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.Amyloid beta-Protein Precursor: 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.Aspartic Acid Endopeptidases: A sub-subclass of endopeptidases that depend on an ASPARTIC ACID residue for their activity.Amyloid beta-Peptides: 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.Alzheimer Disease: 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)Amyloid: 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.Endopeptidases: A subclass of PEPTIDE HYDROLASES that catalyze the internal cleavage of PEPTIDES or PROTEINS.Presenilin-1: 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.Plaque, Amyloid: Accumulations of extracellularly deposited AMYLOID FIBRILS within tissues.Protein PrecursorsMice, Transgenic: Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN.Protease Nexins: Extracellular protease inhibitors that are secreted from FIBROBLASTS. They form a covalent complex with SERINE PROTEASES and can mediate their cellular internalization and degradation.Serum Amyloid A Protein: 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.Peptide Fragments: Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques.Brain: 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.Presenilin-2: 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.Neurons: 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.Protein Processing, Post-Translational: 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.Amyloidosis: 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.Cerebral Amyloid Angiopathy: 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)Presenilins: 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.Molecular Sequence Data: 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.Amino Acid Sequence: 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.tau Proteins: 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).Protein Structure, Tertiary: 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.Membrane Proteins: 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.Nerve Tissue ProteinsAmyloidogenic Proteins: 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.Mutation: 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.Disease Models, Animal: 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.Amyloid Neuropathies: 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)Hippocampus: 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.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Cells, Cultured: 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.Islet Amyloid Polypeptide: 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.Cerebral Cortex: 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.LDL-Receptor Related Proteins: A family of proteins that share sequence similarity with the low density lipoprotein receptor (RECEPTORS, LDL).Protein Transport: 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.Protein Binding: 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.Mice, Inbred C57BLTransfection: 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.Maze Learning: 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)Proteolysis: 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.Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents.CHO Cells: 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.Blotting, Western: 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.Cricetinae: A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.Neurofibrillary Tangles: 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.Axonal Transport: 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)Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.PC12 Cells: 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.ADAM Proteins: 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.Nerve Degeneration: 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.Gene Expression Regulation: 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.Mice, Knockout: 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.Convolvulus: 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.Recombinant Proteins: Proteins prepared by recombinant DNA technology.Serum Amyloid P-Component: 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.Prions: 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.Neuroblastoma: 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)Insulysin: 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.Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (ENDOPEPTIDASES).Receptors, Notch: 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.Neurites: 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.Enzyme-Linked Immunosorbent Assay: 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.Brain Chemistry: 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, Messenger: 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.Aging: The gradual irreversible changes in structure and function of an organism that occur as a result of the passage of time.Congo Red: An acid dye used in testing for hydrochloric acid in gastric contents. It is also used histologically to test for AMYLOIDOSIS.Cell Membrane: The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells.Cricetulus: 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.Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body.Neprilysin: 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.Endosomes: Cytoplasmic vesicles formed when COATED VESICLES shed their CLATHRIN coat. Endosomes internalize macromolecules bound by receptors on the cell surface.Memory Disorders: 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 Fusion Proteins: 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.Cell Line, Tumor: A cell line derived from cultured tumor cells.Gliosis: The production of a dense fibrous network of neuroglia; includes astrocytosis, which is a proliferation of astrocytes in the area of a degenerative lesion.Models, Biological: 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.Immunoprecipitation: 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.Microglia: 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.Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.Peptides: 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.COS Cells: 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).)HEK293 Cells: A cell line generated from human embryonic kidney cells that were transformed with human adenovirus type 5.Dipeptides: Peptides composed of two amino acid units.Clioquinol: 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.Astrocytes: 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.Gene Expression: The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.Signal Transduction: 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.Alzheimer Vaccines: Vaccines or candidate vaccines used to prevent or treat ALZHEIMER DISEASE.Apolipoproteins E: 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.History, Early Modern 1451-1600: The period of history from 1451 through 1600 of the common era.Kinetics: The rate dynamics in chemical or physical systems.Enzyme Precursors: Physiologically inactive substances that can be converted to active enzymes.Neurodegenerative Diseases: 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.Biotinylation: Incorporation of biotinyl groups into molecules.Synaptophysin: 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.Time Factors: Elements of limited time intervals, contributing to particular results or situations.Prealbumin: 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.Cloning, Molecular: 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.Protein Multimerization: The assembly of the QUATERNARY PROTEIN STRUCTURE of multimeric proteins (MULTIPROTEIN COMPLEXES) from their composite PROTEIN SUBUNITS.Fursultiamin: 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, Conditioned: 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).Golgi Apparatus: 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)Protein Isoforms: Different forms of a protein that may be produced from different GENES, or from the same gene by ALTERNATIVE SPLICING.Caspase 6: 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.Down Syndrome: 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)Immunoblotting: 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.Precipitin Tests: 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.Mitochondria: 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)Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. ENDOSOMES play a central role in endocytosis.Receptors, Cell Surface: 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.Neuropil Threads: 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 beta

... 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: ... The peptides derive from the amyloid precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield A ... The gene for the amyloid precursor protein is located on chromosome 21, and accordingly people with Down syndrome have a very ...

*Amyloid precursor protein

The amyloidprecursor protein (AβPP) and all associated secretases are expressed early in development and plays a key role in ... Amyloid precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of ... Mutations in critical regions of amyloid precursor protein, including the region that generates amyloid beta (Aβ), cause ... Zheng H, Koo EH (2006). "The amyloid precursor protein: beyond amyloid". Molecular Neurodegeneration. 1 (1): 5. doi:10.1186/ ...

*Amyloid precursor protein secretase

Among other roles in the cell, secretases act on the amyloid precursor protein (APP) to cleave the protein into three fragments ... Secretases are enzymes that "snip" pieces off a longer protein that is embedded in the cell membrane. ... If α-secretase acts on APP first instead of BACE, no amyloid-β is formed because α-secretase recognizes a target protein ... BACE is a transmembrane protein with an extracellular aspartic acid protease domain. γ-secretase is actually a protein complex ...

*Alpha secretase

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. ...

*Protectin D1

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 ...

*TMEM59

... 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 ... cell surface expression and secretion of the amyloid precursor protein". J Biol Chem. 285 (27): 20664-74. doi:10.1074/jbc. ...

*Insulin-degrading enzyme

... 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 (Apr 2005). "Cytoplasmic domain of the beta-amyloid protein precursor of Alzheimer's disease: function, ...

*APLP1

... 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 ...

*Bart De Strooper

... research interest are the secretases which are proteases which cleave the amyloid peptide from the amyloid precursor protein ( ... "Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein". Nature. 391 (6665): 387-90. doi:10.1038/ ... APP). The amyloid peptide is the main constituent of the plaques in the brain in Alzheimer's Disease. Together with Christian ...

*Presenilin

... or the amyloid precursor protein (APP) can be found. The majority of these cases carry mutant presenilin genes. An important ... protein. To form Aβ, APP must be cut by two enzymes, beta secretases and gamma secretase. Presenilin is the sub-component of ... "Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and ... Gamma secretase can cut APP at several points within a small region of the protein, which results in Aβ of various lengths. The ...

*P3 peptide

... 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 ...
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.
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 ...
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 ...
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 ...
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). 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.
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 ...
Introduction of targeted therapies into oncology requires co development of a drug and its companion diagnostic to achieve clinical efficacy and minimise side effects. Given the aggressive nature of estrogen receptor alpha negative (ERa-ve) breast cancer (BrCa), novel therapeutics are needed. Gamma-secretase enzyme is a relevant target in cancer, and within it, Nicastrin (NCSTN) is amenable to therapeutic intervention using monoclonal antibodies (mAb). NCSTN gene is amplified in a some breast tumours, which correlates with high NCSTN mRNA and adversely impacts overall survival (TCGA, Nature 2012). Immunohistochemistry revealed NCSTN protein overexpression in 47.5% of BrCa (n = 1000), conferring worse prognosis in the ERα-ve cohort. NCSTN genetic depletion in triple negative BrCa cells attenuated tumor growth in vitro and in vivo, invasive capacity, mesenchymal features and cancer stem-cell propagation (Filipovic et al; Lombardo et al). We have developed and characterized anti-NCSTN mAbs in ...
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 ...
PRIMARY OBJECTIVES:. I. To determine the maximum-tolerated dose (MTD) of gamma-secretase inhibitor RO4929097 (RO4929097) when given in combination with fixed-dose Hedgehog antagonist GDC-0449 (GDC-0449) which will become the recommended dose for the phase II portion of this study. (Phase Ib) II. To assess the progression-free survival (PFS) of the combination of RO4929097 with and without GDC-0449 in two arms of patients with advanced sarcoma. (Phase II). SECONDARY OBJECTIVES:. I. To describe the tolerability and adverse event profile of daily GDC-0449 administered orally in combination with daily RO4929097 administered orally for 21 consecutive days. (Phase Ib) II. To describe the pharmacokinetics of the combination of the combination of GDC-0449 and RO4929097. (Phase Ib) III. To assess Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 overall response rates (complete and partial response [CR+PR]) for combination therapy. (Phase Ib and II) IV. To conduct pharmacodynamic studies in ...
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.. ...
It is very satisfying to see a totally independent confirmation of our work, especially when important conclusions are directly attached to it.. After we identified PS1 as essential for γ-secretase activity (De Strooper et al., 1998) we all hoped it would be a-if not the-major therapeutic target in AD.. But in 2002 we had to report that the neuron-specific knockout of PS1 did not rescue the cognitive defects of APP mice, despite the nearly complete elimination of plaque and vascular amyloid pathology in old APPxPS1(n-/-) mice (Dewachter et al., 2002). The outcome was a complete and major surprise for us, difficult to explain and impossible to get past the referees of more than one major journal…and a major blow to the therapeutic potential of γ-secretase inhibitors in AD.. We believe that, despite the criticism on the non-physiological total KO problem, the outcome of the paper of Saura et al., and of our 2002 paper, is as relevant now as it was then-and for more than one ...
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 ...
Objective To research perceptions of minority pregnant women and providers about obesity and gestational weight gain (GWG) and to explore strategies to improve management of obesity in pregnancy with an emphasis on group prenatal care. Most had to "encourage myself" and "do this for me and the baby." Providers expressed discomfort discussing GWG and difficulty finding the right words for obesity which was partially attributed to their own weight. They noted the difficulties they confronted during prenatal care including time constraints cultural myths and system issues. Providers considered a group establishing with social support an ideal environment to address health behaviors in obese women. Conclusions Culturally-tailored programs that use acceptable terms for obesity provide education regarding healthy eating and safe exercise and encourage support from social networks may be effective in addressing GWG in obese minority women. Provider training in communication skills is necessary to ...
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).
We report here a novel GGA1/3-mediated mechanism underlying BACE1 elevation following TBI. We have found that GGA3 is depleted while BACE1 levels increase in the acute phase after TBI. We have demonstrated the role of GGA3 in the regulation of BACE1 in vivo by showing that BACE1 levels are increased in the brain of GGA3-null mice and that GGA3 deletion leads to increased β-secretase activity with aging. We next asked to what extent the deletion of GGA3 affects BACE1 elevation following TBI; we found that head trauma potentiates BACE1 elevation in GGA3-null mice at 48 h after TBI. Consequently, these findings indicate that in addition to the GGA3-mediated posttranslational stabilization of BACE1, other mechanisms also contribute to BACE1 accumulation in the acute phase after injury.. In an effort to find other mechanisms responsible for the BACE1 elevation observed at 48 h after TBI, we discovered that GGA1 is depleted by caspase cleavage both in vitro following apoptosis and in vivo at 48 h ...
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 ...
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Brain, Cells, Microscopy, Confocal Microscopy, Glycoprotein, Human, Immunoblotting, Lead, Mutation, Association, Axons, Brains, Capillaries, Catalytic Subunits, Co-immunoprecipitation, Disease, Family, Fibroblast, Flow Cytometry, Gamma-secretase
How is L-beta A4 amyloid precursor protein abbreviated? L-APP stands for L-beta A4 amyloid precursor protein. L-APP is defined as L-beta A4 amyloid precursor protein rarely.
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 ...
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Reactivity: Chicken, Cow, Dog and more. Compare 59 different BACE ELISA Kits & buy the right one directly at antibodies-online.com!
The amyloid precursor protein (APP) is a large membrane protein whose C terminus projects into the extracellular space. In Alzheimers disease (AD), the APP is proteolytically cleaved at the N-terminal of ABeta by Beta-secretase (BACE) to release a ~100 kD APPsbeta protein into the extracellular space. The remaining 12 kD fragment remains membrane bound where it can be cleaved at its C-terminus by ( -secretase (presenilins) to release the insoluble Abeta peptide into the extracellular space with the ~8 kD APP C-terminal fragment (CTFbeta) remaining membrane bound. The APP is the subject of intensive investigations to determine how this protein is broken down abnormally in AD brains to give rise to Abeta, which is present in senile plaques and vessels. ...
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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.
... (APP) is a type-I transmembrane protein enriched in neuronal tissues that undergoes sequential proteolytic processing through two distinct pathways. One pathway generate non-pathogenic molecules while the other generates Amyloid β (Aβ), which accumulates resulting in neurotoxicity and is associated with Alzheimers disease. BioLegend provides an extensive collection of antibodies and reagents for the study of APP and Aβ. BioLegend develops and manufactures world-class, cutting-edge immunological reagents for biomedical research, offered at an outstanding value.
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
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 ...
In this work we assessed the role of ApoER2 in APP trafficking and processing in cells that do not express LRP1, another receptor of the LDL-R family previously described as a modulator of APP processing [64]. Our findings show that ApoER2 decreased APP internalization rate and increased the amount of APP that partitions into lipid rafts, where Aβ is produced. Interestingly, the expression of ApoER2 also significantly increased γ-secretase activity in two different cell types compared to controls. As a net result of these changes, Aβ levels were significantly increased. The effects that ApoER2 has on APP trafficking and processing might be direct, as ApoER2 and APP co-immunoprecipitate and co-localize at the cell surface of neuronal cells and are also found within the same intracellular vesicles upon internalization. Our results show that ApoER2 increases Aβ production despite elevated cell surface APP levels, due to effects on APP association with lipid rafts and γ-secretase activity. This ...
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 ...
To prove that this polypeptide indeed represents the γ‐secretase‐generated CTFγ, we treated HEK 293 cells stably transfected with swAPP with the previously described γ‐secretase inhibitor DAPT (Dovey et al., 2001). As shown in Figure 1B and C, concomitant with an increase of βAPP CTFβ and CTFα (Figure 1B, upper panel) a dose‐dependent inhibition of CTFγ generation was observed (middle panel). This was further confirmed by the immunoprecipitation of Aβ from the conditioned media of these cells, which consistent with previous results (Dovey et al., 2001) also revealed a dose‐dependent reduction of Aβ generation (Figure 1B, lower panel and C). Similar results were also obtained with N2a cells (data not shown). To further prove the PS dependence of this cleavage, we immunoprecipitated βAPP and its proteolytic fragments from cells expressing PS1 D385N. As shown previously (Steiner et al., 1999; Wolfe et al., 1999), PS1 D385N acts like a dominant‐negative mutation that inhibits ...
Identification of heparin-binding domains in the amyloid precursor protein of Alzheimers disease by deletion mutagenesis and peptide mapping
The processing of amyloid precursor protein (APP) to Aβ is an important event in the pathogenesis of Alzheimers disease (AD). Previous studies suggest that dysregulation of Wnt signaling is involved in the etiology of AD. Genetic variation in the Wnt receptor, low-density lipoprotein receptor-related 6 (LRP6), which is associated with reduced Wnt signaling has been reported as a risk factor for AD. In the present study, we found that LRP6 expression is down-regulated in AD brains. LRP6 and APP colocalized in neurons and interact with one another through their extracellular domains. LRP6 overexpression increases cell surface levels of APP and decreases Aβ production, while RNA interference of LRP6 expression increases APP endocytosis and Aβ levels. These results demonstrate that LRP6 plays an important role in the regulation of APP trafficking and processing to Aβ. Our findings suggest that rescuing LRP6-mediated Wnt signaling might be an attractive therapeutic strategy for AD.. ...
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.
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 ...
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 ...
J:98438 Huppert SS, Ilagan MX, De Strooper B, Kopan R, Analysis of Notch Function in Presomitic Mesoderm Suggests a gamma-Secretase-Independent Role for Presenilins in Somite Differentiation. Dev Cell. 2005 May;8(5):677-88 ...
DAPT (GSI-IX) is a γ-secretase inhibitor with IC50 values of 115 and 200 nM for total Aβ and Aβ42 respectively. Buy Gamma-secretase inhibitor DAPT (GSI-IX) from AbMole BioScience.
It is clear that intramembrane proteolysis regulates many biological processes. As with other intramembrane proteases such as γ‐secretase/presenilin and SPP (Martoglio and Golde, 2003; Selkoe and Schenk, 2003), rhomboids may turn out to be useful therapeutic targets (Opitz et al, 2002; Urban and Freeman, 2003). The lack of an in vitro assay for rhomboid activity has been a limiting factor in the biochemical analysis of their proteolytic mechanisms. We have now demonstrated rhomboid activity both in detergent‐solubilised membrane extracts and in a highly purified fraction. These two versions of the in vitro assay have different utilities. The activity of multiple rhomboids can be rapidly determined in TX100 membrane extracts; and in purified fractions, precise quantification of relative activities can be measured. Here we have exploited both approaches to show that diverse rhomboids have differential activities on three model substrates, and to compare the activities of a number of purified ...
Intramembrane proteolysis, Alzheimer´s disease, Parkinsons disease, type-2 diabetes, γ-secretase, signal peptide peptidase , substrate enzym interactions, TMD, DFG Verbundprojekt, Lemberg, Fluhrer, Lichtenthaler, Steiner, Langosch, Haass, Frishman, Scharnagl, Luy, Huster,
摘 要:淀粉样前体蛋白(amyloid precursor protein,APP) 是一类与阿尔茨海默氏病(Alzheimer{$39}s disease,AD)的发生、发展密切相关的I型跨膜蛋白,具有膜受体样结构,但迄今人们对APP真正的生理功能仍知之甚少。近年来研究发现,APP分子间可以进行二聚化,并且反式的二聚化作用有促进细胞黏附的功能。而APP的降解产物b-淀粉样蛋白 (b-amyloid protein, Ab) 反过来又可以加速APP的聚集,经过一系列反应,最终引发细胞凋亡。本文综述这一领域的研究进展,特别是APP的相互作用,以及这些相互作用对细胞状态和行为的影响 ...
Phosphorylation of T668 was shown to induce cis‐isomerization of proline P669, resulting in a destabilization of the helix cap T668PEE (Ramelot & Nicholson, 2001). The importance of isomerization is emphasized by the interaction of the phosphorylated APP C terminus with prolyl isomerase 1 (Pin1), which accelerates isomerization 1,000‐fold and directly influences APP processing and Aβ production (Pastorino et al, 2006). To test the importance of residue T668 for Fe65‐PTB2 binding and APP C terminus conformation, we solved the AICD/Fe65‐PTB2 structures of the T668A and T668E point mutants, which lack a polar side chain or have been thought to mimic a phospho‐threonine, respectively (supplementary Table S1 online). The two mutations in the full‐length APP have been found previously to impair Fe65 binding both in vitro and in vivo (Ando et al, 2001). In both structures, the helical cap and helix αN are destabilized, as judged from a relative increase of the temperature factors, ...
It has been previously shown that p75NTR can be cleaved by γ-secretase in sympathetic neurons in response to proapoptotic ligands, and that inhibition of this cleavage blocked NRIF nuclear entry and prevented apoptosis (Kenchappa et al., 2006). In another study, it was shown that proteolytic cleavage of p75NTR induced by MAG binding to cerebellar neurons was necessary for activation of Rho and inhibition of neurite outgrowth (Domeniconi et al., 2005). Except for these two studies, however, the significance of intramembrane proteolysis for the signaling and biological activities elicited by p75NTR remains by and large poorly understood. Despite displaying elevated, constitutive activity across several signaling pathways, the disulfide-crosslinked p75NTR mutants described in this study did not show increased levels of intramembrane cleavage compared with the wild-type receptor, either under basal conditions or after phorbol ester stimulation. This suggests that intramembrane cleavage might not ...
Data that have accumulated for well over a decade have implicated the β-amyloid (Aβ) peptide as a central player in the pathogenesis of Alzheimers disease (AD). Amyloid plaques, composed primarily of Aβ progressively form in the brains of AD patients, and mutations in three genes (amyloid precursor protein [APP] and presenilin 1 and 2 [PS1 and PS2]) cause early-onset familial AD (FAD) by directly increasing production of the toxic, plaque-promoting Aβ42 peptide. Given the strong association between Aβ and AD, it is likely that therapeutic strategies to lower the levels of Aβ in the brain should prove beneficial for the treatment of AD. One such strategy could involve inhibiting the enzymes that generate Aβ. Aβ is a product of catabolism of the large type-I membrane protein APP. Two proteases, called β- and γ-secretase, endoproteolyze APP to liberate the Aβ peptide. Recently, the molecules responsible for these proteolytic activities have been identified. Several lines of evidence ...
If the product specification or packaging standard is revised, the images and the actual product specification might be different ...
Principal Investigator:TAKAHATA Naohiko, Project Period (FY):1995 - 1996, Research Category:Grant-in-Aid for Scientific Research (C), Section:一般, Research Field:Psychiatric science
Determined that modestly reducing levels of two enzymes in the brain, BACE-1 and γ-secretase, reduced Aß accumulation and improved cognition in a mouse model of AD. BACE-1 and γ-secretase are involved in generating Aß from amyloid precursor protein and are therapeutic targets for AD. However, large reductions and/or strong inhibition of these enzymes have been associated with unfortunate side effects in animal models. Previous animal studies have demonstrated that more modest reductions in either of these proteins alone reduces side effects but provides only mild protection against accumulation of Aß. These results suggest that a combination therapy that moderately inhibits both proteins could potentially be both safe and more effective than therapies that target only one of these proteins.8 ...
Derek Lowe (below) nearly matched what Hideo Nomo did last year at Camden Yards, both in 3-0 Red Sox victories:. %%. Lowe Nomo. Date 4/5/02 4/4/01. IP 7 9. Hits 1 0. BB 3 3. Ks 1 11. NP 81 110. %% ...
BRI3 binding protein. Plays a role in tumorigenesis. BRI3 is a member of the BRI gene family that includes the familial British and Danish dementia gene BRI2. BRI3 interacts with the Amyloid Precursor Protein, APP, and serves as an endogenous negative regulator of Abeta production (Matsuda et al. 2009 ...
Apbb1 is an adapter protein that forms a transcriptiolly active complex with the gamma-secretase-derived amyloid precursor protein (APP) intracellular…
摘 要:蛋白质的N- 糖基化修饰是生物体调控蛋白质在组织和细胞中的定位、功能、活性、寿命和多样性的一种普遍的翻译后方式。N- 糖基化位点是理解糖链功能的重要前提之一。应用新的糖蛋白、糖肽富集技术和质谱技术,科学家们在不同组织中完成了对N- 糖基化位点的鉴定。此外,不同于经典三联子的N- 糖基化序列的发现使人们对N- 糖基化过程的认识向纵深发展 ...
Yes indeed, Merck announced last night that the first Phase III trial of their beta-secretase (BACE) inhibitor verubecestat was stopped because of futility. The
Mitochondrial targeting of APP under in vitro and in vivo conditions. (A, B and C) WT/APP, 3M/APP, Δ220-290/APP, P450 MT2 (+33/1A1), and P450 MT4 (2B1) prote
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The amyloid precursor protein gene (APP) and its derivative peptides have important functions in the central nervous system. APP and Aβ fulfil criteria as neuractive peptides: presence, release and identity of action. Aβ is a peptide of 1 - 43 amino acids in length, derived from APP and the major component of the core of neuritic plaques found in Alzheimers disease. Analysis of the cDNA of Aβ revealed its origins from the larger precursor protein. There are at least four types of mRNA generated by alternative splicing of exons 7 and 8. Exon 7 encodes a 57 amino acid sequence found in the extracellular domain with major homology to the Kunitz-type of serine protease inhibitors. 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. The γ secretase is a macromolecular enzyme complex composed of presenilin 1, 2 and other molecular constitutents essential for its function.
Several companies are in the early stages of development and testing of this potential class of treatment.[13][14] In March 2008 phase I results were reported for CoMentis Incs candidate CTS-21166.[15] In April 2012 Merck & Co., Inc reported phase I results for its candidate verubecestat (MK-8931).[16] Merck began a Phase II/III trial of MK-8931 in December, 2012 estimated to be completed in July 2019.[17] In February 2017, Merck halted its late-stage trial of verubecestat for mild to moderate Alzheimers disease after it was reported as having "virtually no chance" of working according to an independent panel of experts. This came just three months after Eli Lilly & Co. announced its own setback with solanezumab. The results of Mercks trial of verubecestat on patients with early stage Alzheimers are still expected in February 2019. In September 2014 AstraZeneca and Eli Lilly and Company announced an agreement to codevelop lanabecestat (AZD3293).[18] A pivotal Phase II/III clinical trial of ...
Recombinant Human Amyloid Precursor Protein Protein fragment datasheet (ab124588). Abcam offers quality products including antibodies, assays and other…
The Amyloid Precursor Protein (APP) is a transmembrane protein whose cleavage results in toxic Aß fragment identified as the major constituent in the amyloid plaques of Alzheimers Disease. Recent evidence has shown that fragments of APP including its intracellular domain are secreted into the extracellular space, possibly via the formation and release of extracellular vesicles called exosomes, which are derived from endosomes. in the Drosophila model, we have manipulated specific components of the membrane trafficking machinery predicted to be involved in APP traffic, and measured their effects on in vivo APPeGFP exosome secretion using fluorescence quantification. We targeted the Vps35, Snx1, and Snx3 components of the endosomal sorting complex called Retromer (which is implicated in Alzheimers Disease), and the GTPase Rab11 which has been implicated in exocytosis. Our results indicate that Rab11 and the Snx1 are required for exosome release while Snx3 and Vps35, perhaps working together ...
immune 7-TM Receptors, ?-secretase inhibitors, AR signaling, Bcl-2 Family, BMP inhibitors, c-MET inhibitors, CETP inhibitors, HDAC Inhibitors, IGK-1R signaling, MAPK inhibitors, MCT, mTOR Signaling, NEDD8, PARP inhibitors, PDE inhibitors, PI3K inhibitors, Potassium Channels, proteases inhibitors, Receptor Tyrosine Kinases, Uncategorized, VEGFR Inhibitor, VEGFR inhibitor, WNT AZD6244, GSK1120212, PD0325901 The recognition of BRAF and NRAS mutations in considerable quantities of melanoma patients as well as the viewing that many melanomas proved constitutive MAPK exercise, led to the creation of smaller molecule MEK inhibitors, such as PD0325901, selumetinib (AZD6244) and CI-1040 in unselected teams of melanoma patients69-71 (Physique 2). The initial scientific tests on PD0325901 demonstrated very little evidence of task, with 2 away from 27 people possessing part reactions and a more 5 people getting stable condition. On the part I trial run of AZD6244 just one BRAF mutant melanoma affected ...
Signal sequences are the addresses of proteins destined for secretion. In eukaryotic cells, they mediate targeting to the endoplasmic reticulum membrane and insertion into the translocon. Thereafter, signal sequences are cleaved from the pre-protein and liberated into the endoplasmic reticulum membrane. We have recently reported that some liberated signal peptides are further processed by the intramembrane-cleaving aspartic protease signal peptide peptidase. Cleavage in the membrane-spanning portion of the signal peptide promotes the release of signal peptide fragments from the lipid bilayer. Typical processes that include intramembrane proteolysis is the regulatory or signalling function of cleavage products. Likewise, signal peptide fragments liberated upon intramembrane cleavage may promote such post-targeting functions in the cell.. ...
Beta-amyloid production results from cleavage in the extracellular domain of APP by the beta-secretase (BACE1) , which results in the production of the APP C-terminal fragment C99. This fragment is further cleaved by the gamma-secretase at residues 40-42 to produce beta-amyloid 40 and 42 peptides. Beta-amyloid aggregation and neuritic plaque formation are pathologic hallmarks of Alzheimer disease. This peptide corresponds to the human beta-amyloid 1-40 peptide ...
Alzheimer disease: Aβ, known as the hallmark of Alzheimer disease (AD), is a fragment of amyloid precursor protein (APP) that is proteolytically cleaved by β- and γ-secretases. It was reported that β-secretase cleaves APP in early endosomes, and that Aβ is subsequently sorted into MVBs [61]. Further, APP and β- and γ-secretases were detected in exosomes derived from neuronal cells [62,63]. In clinical studies, both APP and Aβ have been shown to circulate in the CSF and plasma of human AD patients [64-66]. In addition, exosomal Aβ was found to be colocalized with other exosome markers in amyloid plaques in the brains of AD mice and in the postmortem brains of AD patients, suggesting that exosomes may be involved in the pathogenesis of AD [62,67,68]. In Aβ plaques, the aggregation of tau leading to neurofibrillary tangles has been reported to be a pathological feature of AD. in vitro studies have shown that tau secretion can be mediated by exosomes [65,69]. The uptake of tissue ...
The PRESENILIN1 and PRESENILIN2 genes encode structurally related proteases essential for ?-secretase activity. Of nearly 200 PRESENILIN mutations causing early onset, familial Alzheimers disease (FAD) only the K115Efx10 mutation of PSEN2 causes truncation of the open reading frame. If translated, the truncated product would resemble a naturally occurring isoform of PSEN2 named PS2V that is induced by hypoxia and found at elevated levels in late onset Alzheimers disease (AD) brains. The function of PS2V is largely unexplored. We show that zebrafish possess a PS2V-like isoform, PS1IV, produced from the fishs PSEN1 rather than PSEN2 orthologous gene. The molecular mechanism controlling formation of PS2V/PS1IV was probably present in the ancient common ancestor of the PSEN1 and PSEN2 genes. Human PS2V and zebrafish PS1IV have highly divergent structures but conserved abilities to stimulate ?-secretase activity and to suppress the unfolded protein response (UPR) under hypoxia. The putative ...
Reducing production of amyloid-β (Aβ) peptide by direct inhibition of the enzymes that process amyloid precursor protein (APP) is a central therapeutic strategy for treating Alzheimers disease. However, small-molecule inhibitors of the β-secretase (BACE1) and γ-secretase APP processing enzymes have shown a lack of target selectivity and poor penetrance of the blood-brain barrier (BBB). Here, we have developed a high-affinity, phage-derived human antibody that targets BACE1 (anti-BACE1) and is anti-amyloidogenic. Anti-BACE1 reduces endogenous BACE1 activity and Aβ production in human cell lines expressing APP and in cultured primary neurons. Anti-BACE1 is highly selective and does not inhibit the related enzymes BACE2 or cathepsin D. Competitive binding assays and x-ray crystallography indicate that anti-BACE1 binds noncompetitively to an exosite on BACE1 and not to the catalytic site. Systemic dosing of mice and nonhuman primates with anti-BACE1 resulted in sustained reductions in ...
Dysfunction and loss of synapses are early pathogenic events in Alzheimers disease (AD). A central step in the generation of toxic amyloid-β (Aβ) peptides is the cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme (BACE1). Here, we have elucidated whether down-regulation of septin (SEPT) protein family members, which are implicated in synaptic plasticity and vesicular trafficking, affects APP processing and Aβ generation. SEPT8 was found to reduce soluble APPβ and Aβ levels in neuronal cells via a post-translational mechanism leading to the decreased levels of BACE1 protein. In human temporal cortex, we identified alterations in the expression of specific SEPT8 transcript variants in relation to AD-related neurofibrillary pathology. These changes associated with altered β-secretase activity. We also discovered that the overexpression of a specific AD-associated SEPT8 transcript variant increased the levels of BACE1 and Aβ in neuronal cells. These changes were ...
Purpose: Death of retinal ganglion cells (RGCs) is one of the key pathogenic features of glaucoma. The accumulation of amyloid beta (Aβ) may contribute to the RGC death. Olfactomedin 1 (Olfm1), also known as noelin and pancortin, is a secreted glycoprotein highly conserved in vertebrates. Olfm1 belongs to the family of olfactomedin domain-containing proteins, and is expressed both in the retina and brain. Available data suggest that Olfm1 may interact with amyloid precursor protein (APP), suppress its cleavage, and inhibit the subsequent production of Aβ. The mechanisms of APP cleavage inhibition by Olfm1 are unknown. Here, we investigated these mechanisms.. Methods: Primary RGS cultures were established using an immunopanning method from 1 to 5 day-old mice. Interactions between Olfm1 and putative Olfm1 binding proteins were investigated with an alkaline phosphatase fusion protein assay, as well as a co-immunoprecipitation assay using lysates of HEK293 cells transfected with corresponding ...
BioAssay record AID 144358 submitted by ChEMBL: Compound was tested for the inhibition of 1-40 beta-Amyloid Production in N9 cell line expressing beta-APP (wascreated by transfecting the human cDNA encoding beta-APP 695) by using immunoprecipitation assay.
In this study we analysed the influence of the Amyloid precursor protein (APP) interacting proteins on APP function, trafficking and processing in neuronal cells. Firstly, we examined the proposed interaction of APP, APLP1 and APLP2 with conventional kinesin. Previous studies reported that the cytoplasmic domain of APP exhibits high affinity binding with kinesin light chain (KLC). In context of this research project we provide evidence from GST-pull down analyses and co-immunoprecipitation studies that KLC does not interact directly with the cytoplasmic tail of APP, APLP1 or APLP2. Further, quantitative confocal analyses revealed that mutant APP lacking the APP intracellular domain were sorted, similar to wildtyp APP, to both, axons and dendrites. Thus, the intracellular domain and cytosolic interaction partners of APP/APLPs are not essential to mediate polarized transport in neurons. As the sorting of APP and APLP2 depend in non neuronal cells on the presence of the basolateral sorting signal ...
Looking for online definition of secretase in the Medical Dictionary? secretase explanation free. What is secretase? Meaning of secretase medical term. What does secretase mean?
Evidence from clinical studies (Wang et al., 1999; Naslund et al., 2000), in vitro experiments (Lambert et al., 1998; Hartley et al., 1999; Chromy et al., 2003), and in vivo experiments (Shin et al., 1997; Hsia et al., 1999) suggest that the initial pathogenesis of AD is due to the build up of neurotoxic aggregates of the soluble Aβ peptide species Aβ(1-40) and Aβ(1-42). As a result, a number of therapeutic approaches for lowering amyloid are in progress, one of which is the use of γ-secretase inhibitors (Hardy and Selkoe, 2002; Harrison et al., 2004b). With the advent of orally available γ-secretase inhibitors, studies in transgenic mice using these inhibitors have demonstrated reductions of Aβ levels in the brain, CSF, and plasma (Dovey et al., 2001; Lanz et al., 2003, 2004; Wong et al., 2004). However, these models have high levels of Aβ not representative of normal physiological rodent levels.. A previous study used immunoprecipitation and Western blotting to determine the effect of ...
Intramembranous proteolysis (IP) is a recently recognized mechanism for transmembrane signal transduction that involves proteolysis of transmembrane proteins within their membrane-spanning domains. Juxtamembranous proteolysis (JP) is similar, but proteolytic cleavage of a transmembrane protein occurs at a site close to, but not within, the transmembrane domain of the target protein. In both IP and JP, a soluble domain of a transmembrane protein is released from its membrane tether. This domain can then transmit a signal either locally or at some distance from the site of cleavage. In certain signaling pathways, JP and IP are linked. JP on one side of the membrane results in secondary IP, which then releases a signaling domain from the membrane. Whereas well-characterized proteases such as caspases, the proteasome, and metalloprotease disintegrins, have been implicated in JP, three families of multipass membrane proteases (MpMPs) have now been shown to carry out IP. Recent studies of events ...
Numerous transmembrane proteins, including the blood pressure regulating angiotensin converting enzyme (ACE) and the Alzheimers disease amyloid precursor protein (APP), are proteolytically shed from the plasma membrane by metalloproteases. We have used an antisense oligonucleotide (ASO) approach to delineate the role of ADAM10 and tumour necrosis factor-α converting enzyme (TACE; ADAM17) in the ectodomain shedding of ACE and APP from human SH-SY5Y cells. Although the ADAM10 ASO and TACE ASO significantly reduced (, 81%) their respective mRNA levels and reduced the α-secretase shedding of APP by 60% and 30%, respectively, neither ASO reduced the shedding of ACE. The mercurial compound 4-aminophenylmercuric acetate (APMA) stimulated the shedding of ACE but not of APP. The APMA-stimulated secretase cleaved ACE at the same Arg-Ser bond in the juxtamembrane stalk as the constitutive secretase but was more sensitive to inhibition by a hydroxamate-based compound. The APMA-activated shedding of ACE ...
Antibodies , OptimAb Antibodies , OptimAbᵀᴹ Beta-Amyloid 17-24 , Monoclonal Antibody, purified; Beta-Amyloid forms are deposited in the CNS of patients with Alzheimer s disease and Down s syndrome. 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. Both result from the cleavage of Amyloid Precursor Protein (APP) by secretases. The mAb 4G8 reacts to the abnormally processed isoforms, as well as precursor forms.; Host:Mouse
Clone: 4G8
Isotype: IgG2b
Reactivity: Human, Mouse
Immunogen: This antibody is reactive to residues 17-24 of Beta-Amyloid. The epitope lies within amino acids 18-22 of Beta-Amyloid (VFFAE)
Concentration:1 mg/mL
Formulation:PBS (no preservatives); The Ab was purified on Protein G
Applications:The Ab is effective in immunoblotting (WB),
Insoluble beta-amyloid deposits in Alzheimers disease (AD) brain are proteolytically derived from the membrane bound amyloid precursor protein (APP). The APP gene is differentially spliced to produce isoforms that can be classified into those containing a Kunitz-type serine protease inhibitor domain (K(+), APP(751), APP(770), APRP(365) and APRP(563)), and those without (K(-), APP(695) and APP(714)). Given the hypothesis that Abeta is a result of aberrant catabolism of APP, differential expression of mRNA isoforms containing protease inhibitors might play an active role in the pathology of AD. We took 513 cerebral cortex samples from 90 AD and 81 control brains and quantified the mRNA isoforms of APP with TaqMan real-time RT-PCR. After adjustment for age at death, brain pH and gender we found a change in the ratio of KPI(+) to KPI(-) mRNA isoforms of APP. Three separate probes, designed to recognise only KPI(+) mRNA species, gave increases of between 28% and 50% in AD brains relative to controls ...
There are conflicting data regarding alterations in beta-amyloid precursor protein (APP) mRNAs in Alzheimers disease (AD). This may be due partly to variables such as agonal state and choice of control group. We have used in situ hybridization histochemistry to study expression of APP mRNAs, with and without the domain encoding the Kunitz protease inhibitor, in a way that overcomes some of the limitations of the current data. Tissue from frontal cortex was collected at rapid autopsy from patients with AD or other cognitive impairments whose terminal phase was prospectively assessed. There were three main findings. Firstly, the amount of APP mRNAs correlated strongly with glutamate decarboxylase activity and was reduced in association with terminal pyrexia. These correlations suggest that agonal state affects APP mRNA and, therefore, that differences in premortem course may contribute to the varying changes in APP transcript abundance reported in AD. Secondly, a reduction of both forms of APP mRNA,
Effects of Nerve Growth Factor and Nitric Oxide Synthase Inhibitors on Amyloid Precursor Protein mRNA Levels and Protein Stability
PubMed Central Canada (PMC Canada) provides free access to a stable and permanent online digital archive of full-text, peer-reviewed health and life sciences research publications. It builds on PubMed Central (PMC), the U.S. National Institutes of Health (NIH) free digital archive of biomedical and life sciences journal literature and is a member of the broader PMC International (PMCI) network of e-repositories.
Activated microglia-mediated neuroinflammation has been regarded as an underlying key player in the pathogenesis of subarachnoid hemorrhage (SAH)-induced early brain injury (EBI). The therapeutic potential of bone marrow mesenchymal stem cells (BMSCs) transplantation has been demonstrated in several brain injury models and is thought to involve modulation of the inflammatory response. The present study investigated the salutary effects of BMSCs on EBI after SAH and the potential mechanism mediated by Notch1 signaling pathway inhibition. The Sprague-Dawley rats SAH model was induced by endovascular perforation method. BMSCs (3 × 106 cells) were transplanted intravenously into rats, and N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT), a Notch1 activation inhibitor, and Notch1 small interfering RNA (siRNA) were injected intracerebroventricularly. The effects of BMSCs on EBI were assayed by neurological score, brain water content (BWC), blood-brain barrier (BBB) permeability,

Amyloid Precursor Protein Secretases
      - beta-Secretase
     Summary Report | CureHunterAmyloid Precursor Protein Secretases - beta-Secretase Summary Report | CureHunter

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; ...
more infohttp://www.curehunter.com/public/keywordSummaryD053829-Amyloid-Precursor-Protein-Secretases-beta-Secretase.do

HES1 | Cancer Genetics WebHES1 | Cancer Genetics Web

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 ...
more infohttp://www.cancerindex.org/geneweb/HES1.htm

RG-4733 - DrugBankRG-4733 - DrugBank

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. ...
more infohttps://www.drugbank.ca/drugs/DB11870

Burns MP[au] - PubMed - NCBIBurns MP[au] - PubMed - NCBI

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. ...
more infohttps://www.ncbi.nlm.nih.gov/pubmed?cmd=search&term=Burns+MP%5Bau%5D&dispmax=50

The Disintegrin/Metalloproteinase ADAM10 Is Essential for the Establishment of the Brain Cortex | Journal of NeuroscienceThe Disintegrin/Metalloproteinase ADAM10 Is Essential for the Establishment of the Brain Cortex | Journal of Neuroscience

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- ...
more infohttps://www.jneurosci.org/content/30/14/4833?ijkey=3ce369400cd195a7c7e0e7eaa8ebbeaaf8dc1874&keytype2=tf_ipsecsha

a) Immunoblot analysis of β-catenin, cyclin D1, cycli | Open-ia) Immunoblot analysis of β-catenin, cyclin D1, cycli | Open-i

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 ...
more infohttps://openi.nlm.nih.gov/detailedresult.php?img=PMC2195782_JCB0011002.f1c&req=4

Analysis of Neurotoxic Beta Amyloid Peptides in Alzheimers DiseaseAnalysis of Neurotoxic Beta Amyloid Peptides in Alzheimer's Disease

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 ...
more infohttps://www.news-medical.net/whitepaper/20171215/Analysis-of-Neurotoxic-Beta-Amyloid-Peptides-in-Alzheimers-Disease.aspx

γ-secretase components were identified from LC-MS/MS a | Open-iγ-secretase components were identified from LC-MS/MS a | Open-i

Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism*. *Brain/enzymology*. *Membrane Proteins/metabolism* ... Bottom Line: All of the known γ-secretase components were identified.Interestingly, TMP21 and the PS associated protein ... The small volumes used in the LC-system and the high sensitivity of the mass spectrometer allow the identification of proteins ... The small volumes used in the LC-system and the high sensitivity of the mass spectrometer allow the identification of proteins ...
more infohttps://openi.nlm.nih.gov/detailedresult.php?img=PMC4373488_jcmm0014-2675-f3&req=4

Index by author - February 01, 1999, 27 (2) | Biochemical Society TransactionsIndex by author - February 01, 1999, 27 (2) | Biochemical Society Transactions

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. ...
more infohttp://www.biochemsoctrans.org/content/27/2.index-by-author

Table of Contents - February 01, 1999, 27 (2) | Biochemical Society TransactionsTable of Contents - February 01, 1999, 27 (2) | Biochemical Society Transactions

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 ...
more infohttp://www.biochemsoctrans.org/content/27/2

cleaved cell lymphoma drug therapy 2000:2010[pubdate] *count=100 - BioMedLib™ search enginecleaved cell lymphoma drug therapy 2000:2010[pubdate] *count=100 - BioMedLib™ search engine

Amyloid Precursor Protein Secretases; EC 3.4.24.- / ADAM Proteins; EC 3.4.24.81 / ADAM10 protein, human ... MeSH-major] ADAM Proteins / antagonists & inhibitors. Amyloid Precursor Protein Secretases / antagonists & inhibitors. ... MeSH-major] Amyloid Precursor Protein Secretases / physiology. Antineoplastic Combined Chemotherapy Protocols / pharmacology. ... Proto-Oncogene Proteins / analysis. Tumor Suppressor Protein p53 / analysis. bcl-2-Associated X Protein. bcl-X Protein ...
more infohttp://www.bmlsearch.com/?kwr=cleaved+cell+lymphoma+drug+therapy+2000:2010%5Bpubdate%5D&cxts=100&stmp=b1

Traumatic brain injury in aged animals increases lesion size and chronically alters microglial/macrophage classical and...Traumatic brain injury in aged animals increases lesion size and chronically alters microglial/macrophage classical and...

Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury. Nat Med. 2009b;15:377-9. [PMC free ... A time course of contusion-induced oxidative stress and synaptic proteins in cortex in a rat model of TBI. Journal of ... Microglia enhance beta-amyloid peptide-induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen ... Oxidative stress and modification of synaptic proteins in hippocampus after traumatic brain injury. Free Radic Biol Med. 2008a; ...
more infohttp://pubmedcentralcanada.ca/pmcc/articles/PMC3572914/?lang=en-ca

IJMS  | Free Full-Text | Effect of Different Phospholipids on α-Secretase Activity in the Non-Amyloidogenic Pathway of...IJMS | Free Full-Text | Effect of Different Phospholipids on α-Secretase Activity in the Non-Amyloidogenic Pathway of...

... 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 ...
more infohttp://mdpi.com/1422-0067/14/3/5879/htm

Stress and Trauma: Aβs Mysterious Role in Severe Brain Injury | ALZFORUMStress and Trauma: Aβ's Mysterious Role in Severe Brain Injury | ALZFORUM

Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury. Nat Med. 2009 Apr;15(4):377-9. PubMed. ... Caspase-3-mediated cleavage of amyloid precursor protein and formation of amyloid Beta peptide in traumatic axonal injury. J ... Marked increase of beta-amyloid(1-42) and amyloid precursor protein in ventricular cerebrospinal fluid after severe traumatic ... Expression of amyloid precursor protein after rat traumatic brain injury. Neurol Res. 2009 Feb;31(1):103-9. PubMed. ...
more infohttps://www.alzforum.org/news/research-news/stress-and-trauma-avs-mysterious-role-severe-brain-injury?id=2764

the flow - whats happening in nutritionthe flow - whats happening in nutrition

Gamma and beta secretases process amyloid precursor protein (APP) into A-beta. CUR treatment reduced the production of A-beta, ... GSK-3beta is a major kinase involved in amyloid precursor protein (APP) and tau phosphorylation. berberine inhibited GSK-3. ... Protein concentration was determined using the BCA protein assay kit. Equal amounts of protein were separated by 12% SDS-PAGE ... In C2C12 cells, REV stimulated AKT and ERK1,2 activation and AMPK protein levels. These proteins, by activating downstream ...
more infohttp://theflow.org

Fractalkine shedding is mediated by p38 and the ADAM10 protease under pro-inflammatory conditions in human astrocytes | Journal...Fractalkine shedding is mediated by p38 and the ADAM10 protease under pro-inflammatory conditions in human astrocytes | Journal...

ADAMs family members as amyloid precursor protein alpha-secretases. J Neurosci Res. 2003;74:342-52.View ArticlePubMedGoogle ... Constitutive and regulated alpha-secretase cleavage of Alzheimers amyloid precursor protein by a disintegrin metalloprotease. ... The ADAMs family of metalloproteases: multidomain proteins with multiple functions. Genes Dev. 2003;17:7-30.View ArticlePubMed ... Rapid flow arrest of CX3CR1-expressing cells is independent of G-protein activation. J Biol Chem. 1999;274:10053-8.View Article ...
more infohttps://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-016-0659-7

Microglial-derived microparticles mediate neuroinflammation after traumatic brain injury | Journal of Neuroinflammation | Full...Microglial-derived microparticles mediate neuroinflammation after traumatic brain injury | Journal of Neuroinflammation | Full...

MP were characterized by flow cytometry, and MP content was assayed using gene and protein markers for pro-inflammatory ... Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury. Nat Med. 2009;15:377-9.View Article ... Protein from cells was normalized to β-actin, and protein from MP was normalized to Ponceau-S. ... Proteins were extracted using RIPA buffer (Teknova, Hollister, CA), equalized, and loaded equally onto 5-20% gradient gels for ...
more infohttps://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-017-0819-4

burkitts lymphoma associated with aids drug 2000:2010[pubdate] *count=100 - BioMedLib™ search engineburkitt's lymphoma associated with aids drug 2000:2010[pubdate] *count=100 - BioMedLib™ search engine

Nuclear Proteins; 0 / Receptor, Notch1; 0 / latency-associated nuclear antigen; EC 3.4.- / Amyloid Precursor Protein Secretases ... MeSH-major] Amyloid Precursor Protein Secretases / antagonists & inhibitors. Dipeptides / therapeutic use. Herpesviridae ... Neoplasm Proteins / biosynthesis. Neoplasm Proteins / genetics. Neoplasm Proteins / physiology. Proto-Oncogene Proteins c-bcl-2 ... TNFRSF10A protein, human; 0 / TNFRSF10B protein, human; 0 / TNFSF10 protein, human; 0 / Tumor Necrosis Factor-alpha; 0 / bcl-X ...
more infohttp://www.bmlsearch.com/?kwr=burkitt

Neurobiological Role of MicroRNA in Alzheimers
     - Indiana University School of MedicineNeurobiological Role of MicroRNA in Alzheimer's - Indiana University School of Medicine

AD is believed to result from overproduction of amyloid-ß peptide (Aß), derived from Aß precursor protein (APP), and ... Endpoints are APP and BACE1 mRNA & proteins, and Aß peptides, which we predict to change with miRNA. Impact: Manipulation of ... Amyloid Precursor Protein Secretases Untranslated RNA Genetically Modified Animals Amyloid beta-Protein Precursor ... miRNAs are endogenous, short, non-coding RNAs that typically inhibit protein expression by interacting with specific ...
more infohttps://indiana.pure.elsevier.com/en/projects/f4cb460c-182a-4cd1-89b0-4b54933d7700

Bace1 modulates myelination in the central and peripheral nervous system<...Bace1 modulates myelination in the central and peripheral nervous system<...

Bace1 is an endopeptidase that cleaves the amyloid precursor protein at the β-secretase site. Apart from this cleavage, the ... N2 - Bace1 is an endopeptidase that cleaves the amyloid precursor protein at the β-secretase site. Apart from this cleavage, ... AB - Bace1 is an endopeptidase that cleaves the amyloid precursor protein at the β-secretase site. Apart from this cleavage, ... abstract = "Bace1 is an endopeptidase that cleaves the amyloid precursor protein at the β-secretase site. Apart from this ...
more infohttps://jhu.pure.elsevier.com/en/publications/bace1-modulates-myelination-in-the-central-and-peripheral-nervous-3

EP2461673A2 - Novel regulatory proteins and inhibitors 
        - Google PatentsEP2461673A2 - Novel regulatory proteins and inhibitors - Google Patents

... gamma secretase activating protein or gSAP) that activates y-secretase to produce β-amyloid protein (Aβ). Deposition of Aβ has ... The invention thus additionally provides, e.g., screening methods and novel research tools, inhibitors of this novel protein, ... 108010043324 Amyloid Precursor Protein Secretases Proteins 0 claims description 9 * 150000004926 Imatinib derivatives Chemical ... 102000002659 Amyloid Precursor Protein Secretases Human genes 0 claims description 8 * 241000699666 Mus ,mouse, genus, Species ...
more infohttps://patents.google.com/patent/EP2461673A2/en

Exploring Pharmacological Mechanisms of Xuefu Zhuyu Decoction in the Treatment of Traumatic Brain Injury via a Network...Exploring Pharmacological Mechanisms of Xuefu Zhuyu Decoction in the Treatment of Traumatic Brain Injury via a Network...

D. J. Loane, A. Pocivavsek, C. E.-H. Moussa et al., "Amyloid precursor protein secretases as therapeutic targets for traumatic ... β from amyloid precursor protein (APP). Aβ can cause cell death, activate inflammatory pathways [102], and prime proapoptotic ... L. Yang, X. Zhao, and X. Tang, "Predicting disease-related proteins based on clique backbone in protein-protein interaction ... HPRD is a database containing curated proteomic information pertaining to human proteins. The human protein-protein interaction ...
more infohttps://www.hindawi.com/journals/ecam/2018/8916938/

Centre for Regenerative Medicine - Research Output
     - the University of Baths research portalCentre for Regenerative Medicine - Research Output - the University of Bath's research portal

Dietary (-)-epicatechin as a potent inhibitor of βγ-secretase amyloid precursor protein processing. Cox, C. J., Choudhry, F., ... A comparison of two commercially available ELISA methods for the quantification of human plasma heat shock protein 70 during ...
more infohttps://researchportal.bath.ac.uk/en/organisations/centre-for-regenerative-medicine/publications/?page=5

SAP97-mediated ADAM10 trafficking from Golgi outposts depends on PKC phosphorylation<...SAP97-mediated ADAM10 trafficking from Golgi outposts depends on PKC phosphorylation<...

N2 - A disintegrin and metalloproteinase 10 (ADAM10) is the major α-secretase that catalyzes the amyloid precursor protein (APP ... AB - A disintegrin and metalloproteinase 10 (ADAM10) is the major α-secretase that catalyzes the amyloid precursor protein (APP ... A disintegrin and metalloproteinase 10 (ADAM10) is the major α-secretase that catalyzes the amyloid precursor protein (APP) ... is the major α-secretase that catalyzes the amyloid precursor protein (APP) ectodomain shedding in the brain and prevents ...
more infohttps://moh-it.pure.elsevier.com/en/publications/sap97-mediated-adam10-trafficking-from-golgi-outposts-depends-on-
  • 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)
  • 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)
  • Here, we describe that in hippocampal neurons the synapse-associated protein-97 (SAP97), an excitatory synapse scaffolding element, governs ADAM10 trafficking from dendritic Golgi outposts to synaptic membranes. (elsevier.com)
  • This process is mediated by a previously uncharacterized protein kinase C phosphosite in SAP97 SRC homology 3 domain that modulates SAP97 association with ADAM10. (elsevier.com)
  • Several such proteins, notably ADAM10, have been identified as possessing alpha-secretase activity. (wikipedia.org)
  • 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)
  • It is a transcriptional repressor of genes that require a bHLH protein for their transcription. (cancerindex.org)
  • The activity of alpha secretases has been implicated in the regulation of learning and memory formation. (wikipedia.org)
  • If α-secretase acts on APP first instead of BACE, no amyloid-β is formed because α-secretase recognizes a target protein sequence closer to the cell surface than BACE. (wikipedia.org)
  • miRNAs are endogenous, short, non-coding RNAs that typically inhibit protein expression by interacting with specific recognition elements of target transcripts. (elsevier.com)