Jie Shen and Raymond Kelleher's work had been pointing at the opposite conclusion: that these mutations inactivated gamma-secretase, and that this inactivation was a risk factor for Alzheimer's. (sciencemag.org)
  • This is actually good news for the amyloid hypothesis, although clearly bad news for gamma secretase inhibitors. (sciencemag.org)
  • Well over 100 different integral membrane proteins are processed by gamma-secretase. (wikipedia.org)
  • The best-characterized gamma-secretase substrates are the Notch receptor and amyloid precursor protein (APP). (wikipedia.org)
  • Amyloid plaques are a mixture of abnormal proteins and nerve cell fragments that develop in the tissue between nerve cells. (healthcentral.com)
  • Enzymes called secretases split the protein in pieces, forming smaller beta-amyloid fragments. (healthcentral.com)
  • Protein-protein interactions involving the AICD may affect trafficking, processing, and cellular functions of holo-APP and its C-terminal fragments. (jove.com)
  • Tetraspanin-6 (TSPAN6) is increased in AD brains and overexpression in cells exerts paradoxical effects on Amyloid Precursor Protein (APP) metabolism, increasing APP-C-terminal fragments (APP-CTF) and Aβ levels at the same time. (springermedizin.de)
  • APP is cleaved by three secretases known as α, β, and γ secretase which act on APP at different sites producing various fragments of differing amino acid length. (scirp.org)
  • The deposited material is composed of the breakdown product of amyloid precursor protein, which is cleaved by β- and γ-secretases into amyloid-beta (Aβ) fragments of different amino acid lengths (Aβ40 and Aβ42) ( Figure 1 ) (5) . (onlinejacc.org)
  • Among other roles in the cell, secretases act on the amyloid-beta precursor protein (APP) to cleave the protein into three fragments. (wikipedia.org)
  • The two fragments remain in contact with each other in the mature protein. (wikipedia.org)
  • Amyloid plaques and neurofibrillary tangles are the microscopic structural hallmarks of Alzheimer's disease. (healthcentral.com)
  • It remains unclear whether amyloid plaques and neurofibrillary tangles are the cause of Alzheimer's or simply a byproduct of the disease, but researchers now have a better understanding of how plaques and tangles are formed. (healthcentral.com)
  • Patients suffering from Alzheimer's disease (AD) are typified and diagnosed postmortem by the combined accumulations of extracellular amyloid plaques and of intracellular tauopathy, consisting of neuropil treads and neurofibrillary tangles in the somata. (hindawi.com)
  • The pathology is visualized postmortem as intraneuronal aggregates of protein Tau, known as neuropil treads and neurofibrillary tangles. (hindawi.com)
  • The other main neuropathologic hallmarks of Alzheimer's disease are the neurofibrillary tangles of tau protein. (google.com)
  • Signaling Pathways: Amyloid Plaque and Neurofibrillary Tangle Formation in Alzheimer's Disease. (google.com)
  • Neurofibrillary tangles and β-amyloid plaques, which many believe are neurotoxic, are classic pathological findings in the brains of patients. (sciencemag.org)
  • Hcy contributes to pathological cascades involving amyloid plaques and neurofibrillary tangles (NFTs). (primarypsychiatry.com)
  • The formation of beta-amyloid plaques and neurofibrillary tangles in the brains of the patients were found to be related to dementia symptoms (Wilcock & Esiri, 1982). (scholarpedia.org)
  • The tau hypothesis (Boutajangout & Wisniewski, 2014) proposes that hyperphosphorylated tau proteins form neurofibrillary tangles inside the nerve cell bodies, causing microtubules to disintegrate, collapsing the neuron's transport system. (scholarpedia.org)
  • 1999). Purification and cloning of amyloid precursor protein β-secretase from human brain. (news-medical.net)
  • The metalloproteinase and major amyloid precursor protein (APP) α-secretase candidate ADAM10 is responsible for the shedding of proteins important for brain development, such as cadherins, ephrins, and Notch receptors. (jneurosci.org)
  • Our study reveals that ADAM10 plays a central role in the developing brain by controlling mainly Notch-dependent pathways but likely also by reducing surface shedding of other neuronal membrane proteins including APP. (jneurosci.org)
  • In this article, we critically review the recent knowledge about the trafficking and co-localization of AβPP and related secretases in the brain under physiological and AD conditions. (iospress.com)
  • The result is that the beta-amyloid fragment is deposited in the brain. (healthcentral.com)
  • Researchers can now detect levels of beta-amyloid in the brain through imaging test scans and spinal fluid tests. (healthcentral.com)
  • Studies show that markers of beta-amyloid in many "normal" older people are associated with brain changes consistent with mild cognitive impairment and Alzheimer's dementia, and this may identify people who are not yet showing symptoms of Alzheimer's. (healthcentral.com)
  • Supporting this notion are studies demonstrating that deletion of the BACE1 gene in mice prevents the formation of amyloid-beta in cultured neurons and the brain. (biospace.com)
  • In certain embodiments, compounds inhibit BACE (β-site APP-cleaving enzyme), and thus are useful in the treatment or prevention of a disease characterized by β-amyloid deposits in the brain (including, but not limited to, Alzheimer's Disease). (google.nl)
  • Matters are, however, complicated further by recent data originating from several clinical trials that identified a large fraction of individuals in the control groups with considerable brain amyloid load using PET-imaging [ 12 - 14 ]. (hindawi.com)
  • Obviously, this means that high-amyloid concentration in the brain is not per se incompatible with normal cognitive functioning in old age. (hindawi.com)
  • Affinity pulldown of γ-secretase and associated proteins from human and rat brain. (nih.gov)
  • All of the known γ-secretase components were identified.Interestingly, TMP21 and the PS associated protein syntaxin1 were associated to γ-secretase in rat brain.We suggest that the present method can be used for further studies on the composition of the γ-secretase complex. (nih.gov)
  • Notch proteins have been recognized for many years as part of signaling cascades that drive the development of the fetal brain, nerves and blood vessels. (bio-medicine.org)
  • Normally, tau proteins serve to stabilize microtubules in the neurons in the brain, and are essential for axonal growth and development. (google.com)
  • A postgraduate student at SPbPU, analyzes the expression of proteins in mouse brain cells used to model Alzheimer's disease. (medicalxpress.com)
  • All of them lead to the formation of amyloid plaques in the brain, and those break synaptic contacts and therefore cause the development of the disease. (medicalxpress.com)
  • Enhanced expression of low-density lipoprotein receptor-related protein (LRP) in brain microvessels and the Aβ-degrading protease neprilysin (NEP) occurred 14-21 d after a substantial decrease in brain Aβ levels. (pnas.org)
  • Among other mechanisms, influx and efflux of brain Aβ are regulated by receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein (LRP), respectively ( 4 ). (pnas.org)
  • To establish a linkage between Aβ levels and BACE, we examined BACE protein, mRNA expression and enzymatic activity in the same brain region of AD brains. (elsevier.com)
  • Brain pyroglutamate amyloid-β is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer's disease therapeutic. (semanticscholar.org)
  • R. L. Neve, E. A. Finch and L. R. Dawes, "Expression of the Alzheimer Amyloid Precursor Gene Transcripts in the Human Brain," Neuron, Vol. 1, 1988, pp. 669-667. (scirp.org)
  • CAA is a form of amyloidopathy in which -amyloid deposits form in the walls of the small blood vessels located mainly in the subcortical region of the brain. (termedia.pl)
  • Recent evidence showed that amyloid-β, Aβ42, formed spherulites in vitro and, possibly, in vivo in Alzheimer's disease brain tissue. (j-alz.com)
  • These approaches report reduction of Aß deposition in the brain, supporting the amyloid attenuating effects observed with complete antibodies. (sdbonline.org)
  • In the original report, expression of scFv9 and scFv42.2 in CRND8 mice by somatic brain transgenesis shows significant reduction of insoluble Aß42 in brain homogenates and fewer amyloid plaques by histological analysis. (sdbonline.org)
  • Amyloid plaques in the brain are one of the characteristic features of Alzheimer pathology. (actionalz.org)
  • As PS1 has been shown to play a critical role in facilitating γ-secretase activity, and mutations in this protein are associated with familial AD (FAD), we have cloned it from SAMP8 mouse hippocampus and compared its sequence with those of other species. (biologists.org)
  • Furthermore, we discuss some possible signals that govern the dynamic encounter of AβPP with each group of secretases, such as AβPP mutations, estrogen deprivation, chronic stress, metabolic impairment, and alterations in sleep pattern-associated with aging. (iospress.com)
  • Other mutations may occur in the genes that code presenilins (proteins in the cellular membrane that are part of an secretase that cleaves APP to produce beta amyloid). (medicalxpress.com)
  • These mutations result in abnormal processing of APP and increased generation of β amyloid peptide 1-42 (Aβ42), which aggregates as β sheets ( 1 ). (pnas.org)
  • The two mutations occur in a gene called ADAM10 coding for an enzyme involved in processing the amyloid precursor protein which now becomes the second pathologically-confirmed gene for late-onset AD and the fifth AD gene overall. (seniorjournal.com)
  • found that activating mutations in protein kinase Cα (PKCα) correlated with the disease. (sciencemag.org)
  • Tg2576 mice (Tg(APPSWE)2576Kha), which express human [beta]-amyloid precursor proteins (hAPP) containing the K670N and M671L mutations on a 129S6 genetic background, were purchased from Taconic Farms, Inc. (Hudson, NY, USA) [11]. (thefreelibrary.com)
  • Alzheimer's disease is not normally a hereditary disease, although cases linked to genetics share a common problem: a mutation in the genes that code for the presinilin proteins. (google.com)
  • One substrate of γ-secretase is encoded by the gene AMYLOID BETA A4 PRECURSOR PROTEIN (A βPP/APP ) that is a fAD mutation locus. (iospress.com)
  • PS2M1 mice express human PS2 proteins containing the N141I mutation on a C57BL/6JJcl background (purchased from Immuno-Biological Laboratories Co, Ltd., Fujioka, Japan) [22, 23]. (thefreelibrary.com)
  • In N2a cells stably expressing human amyloid precursor protein with the Swedish mutation (APPswe), the reduction in Aβ production induced by 1 μM bis(7)-Cognitin was not altered by the co-pretreatment of muscarinic and nicotinic cholinergic receptor antagonists, indicating that the regulation of APP processing by this dimer is independent of cholinergic transmission. (elsevier.com)
  • Beta-Amyloid forms are deposited in the CNS of patients with Alzheimer s disease and Down s syndrome. (anaspec.com)
  • This resembles the β-amyloid precursor protein (APP) in Alzheimer disease (AD), which can be physiologically processed by α-, β-, and γ-secretases. (mdpi.com)
  • To release the amyloidogenic peptide Aβ from the Alzheimer amyloid precursor protein (APP), two secretases act sequentially: first, β-secretase cleaves close to the membrane within the ectodomain and then γ-secretase cuts within the transmembrane domain1. (nature.com)
  • Generation of Alzheimer β-amyloid protein in the trans-Golgi network in the apparent absence of vesicle formation. (nature.com)
  • Intracellular and secreted Alzheimer β-amyloid species are generated by distinct mechanisms in cultured hippocampal neurons. (nature.com)
  • Abstract Neuritic plaques of Alzheimer patients are composed of multiple protein components. (semanticscholar.org)
  • The amyloid β-peptide (Aβ peptide) is assumed to play a crucial and early role in the pathogenesis of Alzheimer disease. (jci.org)
  • This echoes Karran and Hardy's paper (A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease. (sciencemag.org)
  • APP is a ubiquitous membrane protein that is physiologically processed by site-specific proteolysis firstly by α- or β-secretases, releasing a large fragment called APP S that contains most of the extracellular sequences of APP, a small extracellular stub, the transmembrane region and the cytoplasmic tail of APP (`AICD'-APP intracellular domain). (biologists.org)
  • Disturbances on AβPP and secretases intracellular trafficking and, consequently, in their localization may affect dynamic interactions between these proteins with consequences in the AD pathogenesis. (iospress.com)
  • When a ligand binds to Notch in particular, part of the protein, the notch intracellular domain (NICD), breaks away inside of the cell, travels to the cells nucleus and influences gene expression there. (bio-medicine.org)
  • Aβ generation can be affected by the intracellular trafficking of APP or its related secretases, which is thus important to understanding its pathological alterations. (sigmaaldrich.com)
  • Ectodomain shedding directly affects the responsiveness of cells to extracellular signals via activation of intracellular signalling or down-regulation of cell surface receptors, or indirectly through the release of soluble mediators from their membrane-bound precursors. (portlandpress.com)
  • Nevertheless, there is a strong correlation between the neurotoxicity caused by prion proteins and the blockade of their normal proteolysis. (mdpi.com)
  • Amyloid beta (Aß) is a short peptide derived from the proteolysis of a larger transmembrane molecule, the amyloid precursor protein (APP). (perkinelmer.com)
  • A is derived from proteolysis of the amyloid precursor protein (APP) by consecutive action of and -secretases. (dissertations.se)
  • All the identified proteins share common structural features, which are typical for their proteolysis. (j-alz.com)
  • It is a transcriptional repressor of genes that require a bHLH protein for their transcription. (cancerindex.org)
  • Having been around since early in evolution, Notch proteins are named for notches in the wings of the flies in which Notch-related genes were discovered. (bio-medicine.org)
  • Gene expression is the process whereby genetic instructions encoded in genes are converted into protein workhorses that make up the bodys structures and carry its signals. (bio-medicine.org)
  • Some of them can be found in the genes that code amyloid precursor protein (APP). (medicalxpress.com)
  • Cholesterol homeostasis is tightly regulated by feedback mechanisms: sterol regulatory element binding proteins (SREBPs) and liver X receptors (LXRs) regulate the expression of genes that control the uptake, synthesis, and export of cholesterol. (rupress.org)
  • By searching potential Fe65 -like genes in the nematode Caenorhabditis elegans , we identified a single gene, feh-1 ( Fe 65 h omolog-1), encoding a protein with a high sequence similarity to mammalian Fe65s. (biologists.org)
  • Most of the genes encoding the proteins taking part in this complex molecular machinery have been isolated and, in some instances, characterised in C. elegans . (biologists.org)
  • 3 Eventually, the degenerate neurons become clumped into the amyloid plaques which are insoluble and unable to be broken down by the body. (google.com)
  • Beta-amyloid and Its Damaging Effects on Neurons. (google.com)
  • We have established that translation of amyloid precursor protein (APP), which is cleaved to generate neurotoxic βamyloid, is normally repressed by the fragile X mental retardation protein (FMRP) in the dendritic processes of neurons. (pubmedcentralcanada.ca)
  • Bouillot, C., Prochiantz, A., Rougon, G. & Allinquant, B. Axonal amyloid precursor protein expressed by neurons in vitro is present in a membrane fraction with caveolae-like properties. (nature.com)
  • The proteins' role in calcium homeostasis in neurons has been a subject of interest. (wikipedia.org)
  • The co-deposition of chaperon proteins, the distribution of amyloid proteins and clinical features are also auxiliary to subtype cardiac amyloidosis. (bireme.br)
  • These findings demonstrate correlation between Aβ loads and BACE elevation and also suggest that as a consequence, BACE elevation may lead to increased Aβ production and enhanced deposition of amyloid plaques in sporadic AD patients. (elsevier.com)
  • Plays a regulatory role in the processing of the amyloid-beta A4 precursor protein (APP) and acts as an inhibitor of the amyloid-beta peptide aggregation and fibrils deposition. (uniprot.org)
  • SoSe exposure elevated CerS1 mRNA and protein (fig. S1F) and in addition induced ceramide deposition in mitochondria (Fig. 1F). (antibodyassay.com)
  • CAA is a cerebrovascular disease caused by the deposition of β-amyloid in the walls of cerebral arteries, arterioles, and capillaries. (onlinejacc.org)
  • Beta-secretase, one of the enzymes that slices the amyloid precursor protein, cuts the protein into a piece that is insoluble, that is, not easily dissolved. (healthcentral.com)
  • Cellular enzymes (secretases) cut the mutated protein, and amyloid beta peptide is formed. (medicalxpress.com)
  • The process leading to the generation of A-beta which accumulates in characteristic plaques in the brains of AD patients begins when the amyloid precursor protein (APP) is cut into smaller proteins by enzymes called secretases. (seniorjournal.com)
  • A leading strategy for preventing the formation of beta-amyloid is the use of drugs that inhibit the enzymes that produce it. (actionalz.org)
  • Beta-amyloid is produced from a parent protein, amyloid precursor protein (APP), by the cutting activity of enzymes known as secretases. (actionalz.org)
  • Secretases are made up of three main subclasses of protease enzymes: α, β, and γ. (biovision.com)
  • Secretases are enzymes that "snip" pieces off a longer protein that is embedded in the cell membrane. (wikipedia.org)
  • Alzheimer's disease (AD), the prevalent neurodegenerative disorder in humans later in life ( Hedera and Turner, 2002 ), is a multifactorial syndrome linked to abnormal metabolism of the transmembrane protein, amyloid-β precursor protein (APP) ( Selkoe, 2001 ). (jneurosci.org)
  • Pavlov PF, Wiehager B, Sakai J, Frykman S, Behbahani H, Winblad B, Ankarcrona M . Mitochondrial γ-secretase participates in the metabolism of mitochondria-associated amyloid precursor protein . (alzforum.org)
  • Overall, our data presents for the first time that PPIs can affect amyloid metabolism, both in vitro and in vivo. (jove.com)
  • Thus in patients, it is anticipated that inhibitors blocking BACE1 could prevent the build up of amyloid-beta plaques and help slow or stop the progression of disease. (biospace.com)
  • The secretases that cleave these membrane proteins share several properties including upregulation by phorbol esters and muscarinic agonists, and inhibition by hydroxamate-based zinc metalloprotease inhibitors such as batimastat. (biologists.org)
  • The identity of γ-secretase with presenilins, or with protein complexes involving presenilins, has been recently suggested ( Wolfe and Haass, 2001 ). (biologists.org)
  • Presenilins also have additional non-catalytic roles in other cellular signaling processes, including calcium homeostasis, lysosomal acidification, autophagy, and protein trafficking. (wikipedia.org)
  • The extracellular deposits known as neuritic plaques, a typical neuropathological feature in AD brains, contain large amounts of amyloid-β peptide (Aβ), which is generated from APP by two endoproteolytic cleavages ( Sisodia and St George-Hyslop, 2002 ). (jneurosci.org)
  • Amyloid deposits were successfully subtyped as AL-λ, ATTR, AL-κ and ApoAⅠby IHC in the former two groups with the sensitivity of 11/19. (bireme.br)
  • In the third group, amyloid deposits could not be subtyped by immunohistochemistry due to their poor specificity. (bireme.br)
  • Amyloid deposits can be reliably subtyped in diagnostic cardiac specimens using IHC. (bireme.br)
  • The dissociated tau protein becomes tangled and deposits inside the cell. (google.com)
  • Although the underlying mechanisms are not yet clear, several studies have provided evidence for the involvement of cholesterol-rich lipid rafts in the production of amyloid beta peptide (Abeta), the major component of amyloid deposits in AD. (jove.com)
  • 2. Amyloid deposits in the cortical vessels of the affected region. (termedia.pl)
  • Alzheimer's disease is characterized by the deposits of the 4-kDa amyloid β peptide (Aβ). (elsevier.com)
  • p53, ZNF237 and Chromodomain helicase DNA-binding protein 3 which are repressors of PS1 transcription, also reduced Ca²⁺ leak across ER membrane in SK-N-SH cells but γ-secretase inhibitor or dominant negative γ-secretase-specific PS1 mutant (PS1-D257A) had no significant effect. (nih.gov)
  • Amyloid precursor protein is part of the cell membrane that encases every nerve cell. (healthcentral.com)
  • Despite the fact that ACE is expressed as a type I integral membrane protein, a soluble form of the enzyme exists in plasma and other body fluids ( Hooper, 1991 ). (biologists.org)
  • The resulting low-density, detergent-insoluble membrane fraction is enriched not only in cholesterol and glycosphingolipids but also in certain proteins, including multiple glycosylphosphatidylinositol (GPI)-anchored proteins ( Hooper and Turner, 1988 ). (biologists.org)
  • The samples were eluted with RapiGest (a detergent which is suitable for tryptic digestion of membrane proteins) supplemented with reducing agent, the SA beads were removed, and the samples were incubated with trypsin at 37°C overnight. (nih.gov)
  • Genetic ablation of GDE2 phenocopies increased membrane RECK in AD, which is causal for reduced sAPPα, increased Aβ, and synaptic protein loss. (sciencemag.org)
  • Such protein receptors span a cells outer membrane, enabling external biochemical messages to penetrate cells. (bio-medicine.org)
  • The human cellular prion protein (PrP C ) is a glycosylphosphatidylinositol (GPI) anchored membrane glycoprotein with two N-glycosylation sites at residues 181 and 197. (mdpi.com)
  • Cholesterol is a major component of the lipid bilayer membrane, where β- and γ-secretases are located. (rupress.org)
  • Flotillin and epidermal surface antigen define a new family of caveolae-assofiated integral membrane proteins. (nature.com)
  • Aβ is a fragment of a transmembrane protein that penetrates through the neuron 's membrane, the amyloid precursor protein (APP). (scholarpedia.org)
  • Amyloid β protein precursor A membrane-spanning glycoprotein of unknown function, which is expressed in many mammalian tissues, the gene for which maps to chromosome 21. (thefreedictionary.com)
  • Abnormal phosphorylation of amyloid-β precursor protein (APP) is a pathologic feature of Alzheimer's disease. (jneurosci.org)
  • Senescence-accelerated mice (SAMP8) serve as a model for Alzheimer's disease (AD) as they exhibit early loss of memory and increased amyloid precursor protein (APP) expression. (biologists.org)
  • The inhibition of BACE - an enzyme involved in the formation of amyloid-beta plaques which accumulate in the brains of patients with Alzheimer's disease - offers the potential to slow or even halt disease progression. (biospace.com)
  • The amyloid-beta peptide is the major component of such plaques and is considered to be the major culprit in the pathogenesis of Alzheimer's disease. (biospace.com)
  • Amyloid precursor protein (APP) is a type I transmembrane protein associated with the pathogenesis of Alzheimer's disease (AD). (jove.com)
  • The amyloid precursor protein (APP) plays a central role in Alzheimer's disease, but its actions in normal development are not well understood. (biologists.org)
  • Amyloid precursor protein (APP) is a transmembrane protein that plays a key role in Alzheimer's disease. (biologists.org)
  • Ordered assembly of the amyloid-β protein (Aβ) into amyloid fibrils is a critical step in Alzheimer's disease (AD). (nature.com)
  • Amyloid precursor protein (APP) is cleaved by β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) to produce β-amyloid (Aβ), a critical pathogenic peptide in Alzheimer's disease (AD). (sigmaaldrich.com)
  • Whether elevated β-secretase (BACE) activity is related to plaque formation or amyloid β peptide (Aβ) production in Alzheimer's disease (AD) brains remains inconclusive. (elsevier.com)
  • under pathological conditions, the β-amyloid peptide, generated by β- andγ -secretase activities, accumulates in the senile plaques typical of Alzheimer's disease. (biologists.org)
  • G. G. Glenner and C. W. Wong, "Alzheimer's Disease: Initial Report of the Purification and Characterization of a Novel Cerebro-Vascular Amyloid Peptide," Biochemical and Biophysical Research Communications, Vol. 120, 1984, pp. 885-890. (scirp.org)
  • J. Kang and B. Müller-Hill, "Differential Splicing of Alzheimer's Disease Amyloid A4 Precursor RNA in Rat Tissues," Nature, Vol. 325, 1987, pp. 733-736. (scirp.org)
  • T. E. Golde, S. Estus, M. Usiak, L. H. Younkin and S. G. Younkin, "Expression of B Amyloid Protein Precursor mRNAs: Recognition of a Novel Alternatively Spliced Form and Quantitation in Alzheimer's Disease Using PCR," Neuron, Vol. 4, 1990, pp. 253-267. (scirp.org)
  • Both active and passive immunotherapy protocols decrease insoluble amyloid-ß42 (Aß42) peptide in animal models, suggesting potential therapeutic applications against the main pathological trigger in Alzheimer's disease (AD). (sdbonline.org)
  • See Alzheimer's disease , β-amyloid. (thefreedictionary.com)
  • Because beta-amyloid appears to play a key role in Alzheimer's disease, numerous therapeutic strategies have been proposed that involve removal of beta-amyloid or prevention of its formation. (actionalz.org)
  • All three groups of secretases play a pivotal role in the processing of Amyloid proteins thereby cementing their importance in the development and progression of Alzheimer's disease (AD). (biovision.com)
  • To determine whether induction of endogenous CerS1 is important in mediating mitochondrial tension signaling, we treated UM-SCC-22A cells using the known tension inducer, SoSe (5 M, 3 hours), and assessed its results on CerS1 mRNA/protein LY2109761 enzyme inhibitor great quantity, mitophagy, and cell loss of life. (antibodyassay.com)
  • We exposed APP-PS1-HEK293 cells to ICT to investigate its effect on beta-site amyloid cleaving enzyme (BACE)1. (peerj.com)
  • What does this gene/protein do? (cancerindex.org)
  • What pathways are this gene/protein implicaed in? (cancerindex.org)
  • In addition, it has been shown that amyloid-beta-associated memory deficits, which occur in mutant mice overexpressing APP, are prevented when the BACE1 gene is deleted. (biospace.com)
  • The targeted App gene encodes amyloid beta precursor protein, a transmembrane cell surface receptor that is cleaved by secretases. (jax.org)
  • The targeted Trem2 gene encodes a protein that is part of a receptor signaling complex with TYRO protein tyrosine kinase binding protein, and that activates macrophages and dendritic cells during immune responses. (jax.org)
  • The CGG expansion is associated with hypermethylation of the surrounding DNA, chromatin condensation, and subsequent transcriptional silencing of the fmr-1 gene, resulting in the loss of expression of fragile X mental retardation protein (FMRP) [ 7 ]. (pubmedcentralcanada.ca)
  • MP were characterized by flow cytometry, and MP content was assayed using gene and protein markers for pro-inflammatory mediators. (biomedcentral.com)
  • SIRT1 suppresses β-amyloid production by activating the α-secretase gene ADAM10. (sciencemag.org)
  • Pharmacologically inhibiting PKCα or deleting the gene encoding it prevented amyloid-β from impairing synaptic activity in hippocampal tissue slices from mice. (sciencemag.org)
  • Through whole-genome sequencing of 1345 individuals from 410 families with late-onset AD (LOAD), we identified three highly penetrant variants in PRKCA , the gene that encodes protein kinase Cα (PKCα), in five of the families. (sciencemag.org)
  • A disintegrin and metalloprotease 10 (ADAM10) is the α-secretase for amyloid precursor protein (APP). (sciencemag.org)
  • The sirtuins are NAD + -dependent deacetylase proteins that enhance longevity and have neuroprotective properties, but the role of sirtuins in AD and ADAM10 regulation was unknown. (sciencemag.org)
  • A disintegrin and metalloprotease 10 (ADAM10) is a ubiquitously expressed transmembrane protein which is essential for embryonic development through activation of Notch proteins. (portlandpress.com)
  • We propose that ADAM10 should now be regarded as six different scissor proteins depending on the interacting TspanC8. (portlandpress.com)
  • Western blotting and immunofluorescence confirmed that protein expression of ADAM10, BACE1 and PS1 showed the same trend. (peerj.com)
  • Three secretase subtypes referred to as alpha, beta, and gamma have been identified based upon the region of amyloid protein precursor they cleave. (curehunter.com)
  • secretases cleave the respective N- and C-terminal ends of the Aß sequence, liberating the Aß peptide from APP. (perkinelmer.com)
  • α- Secretases cleave the amyloid precursor protein (APP) within its transmembrane region generating non-amyloidogenic APP (default normal processing of APP). (biovision.com)
  • Their main component is beta-amyloid, a protein fragment that breaks off from a larger molecule called the amyloid precursor protein. (healthcentral.com)
  • The major culprit in the occurrence of AD is a short protein fragment called amyloid-beta peptide, or A-beta for short. (healthcanal.com)
  • The primary component of these plaques is the protein fragment beta-amyloid, which has toxic effects on nerve cells. (actionalz.org)
  • One strategy for removal of beta-amyloid involves the use of antibodies that recognize the protein fragment and target it for removal by the immune system. (actionalz.org)
  • The Aβ protein precursor (APP) is cleaved by β-secretase to generate a C-terminal fragment, CTFβ, which in turn is cleaved by γ-secretase to generate Aβ. (elsevier.com)
  • The plaques are predominantly composed of beta-amyloid (Aβ), a 39-42 amino acid peptide cleaved from the amyloid precursor protein (APP). (pubmedcentralcanada.ca)
  • Namely, both experimental and theoretical thermodynamic stabilities of a series of amyloid fibrils proteins revealed that this structural form is likely to be the most stable one, a stability that can be acquired even under physiological conditions. (degruyter.com)
  • One of the main pathological hallmarks of AD is the aggregation of a small peptide, called amyloid-β (Aβ), as senile plaques in the brains of affected individuals [ 1 , 2 ]. (mdpi.com)
  • The original pathological importance ascribed to amyloid plaques was weakened, if not eliminated based on information gathered in transgenic models expressing mutant APP. (hindawi.com)
  • A total of 119 bioactive ingredients from XFZYD were predicted to act on 47 TBI associated specific proteins which intervened in several crucial pathological processes including apoptosis, inflammation, antioxidant, and axon genesis. (hindawi.com)
  • This review provides a thorough description of several factors involved in the development of the pathological changes associated with AD, such as neuroinflammatory oxidative stress and methylation, apoptosis, NFTs, amyloid plaques, and cerebrospinal fluid biomarkers. (primarypsychiatry.com)
  • This study suggests that PKCα variants mediate the pathological effects of amyloid-β in some patients with late-onset AD. (sciencemag.org)
  • Controversial experimental data leave nevertheless many questions open with regards to the exact composition and size of the amyloid oligomers in vivo [ 3 - 5 ]. (hindawi.com)
  • A variety of amyloid diseases begin as benign amyloid-β monomer fibril proteins which then develop into toxic amyloid dimers/oligomers ( 15 ). (degruyter.com)
  • Bri23 peptide prevents aggregation of APP amyloid-beta protein 42 into toxic oligomers. (uniprot.org)
  • Endopeptidases that are specific for AMYLOID PROTEIN PRECURSOR. (curehunter.com)
  • We found that SNX4 protein levels changed in the brains of patients with AD and of AD model mice. (sigmaaldrich.com)
  • AβPP is the source of the amyloid-β (Aβ) peptide enriched in the brains of people with fAD or the more common, late onset, sporadic form of AD, sAD. (iospress.com)
  • We now confirm the presence of spherulites in human brains and that they are composed of β sheets of amyloid. (j-alz.com)
  • The AlphaLISA ® Mouse/Rat Amyloid beta (Aß 1-40) Detection Kit is designed for detection and quantitation of mouse or rat Aß 1-40 in serum, cerebrospinal fluid (CSF), buffered solution or cell culture medium in a homogeneous (no-wash steps, no separation steps) assay. (perkinelmer.com)
  • OBJECTIVE: Here, we assess the association of cerebrospinal fluid (CSF) BACE1 activity with multiple sclerosis (MS). METHODS: BACE1 activity and levels of secreted amyloid precursor protein (APP) and amyloid-beta (Abeta) isoforms were analyzed in CSF from 100 patients with MS and 114 neurologically healthy controls. (gu.se)
  • BACE1 activity correlated with the different amyloid markers in all study groups. (gu.se)
  • Amyloid Precursor Protein Secretases" is a descriptor in the National Library of Medicine's controlled vocabulary thesaurus, MeSH (Medical Subject Headings) . (ucdenver.edu)
  • Most examples of molecular mimicry in medicine have involved homologies of primary protein structure which cause disease. (iospress.com)
  • Our data support a growing consensus that FMRP binds to guanine-rich domains of some dendritic mRNAs, suppressing their translation and suggest that AD (neurodegenerative disorder) and FXS (neurodevelopmental disorder) may share a common molecular pathway leading to the overproduction of APP and its protein-cleaving derivatives. (pubmedcentralcanada.ca)
  • Investigating appropriate molecular and chemical methods for ingredient identity testing of plant-based protein powder dietary supplements. (nih.gov)
  • The non-redundant system of the nematode will prove useful for studying the basic biology of the Fe65-APP interaction and the molecular events regulated by this evolutionarily conserved system of interacting proteins. (biologists.org)
  • The common modular structure of the Fe65s, composed of a WW domain and two independent phosphotyrosine-binding domains (PTB), PTB1 and PTB2, suggests the function of molecular adaptors for these proteins. (biologists.org)
  • A-beta is produced in the nerve cells from the amyloid precursor protein (APP), a larger protein that is cut into pieces by molecular scissors (secretases). (healthcanal.com)
  • Amyloid Beta is a derivative of the Amyloid Precursor Protein (APP), which is a protein that is believed to modulate neuronal excitability, synaptic plasticity, synaptogenesis, and neurite outgrowth. (google.com)
  • IHC was performed with monoclonal antibodies against AA amyloid and polyclonal antibodies against transthyretin (ATTR), λ-light chain (AL-λ), κ-light chain (AL-κ), ApoAⅠ, ApoAⅡ, ApoA Ⅳ and (2)-microglobin. (bireme.br)
  • Furthermore, this strategy will not prevent the formation of new amyloid plaques unless the antibodies are administered regularly. (actionalz.org)
  • The activity of α-secretases has been implicated in the regulation of learning and memory, maturation of MHC class I proteins etc. β-Secretases are aspartic-acid proteases involved in the formation of myelin sheaths in peripheral nerve cells. (biovision.com)
  • Fragile X mental retardation protein (FMRP) is a cytoplasmic mRNA binding protein whose expression is lost in fragile X syndrome. (pubmedcentralcanada.ca)
  • We found that both BACE mRNA and protein expression is elevated in vivo in the frontal cortex. (elsevier.com)
  • Moreover, we found few changes of BACE protein and mRNA levels in Swedish mutated amyloid precursor protein-transfected cells. (elsevier.com)
  • Effects of ICT on the mRNA expression of APP were assessed by quantitative polymerase chain reaction, and protein expression was measured by western blotting and immunofluorescence. (peerj.com)
  • S. S. Sisodia, E. H. Koo, P. N. Hoffman, G. Perry and D. L. Price, "Identification and Transport of Full-Length Amyloid Precursor Proteins in Rat Peripheral Nervous System," Journal of Neuroscience, Vol. 13, 1993, pp. 3136-3142. (scirp.org)
  • The array of synaptic proteins is complex and the mechanisms underlying excitatory synaptic transmission are finely tuned by synaptic activity. (nature.com)
  • In AD, the dysregulation of the amyloid-beta (Aβ) level leads to the appearance of senile plaques which contain Aβ depositions. (karger.com)
  • We evaluate the hypothesis that antioxidants, enrichment, or the combination intervention reduces age-related beta-amyloid (Abeta) neuropathology, as one mechanism mediating observed functional improvements. (nih.gov)
  • Measures assessed were Abeta neuropathology in plaques, biochemically extractable Abeta(40) and Abeta(42) species, soluble oligomeric forms of Abeta, and various proteins in the beta-amyloid precursor protein (APP) processing pathway. (nih.gov)
  • The App-201 isoform (695 aa protein) is encoded by 16 exons, of which the Abeta sequence is encoded by exon 14. (jax.org)
  • The App-206 isoform (770 aa protein) is encoded by 18 exons, of which the Abeta sequence is encoded by exon 16. (jax.org)
  • The production of Aβ and of other AβPP catabolites depends on the spatial and temporal co-localization of AβPP with α- or β-secretases and γ-secretase, which … traffic through the secretory pathway in a highly regulated manner. (iospress.com)
  • Investigators hope that blocking beta-secretase activity might prevent production of this undesirable form of beta-amyloid, and experiments are currently under way to test this hypothesis. (healthcentral.com)
  • Whereas a wild-type structure of substrate-bound γ-secretase became recently available from cryogenic electron microscopy (6IYC), the structure and dynamics of mutant proteins remain obscure. (dtu.dk)
  • Mature BRI2 (mBRI2) functions as a modulator of the amyloid-beta A4 precursor protein (APP) processing leading to a strong reduction in the secretion of secretase-processed amyloid-beta protein 40 and amyloid-beta protein 42. (uniprot.org)
  • Proteins of the tetraspanin family modulate Aβ production by interacting to γ-secretase. (springermedizin.de)
  • A growing number of additional proteins cleaved by PS/γ-secretase continue to be discovered. (j-alz.com)
  • Then we summarize the typical features of PS/g-secretase-mediated protein processing. (j-alz.com)
  • This approach will utilize a short-term treatment with an anti-beta-amyloid antibody to remove existing plaques, in combination with long-term treatment using a drug to inhibit secretase activity. (actionalz.org)
  • We have recently demonstrated that bis(7)-Cognitin, a promising multifunctional anti-Alzheimer's dimer, can remarkably reduce the generation of amyloid β peptide (Aβ) by inhibiting β-secretase (BACE-1) and activating α-secretase activity. (elsevier.com)
  • If alpha-secretase (α-secretase) acts on APP first instead of BACE, no amyloid beta is formed because α-secretase recognizes a target protein sequence closer to the cell surface than BACE. (wikipedia.org)
  • Because of their high lipid-to-protein ratio, the detergent-insoluble rafts float to a low density during buoyant sucrose density gradient centrifugation in the presence of Triton X-100. (biologists.org)
  • This study shows that scFvs against the N- and C-terminus of Aß42 (scFv9 and scFV42.2, respectively) that decrease insoluble Aß42 in CRND mice are neuroprotective in Drosophila models of Aß42 and amyloid precursor protein neurotoxicity. (sdbonline.org)
  • Yusa S-I, Oliveira-Martins JB, Sugita-Konishi Y, Kikuchi Y. Cellular Prion Protein: From Physiology to Pathology. (mdpi.com)
  • During maturation through the secretory pathway, APP can be cleaved by proteases termed α, β, and γ-secretases 1 . (jove.com)
  • A protein signaling pathway recently. (bio-medicine.org)
  • A protein signaling pathway recently discovered to guide the formation. (bio-medicine.org)
  • A protein signaling pathway recently discovered to guide the formation of the skeleton in the fetus also keeps bones strong through adult life, according to two papers published recently in the journal Nature Medicine. (bio-medicine.org)
  • In addition, evidence indicates that cGMP/protein kinase G (PKG) pathway is involved in the modulation of glial cell activity. (intechopen.com)
  • Immunogen: This antibody is reactive to residues 17-24 of Beta-Amyloid. (anaspec.com)
  • Injection of the beta-amyloid (A-beta) peptide into rats resulted in learning developmental abilities. (theflow.org)
  • Cellular Actions of Beta-amyloid Precursor Protein and Its Soluble and Fibrillogenic Derivatives. (google.com)
  • The amyloid hypothesis (Hardy & Selkoe, 2002) proposes that extracellular beta-amyloid (Aβ) plaques are the fundamental cause of the disease. (scholarpedia.org)
  • Early tests have found that this strategy may successfully remove beta-amyloid, but it may cause some intolerable side effects. (actionalz.org)
  • Drugs that inhibit the secretases prevent the formation of beta-amyloid. (actionalz.org)
  • The total amount of amyloid protein is decreased, but the proportion of 42-amino-acid beta amyloid, long thought to be the dangerous species, is increased. (sciencemag.org)
  • The templating mechanism appears to be general in that a different amyloid formed by (Orn)V(Orn)V(Orn)V(Orn)V-NH and Ac-VDVDVDVDV-NH is regioselective and stereoselective for N-terminal, L-amino-acid addition while the ornithine-valine peptide alone yields predominantly sidechain condensation products with little stereoselectivity. (bireme.br)
  • RECK reduction restores the balance of APP processing and rescues synaptic protein deficits. (sciencemag.org)
  • Cell development and function are regulated by cell surface receptors and secreted proteins that co-ordinate intra- and intercellular signalling. (portlandpress.com)
  • Familial (hereditary) and sporadic types of cerebral amyloid angio-pathy have been distinguished to date. (termedia.pl)
  • We also found that JNK-interacting protein-3 (JIP-3), a JNK scaffolding protein that does not directly interact with APP, facilitates this phosphorylation and induces neurite elongation. (jneurosci.org)
  • By inhibiting HMGCoA, then, statins might ultimately reduce ROCK-mediated protein phosphorylation. (alzforum.org)
  • Phosphorylation of proteins by GSK-3 can result in their targeting to the proteasome and subsequent degradation. (theflow.org)
  • Inhibition of basal c-jun-NH2-terminal kinase (JNK) activity by JNK inhibitor SP600125 repressed PS1 transcription and PS1 protein expression by augmenting p53 protein level in SK-N-SH cells (Lee and Das 2008). (nih.gov)
  • In both cell types, GPI-ACE, but not WT-ACE, was sequestered in caveolin or flotillin-enriched lipid rafts and was released from the cell surface by treatment with phosphatidylinositol-specific phospholipase C. When cells were treated with activators of the protein kinase C signalling cascade (phorbol myristate acetate or carbachol) the shedding of GPI-ACE was stimulated to a similar extent to that of WT-ACE. (biologists.org)
  • These data clearly show that the protein kinase C-stimulated shedding of ACE does not require the transmembrane or cytosolic regions of the protein, and that sequestration in lipid rafts does not regulate the shedding of the protein. (biologists.org)
  • Furthermore, bis(7)-Cognitin (0.1-3 μM) significantly increased protein kinase C (PKC) activity in cells and in vitro in a concentration-dependent manner. (elsevier.com)