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.
Endopeptidases that are specific for AMYLOID PROTEIN PRECURSOR. Three secretase subtypes referred to as alpha, beta, and gamma have been identified based upon the region of amyloid protein precursor they cleave.
A sub-subclass of endopeptidases that depend on an ASPARTIC ACID residue for their activity.
Peptides generated from AMYLOID BETA-PEPTIDES PRECURSOR. An amyloid fibrillar form of these peptides is the major component of amyloid plaques found in individuals with Alzheimer's disease and in aged individuals with trisomy 21 (DOWN SYNDROME). The peptide is found predominantly in the nervous system, but there have been reports of its presence in non-neural tissue.
A degenerative disease of the BRAIN characterized by the insidious onset of DEMENTIA. Impairment of MEMORY, judgment, attention span, and problem solving skills are followed by severe APRAXIAS and a global loss of cognitive abilities. The condition primarily occurs after age 60, and is marked pathologically by severe cortical atrophy and the triad of SENILE PLAQUES; NEUROFIBRILLARY TANGLES; and NEUROPIL THREADS. (From Adams et al., Principles of Neurology, 6th ed, pp1049-57)
A fibrous protein complex that consists of proteins folded into a specific cross beta-pleated sheet structure. This fibrillar structure has been found as an alternative folding pattern for a variety of functional proteins. Deposits of amyloid in the form of AMYLOID PLAQUES are associated with a variety of degenerative diseases. The amyloid structure has also been found in a number of functional proteins that are unrelated to disease.
A subclass of PEPTIDE HYDROLASES that catalyze the internal cleavage of PEPTIDES or PROTEINS.
Integral membrane protein of Golgi and endoplasmic reticulum. Its homodimer is an essential component of the gamma-secretase complex that catalyzes the cleavage of membrane proteins such as NOTCH RECEPTORS and AMYLOID BETA-PEPTIDES precursors. PSEN1 mutations cause early-onset ALZHEIMER DISEASE type 3 that may occur as early as 30 years of age in humans.
A type of ALPHAPAPILLOMAVIRUS associated with high risk for anogenital neoplasms.
Accumulations of extracellularly deposited AMYLOID FIBRILS within tissues.
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.
A notch receptor that interacts with a variety of ligands and regulates SIGNAL TRANSDUCTION PATHWAYS for multiple cellular processes. It is widely expressed during EMBRYOGENESIS and is essential for EMBRYONIC DEVELOPMENT.
Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques.
The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.
Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN.
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)
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.
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.
Extracellular protease inhibitors that are secreted from FIBROBLASTS. They form a covalent complex with SERINE PROTEASES and can mediate their cellular internalization and degradation.
A familial disorder marked by AMYLOID deposits in the walls of small and medium sized blood vessels of CEREBRAL CORTEX and MENINGES.
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.
Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.
The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.
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.
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).
Any of various enzymatically catalyzed post-translational modifications of PEPTIDES or PROTEINS in the cell of origin. These modifications include carboxylation; HYDROXYLATION; ACETYLATION; PHOSPHORYLATION; METHYLATION; GLYCOSYLATION; ubiquitination; oxidation; proteolysis; and crosslinking and result in changes in molecular weight and electrophoretic motility.
A group of sporadic, familial and/or inherited, degenerative, and infectious disease processes, linked by the common theme of abnormal protein folding and deposition of AMYLOID. As the amyloid deposits enlarge they displace normal tissue structures, causing disruption of function. Various signs and symptoms depend on the location and size of the deposits.
A 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.
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.
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.
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.
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.
Established cell cultures that have the potential to propagate indefinitely.
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.
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.
The level of protein structure in which combinations of secondary protein structures (alpha helices, beta sheets, loop regions, and motifs) pack together to form folded shapes called domains. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Small proteins usually consist of only one domain but larger proteins may contain a number of domains connected by segments of polypeptide chain which lack regular secondary structure.
Proteins 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.
Histochemical localization of immunoreactive substances using labeled antibodies as reagents.
Compounds which inhibit or antagonize biosynthesis or actions of proteases (ENDOPEPTIDASES).
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)
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.
Unsaturated azacyclopropane compounds that are three-membered heterocycles of a nitrogen and two carbon atoms.
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.
The gradual irreversible changes in structure and function of an organism that occur as a result of the passage of time.
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.
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.
A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.
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.
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.
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.
A family of proteins that share sequence similarity with the low density lipoprotein receptor (RECEPTORS, LDL).
The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.
Peptides composed of two amino acid units.
Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids.
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.
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)
Proteins prepared by recombinant DNA technology.
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.
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.
The best-characterized gamma-secretase substrates are the Notch receptor and amyloid precursor protein (APP). Presenilins' role ... beta secretases and gamma secretase. Presenilin is the sub-component of gamma secretase that is responsible for the cutting of ... Gamma secretase can cut APP at several points within a small region of the protein, which results in Aβ of various lengths. The ... Presenilins are transmembrane proteins with nine alpha helices. Structures have been solved of the assembled gamma secretase ...
"Protein kinase C-dependent alpha-secretase competes with beta-secretase for cleavage of amyloid-beta precursor protein in the ... to the Alzheimer's disease-associated peptide amyloid beta when APP is instead processed by beta secretase and gamma secretase ... Alpha secretases are a family of proteolytic enzymes that cleave amyloid precursor protein (APP) in its transmembrane region. ... The alpha-secretase pathway is the predominant APP processing pathway. Thus, alpha-secretase cleavage precludes amyloid beta ...
Sequential cleavage by beta-secretase 1 (BACE) and gamma-secretase (γ-secretase) produces the amyloid-beta peptide fragment ... Among other roles in the cell, secretases act on the amyloid-beta precursor protein (APP) to cleave the protein into three ... If alpha-secretase (α-secretase) acts on APP first instead of BACE, no amyloid beta is formed because α-secretase recognizes a ... BACE is a transmembrane protein with an extracellular aspartic acid protease domain. γ-secretase is actually a protein complex ...
... by beta secretase (or β-amyloid cleaving enzyme (BACE) outside the membrane, and second, by gamma secretase (γ-secretase), an ... Selkoe, DJ (1999). "Chapter 19: Biology of β-amyloid precursor protein and the mechanism of Alzheimer disease". In Terry, RD; ... The sequential actions of these secretases results in Aβ protein fragments that are released into the extracellular space The ... Amyloid beta (Aβ) is a small protein, most often 40 or 42 amino acids in length, that is released from a longer parent protein ...
The peptides derive from the amyloid precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield A ... including the proteolytic enzymes gamma- and β-secretases which generate Aβ from its precursor protein, APP (amyloid precursor ... Hiltunen M, van Groen T, Jolkkonen J (2009). "Functional roles of amyloid-beta protein precursor and amyloid-beta peptides: ... October 1999). "Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE". ...
Cleavage by gamma secretase within the membrane-spanning domain after beta-secretase cleavage generates the amyloid-beta ... The amyloidprecursor protein (AβPP), and all associated secretases, are expressed early in development and play a key role ... "Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production". Nature. 360 ... a reproductive regulator that modulates the processing of amyloid-beta precursor protein and amyloid-beta deposition". The ...
2003). "Processing of beta-amyloid precursor-like protein-1 and -2 by gamma-secretase regulates transcription". J. Biol. Chem. ... The encoded protein is a membrane-associated glycoprotein that is cleaved by secretases in a manner similar to amyloid beta A4 ... 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 ...
... and γ-secretase cleavage from the amyloid precursor protein (APP). It is known to be the major constituent of diffuse plaques ... p3 can be found as a 24 or 26 residues peptide, depending on which is gamma secretase's cleavage. The peptide which has 26 ... PDB: 3MOQ​ McCandless, Gregory T. (2008). Synthesis of disubstituted amino acids and peptide inhibitors of amyloid beta ... Under normal physiological conditions, APP is processed with three different proteolytic enzymes: α-, β- and γ-secretases. At ...
"Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE". Science 286 ( ... a proteína Aβ xérase pola acción sucesiva das β e γ secretases. A γ secretase, que orixina o extremo C-terminal do péptido Aβ, ... "Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch". J. Biol. Chem. 274 (51): 36801-7. ... Hiltunen M, van Groen T, Jolkkonen J (2009). "Functional roles of amyloid-beta protein precursor and amyloid-beta peptides: ...
The majority of known Alzheimer's disease risk gene products including the amyloid precursor protein (APP) and gamma-secretase ... A delicate balance of the enzymes secretases regulate the amyloid-beta accumulation. Alpha Secretase can render a non- ... Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor ... 2006). "The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production". Nature. 440 ( ...
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. ... beta-Secretase; alpha-Secretase; gamma-Secretase; Secretase; APP Secretase; Amyloid Precursor Protein Secretase; Secretases; ... Amyloid Precursor Protein Secretases (beta-Secretase). Subscribe to New Research on Amyloid Precursor Protein Secretases ...
Signalling through the receptor protein Notch, which is involved in crucial cell-fate decisions during development, requires ... Amyloid Precursor Protein Secretases * Amyloid beta-Protein Precursor / metabolism * Animals * Aspartic Acid Endopeptidases ... and is reminiscent of gamma-secretase-mediated cleavage of beta-amyloid precursor protein (APP), a critical event in the ... A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain Nature. 1999 Apr 8;398( ...
We now showed that repression of PS1 transcription by JNK inhibitor SP600125 inhibited gamma-secretase med … ... Amyloid Precursor Protein Secretases / metabolism* * Amyloid beta-Peptides / metabolism * Amyloid beta-Protein Precursor / ... of PS1 transcription by JNK inhibitor SP600125 inhibited gamma-secretase mediated processing of amyloid precursor protein (APP ... Transcriptional regulation of the presenilin-1 gene controls gamma-secretase activity Front Biosci (Elite Ed). 2010 Jan 1;2:22- ...
PS1 is important in gamma-secretase activity. Gamma and beta secretases process amyloid precursor protein (APP) into A-beta. ... insoluble beta-amyloid in mouse brain homogenates. GSK-3beta is a major kinase involved in amyloid precursor protein (APP) and ... beta-catenin protein levels in colonic tissue. Thus, CUR and THC may suppress WNT1 and beta-catenin protein levels as well as ... Injection of the beta-amyloid (A-beta) peptide into rats resulted in learning developmental abilities. ...
PS1 is important in gamma-secretase activity. Gamma and beta secretases process amyloid precursor protein (APP) into A-beta. ... insoluble beta-amyloid in mouse brain homogenates. GSK-3beta is a major kinase involved in amyloid precursor protein (APP) and ... beta-catenin protein levels in colonic tissue. Thus, CUR and THC may suppress WNT1 and beta-catenin protein levels as well as ... Injection of the beta-amyloid (A-beta) peptide into rats resulted in learning developmental abilities. ...
"Protein kinase C-dependent alpha-secretase competes with beta-secretase for cleavage of amyloid-beta precursor protein in the ... to the Alzheimers disease-associated peptide amyloid beta when APP is instead processed by beta secretase and gamma secretase ... Alpha secretases are a family of proteolytic enzymes that cleave amyloid precursor protein (APP) in its transmembrane region. ... The alpha-secretase pathway is the predominant APP processing pathway. Thus, alpha-secretase cleavage precludes amyloid beta ...
Platelet-derived growth factor induces the beta-gamma-secretase-mediated cleavage of Alzheimers amyloid precursor protein ... Some more evidence that the pathways to gamma and beta secretases are via g protein-coupled receptors and receptor tyrosine ... A GPCR/secretase complex regulates beta- and gamma-secretase specificity for Abeta production and contributes to AD ... The total amount of amyloid protein is decreased, but the proportion of 42-amino-acid beta amyloid, long thought to be the ...
Sequential cleavage by beta-secretase 1 (BACE) and gamma-secretase (γ-secretase) produces the amyloid-beta peptide fragment ... Among other roles in the cell, secretases act on the amyloid-beta precursor protein (APP) to cleave the protein into three ... If alpha-secretase (α-secretase) acts on APP first instead of BACE, no amyloid beta is formed because α-secretase recognizes a ... BACE is a transmembrane protein with an extracellular aspartic acid protease domain. γ-secretase is actually a protein complex ...
Cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases results in generation of the amyloid-beta protein ... which is generated by cleavage of the Abeta protein precursor (APP) by beta-secretase (BACE-1) followed by gamma-secretase. ... is generated by beta- and gamma-secretase processing of a larger integral membrane protein precursor (APP). Intramembrane ... mutations in the amyloid precursor protein (APP) and its processing pathways, but suggests a new perspective beyond toxicity of ...
Amyloid-beta is generated from amyloid precursor protein (APP) by proteolytic processing by beta and gamma secretases. Since ... beta-secretase (beta-site APP cleaving enzyme 1, or BACE1) cleavage is rate limiting for the production of amyloid-beta, ... The amyloid-beta peptide is the major component of such plaques and is considered to be the major culprit in the pathogenesis ... Thus in patients, it is anticipated that inhibitors blocking BACE1 could prevent the build up of amyloid-beta plaques and help ...
... and gamma-secretases. Alpha-secretase generates soluble amyloid protein, while beta- and gamma-secretases generate APP ... Amyloid beta A4 protein antibody,Amyloid Beta A4 Protein Precursor Isoform A antibody,Amyloid beta A4 protein precursor isoform ... Amyloid beta A4 protein precursor isoform c antibody,Amyloid Beta Peptide antibody,Amyloid beta protein antibody,Amyloid ... anti-APP Antikörper (Amyloid beta (A4) Precursor Protein) (AA 18-32) APP Antikörper (Amyloid beta (A4) Precursor Protein) (AA ...
... resulting from the sequential cleavage of amyloid precursor protein (APP) by beta and gamma secretases. This research compiles ... in this study emphasize the inhibition of amyloid plaques by blocking the action of gamma secretase protein with inhibitors ( ... discuss the use of protein- based nanoparticles as carriers for drugs targeting protein-protein interactions and also highlight ... Protein/Hormone Based Nanoparticles as Carriers for Drugs Targeting Protein-Protein Interactions, authors Al-Suhaimi et al. ...
Amyloid Precursor Protein Secretases/antagonists & inhibitors*. *Amyloid Precursor Protein Secretases/metabolism*. *Amyloid ... Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta ... Amyloid beta-Protein Precursor/blood. *Amyloid beta-Protein Precursor/cerebrospinal fluid. *Amyloid beta-Protein Precursor/ ... Acute γ-secretase Inhibition of Nonhuman Primate CNS Shifts Amyloid Precursor Protein (APP) Metabolism from Amyloid-β ...
The two mutations occur in a gene called ADAM10 coding for an enzyme involved in processing the amyloid precursor protein which ... begins when the amyloid precursor protein (APP) is cut into smaller proteins by enzymes called secretases. A-beta results if ... cut into two segments by an enzyme called beta-secretase, and one of those segments is further cut by a gamma-secretase enzyme ... amyloid beta (A-beta) protein in the brains of a mouse model of AD. ...
... of ten FAD cases expressing independent PSEN mutations and determined the degradation patterns of amyloidprecursor protein ( ... These observations imply that missense mutations in PSEN genes can alter a range of key γ-secretase activities to produce an ... We observed a wide variation in type, number and distribution of amyloid deposits and neurofibrillary tangles. Four of the ten ... AβPP), Notch, N-cadherin and Erb-B4 by γ-secretase. In addition, the levels of Aβ40/42 peptides were quantified by ELISA. ...
... clinicaltrials.gov The objective of this study is to test and determine whether a high protein diet is efficacious, safe and ... Endopeptidases that are specific for AMYLOID PROTEIN PRECURSOR. Three secretase subtypes referred to as alpha, beta, and gamma ... Amyloid Precursor Protein Secretases. ... protein-based.... High Protein Diet Versus Normal Protein Diet ... Protein powder supplement, High Level Protein, based on 1 gram of protein per pound of lean body mass: 25% protein and 45% ...
... is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity. Biochemistry 39,8698 -8704. ... Dominguez, D. I., De S. and Annaert, W. (2001). Secretases as therapeutic targets for the treatment of Alzheimers disease. ... 1 regulates the processing of beta-amyloid precursor protein C-terminal fragments and the generation of amyloid beta-protein in ... Beta-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications ...
A number of secretases are involved in beta-amyloid peptide (40-42 amino acids) production from amyloid precursor protein buy ... R-flurbiprofen order duloxetine 40mg line, a gamma-secretase modulator, leads to shorter amino acids that do not lead to Aβ ... Lewy bodies contain ubiquitin and alpha-synuclein and antibodies to these proteins can be used in postmortem tissue as a method ... Hypercholesterolaemia accelerates amyloid pathology and reduced cholesterol intake slows plaque 2814 development in transgenic ...
... 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 ... Although several studies have focused on γ-secretase, the effect of the membrane lipid microenvironment on α-secretase is ... saturation grade and the FA double-bond position on α-secretase activity. We found that α-secretase activity is significantly ...
Presenilin-dependent gamma-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of ... Novel research horizons for presenilins and γ-secretases in cell biology and disease. Annu Rev Cell Dev Biol. 2010 Nov 10;26: ... Distinct intramembrane cleavage of the beta-amyloid precursor protein family resembling gamma-secretase-like cleavage of Notch ... Distinct intramembrane cleavage of the beta-amyloid precursor protein family resembling gamma-secretase-like cleavage of Notch ...
... or amyloid precursor protein, is chopped into smaller pieces by scissor-like proteins called beta-secretase and gamma-secretase ... Drug researchers have been searching for compounds that inhibit these secretases, because blocking their activity would halt ... "Rather, it seems to affect another protein or proteins that regulate gamma-secretase." ... "One of the reasons Gleevec differs from other gamma-secretase inhibitors is that it probably does not inhibit gamma-secretase ...
Endopeptidases that are specific for AMYLOID PROTEIN PRECURSOR. Three secretase subtypes referred to as alpha, beta, and gamma ... "Amyloid Precursor Protein Secretases" by people in this website by year, and whether "Amyloid Precursor Protein Secretases" was ... Amyloid Precursor Protein Secretases*Amyloid Precursor Protein Secretases. *Secretases. *Secretase. *Amyloid Precursor Protein ... "Amyloid Precursor Protein Secretases" is a descriptor in the National Library of Medicines controlled vocabulary thesaurus, ...
In this review the authors discuss the possible neuropathological role of intracellular amyloid-β accumulation in Alzheimers ... Enhanced release of amyloid beta-protein from codon 670/671 "Swedish" mutant beta-amyloid precursor protein occurs in both ... Vassar, R. and Citron, M. (2000) Abeta-generating enzymes: recent advances in beta- and gamma-secretase research. Neuron 27, ... uncovering the secrets of secretases. Curr. Opin. Neurobiol. 11, 585-590.PubMedGoogle Scholar ...
... then further clipped by gamma secretase, resulting in amyloid beta peptides.. amyloid precursor protein search for term is ... Enzymes called secretases snip it apart into three protein fragments, two of which are released outside the cell and one inside ... amyloid beta peptides search for term peptides derived from amyloid precursor protein, these fragments of amyloid beta are the ... A subunit of gamma-secretase, the protein CD147, is now thought to regulate the production of A-beta 42. Amyloid beta peptides ...
Beta-secretase cleavage of Alzheimers amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999. ... Membrane protein secretases. Biochem. J. 1997. 321:265-279. View this article via: PubMed Google Scholar ... The role of presenilin cofactors in the gamma-secretase complex. Nature. 2003. 422:438-441. View this article via: PubMed ... Oxidative stress increases production of beta-amyloid precursor protein and beta-amyloid (Abeta) in mammalian lenses, and Abeta ...
Abeta is a fragment of amyloid-beta precursor protein (APP) generated in neurons by two proteases, beta- and gamma-secretases. ... receptor 2 and X11 alpha/beta mediate apolipoprotein E-induced endocytosis of amyloid-beta precursor protein and beta-secretase ... Processing of ß-amyloid precursor protein (APP) by ß- and γ-secretases in neurons produces amyloid-ß (Aß), whose excess ... Expression and processing of fluorescent fusion proteins of amyloid precursor protein (APP). ...
2002) Generation of C-terminally truncated amyloid-beta peptides is dependent on gamma-secretase activity. J Neurochem 82:563- ... 2011) Processing of the synaptic cell adhesion molecule Neurexin-3β by Alzheimer disease α- and γ-secretases. J Biol Chem 286: ... 1999) Beta-secretase cleavage of Alzheimers amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286 ... 1999) Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402:537-540. ...
... and derivatives of amyloid precursor protein (APP) including Aβ40 and Aβ42. [0018] Neuronal thread protein is described to be ... Formation of Aβ occurs through combined action of beta and gamma secretase cleavage of APP leading to the neurotoxic Aβ40/42. ... Mutations in presenilin-1 and 2 (gamma secretases) are also associated with FAD and lead to increased production of Aβ40/42. ... deposition of the same protein together with beta amyloid peptide was found as cerebral amyloid angiopathy (CAA) in different ...
The effects of EOs on pathological targets of AD and dementia including amyloid deposition (Aβ), neurofibrillary tangles (NFTs ... The effects of EOs on pathological targets of AD and dementia including amyloid deposition (Aβ), neurofibrillary tangles (NFTs ... The amyloidogenic process is initiated by the enzymatic breakdown of amyloid precursor protein (APP) by beta amyloid cleaving ... called beta secretase at beta site. This is followed by catalytic cleavage of APP by gamma secretase to form non-soluble ...
Amyloid Beta (Aβ). Amyloid Beta is a derivative of the Amyloid Precursor Protein (APP), which is a protein that is believed to ... 8 Presenilins are a set of proteins that are part of the gamma secretase complex, which helps cleave APP to form Aβ. Mutations ... The cleavage is performed by α, β, and γ secretases in the brain. Recent evidence suggests that oligomers of Aβ attach to ... "Cellular Actions of Beta-amyloid Precursor Protein and Its Soluble and Fibrillogenic Derivatives." Physiological Reviews. Web. ...
  • Injection of the beta-amyloid (A-beta) peptide into rats resulted in learning developmental abilities. (theflow.org)
  • CUR treatment prevented A-beta peptide induced downregulation of Akt phosphorylation at T308 and S473. (theflow.org)
  • CUR also had effects on PTEN levels as CUR depressed A-beta peptide-induced up- regulation of PTEN. (theflow.org)
  • Specifically, alpha secretases cleave within the fragment that gives rise to the Alzheimer's disease-associated peptide amyloid beta when APP is instead processed by beta secretase and gamma secretase. (wikipedia.org)
  • Alpha secretase activity has also been observed to be upregulated in response to the signaling peptide PACAP. (wikipedia.org)
  • Sequential cleavage by beta-secretase 1 (BACE) and gamma-secretase (γ-secretase) produces the amyloid-beta peptide fragment that aggregates into clumps called amyloid plaques in the brains affected by Alzheimer's disease. (wikipedia.org)
  • This article presents a new hypothesis that takes into account the numerous familial AD (FAD) mutations in the amyloid precursor protein (APP) and its processing pathways, but suggests a new perspective beyond toxicity of forms of the amyloid beta-peptide (Abeta). (jove.com)
  • The amyloid-beta peptide is the major component of such plaques and is considered to be the major culprit in the pathogenesis of Alzheimer's disease. (biospace.com)
  • Alzheimer's disease (AD) is characterized by extracellular accumulation of amyloid-β peptide (Aβ), generated by proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretase. (mdpi.com)
  • One of the main pathological hallmarks of AD is the aggregation of a small peptide, called amyloid-β (Aβ), as senile plaques in the brains of affected individuals [ 1 , 2 ]. (mdpi.com)
  • 1992) Amyloid b-peptide is produced by cultured cells during normal metabolism. (springer.com)
  • 4 Amyloid Beta ( Aβ) is formed through cleavage of the APP, generating a peptide 36-43 amino acids long. (google.com)
  • These proteases are major therapeutic targets for the prevention of Alzheimer's disease because they are also involved in the proteolytic generation of the neurotoxic amyloid β-peptide. (jneurosci.org)
  • Amyloid-beta (Abeta or Aβ), a peptide of 39-43 amino acids, is the main constituent of amyloid plaques. (lmreview.com)
  • Abnormal accumulation of β-amyloid peptide (Aβ) in the brain is characteristic of Alzheimer's disease (AD). (biomedcentral.com)
  • The Aβ peptide is generated by processing a large type I transmembrane spanning glycoprotein, the amyloid precursor protein (APP), through the successive action of proteolytic enzymes called secretases. (biomedcentral.com)
  • see also Figure 1 A). When APP molecules are cleaved by α-secretase within the Aβ domain, the generation of the Aβ peptide is precluded. (biomedcentral.com)
  • G. G. Glenner and C. W. Wong, "Alzheimer's Disease: Initial Report of the Purification and Characterization of a Novel Cerebro-Vascular Amyloid Peptide," Biochemical and Biophysical Research Communications, Vol. 120, 1984, pp. 885-890. (scirp.org)
  • So the senile plaques are extracellular aggregates of this amyloid peptide. (coursera.org)
  • Plays a regulatory role in the processing of the amyloid-beta A4 precursor protein (APP) and acts as an inhibitor of the amyloid-beta peptide aggregation and fibrils deposition. (uniprot.org)
  • Bri23 peptide prevents aggregation of APP amyloid-beta protein 42 into toxic oligomers. (uniprot.org)
  • Related to Alzheimer's, APP cleavage by gamma-secretase leads to amyloid beta peptide production, one possible cause of Alzheimer's symptoms. (vib.be)
  • AβPP is the source of the amyloid-β (Aβ) peptide enriched in the brains of people with fAD or the more common, late onset, sporadic form of AD, sAD. (iospress.com)
  • About 1/3 of the 39 - 43 amino acid amyloid beta peptide (A beta peptide) is found within the transmembrane segment of APP the other two thirds being found just outside the membrane. (wordpress.com)
  • Alpha secretase (yet another enzyme) also cleaves the APP in its carboxy terminal extramembranous part, but does so closer to the membrane, so that part of the protein which would form the aBeta peptide is removed. (wordpress.com)
  • R. Scheckman personal communication (2012) - The Abeta peptide is appears to be cleaved by gamma secretase from the fragment generated by beta secretase. (wordpress.com)
  • Nature vol. 526 pp. 443 - 447 '15 ] describes a totally new kid on the block, which (if replicated) should make us rethink everything we thought we knew about the amyloid precursor protein and the Abeta peptide. (wordpress.com)
  • The amyloid precursor protein (APP), the source of the neurotoxic amyloid beta (A beta) peptide involved in Alzheimer's disease (AD), belongs to a conserved family of related proteins. (phoenixpeptide.com)
  • amyloid peptide to form oligomers and aggregates in vitro," Brain Res. (patentgenius.com)
  • Brain cathepsin B but not metalloendopeptidases degrade rAPP.sup.751 with production of amyloidogenic fragments," Int. J. of Peptide & Protein Res. (patentgenius.com)
  • Protein Processing in Alzheimer's Disease," Peptide Res. (patentgenius.com)
  • Secretase Proteases Using Peptide and Amyloid Precursor Protein Substrates," J. Of Neurochem. (patentgenius.com)
  • Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. (springermedizin.de)
  • Beta-Amyloid peptide antibodies were generated against a KLH-conjugated N-terminal sequence contained within both the 40- and 42-amino acid versions of the human Beta-Amyloid peptide (i.e. (antibodiesinc.com)
  • Beta-Amyloid peptide is a 40- or 42-amino acid fragment of the human Beta-Amyloid Peptide: Precursor Protein (770 amino acids) produced by the proteolytic actions of Beta and Gamma-secretases. (antibodiesinc.com)
  • Both forms of Beta-Amyloid peptide are rather insoluble and tend to self-aggregate into distinctive extracellular "plaques. (antibodiesinc.com)
  • In the case of Alzheimer's disease, it has been suggested that these extracellular Beta-Amyloid peptide plaques are themselves cytotoxic (rather than simply being markers of brain pathology), and are responsible for the dendritic pruning and other neurodegenerative changes seen. (antibodiesinc.com)
  • Synthetic peptide (DAE FRH DSG YEV HHQ KL) contained within both the 40- and 42 amino acid versions of the human Beta-Amyloid peptide (Amyloid Precursor Protein residues #672-688). (antibodiesinc.com)
  • Hens were immunized with a synthetic peptide (corresponding to DAE FRH DSG YEV HHQ KL, residues #1-17 of the amyloid beta-peptide) coupled to keyhole limpet hemocyanin (KLH). (antibodiesinc.com)
  • APP-C99 is further cleaved to release a ~4-kDa peptide, Aβ, and the amyloid precursor protein i ntra c ellular d omain (AICD). (biomedcentral.com)
  • Peptide APP-C99 is the product of β-secretase, which therefore contains α- and γ-, but not β-cleavage sites. (biomedcentral.com)
  • Here we provide evidence that after cleavage by signal peptidase, the signal peptide is further processed by the intramembrane-cleaving protease SPP that promotes the release of core protein from the ER membrane. (embl-heidelberg.de)
  • Subsequent cleavages by γ -secretase in the transmembrane domain generate the amyloidogenic A β peptide or the nonamyloidogenic p3 peptide along with the intracellular C-terminal domain of APP (AICD). (hindawi.com)
  • Anti-APP (CT) [Rabbit antibody to peptide corresponding to aa 737-751 of human amyloid protein precursor (APP) or aa 85-99 of the C99 fragment generated by b-secretase cleavage. (mybiosource.com)
  • Accumulation of the amyloid- beta peptide (A beta ) in the cerebral cortex is a critical event in the pathogenesis of Alzheimer's disease. (mybiosource.com)
  • The C99 fragment serves as substrate for gamma -secretase to generate the 4 kD amyloid- beta peptide which is deposited in the brain. (mybiosource.com)
  • Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by the accumulation of beta amyloid (Aβ), an insoluble peptide deposited extracellularly in the brain, causing senile plaques [ 1 ]. (biomedcentral.com)
  • PMID 12927332 ] APP is best known and most commonly studied as the precursor molecule whose proteolysis generates amyloid beta (Aβ), a 39- to 42- amino acid peptide whose amyloid fibrillar form is the primary component of amyloid plaque s found in the brains of Alzheimer's disease patients. (enacademic.com)
  • The amyloidogenic Aβ 1-42, the amyloidogenic peptide product of the amyloid precursor protein damages and kills neurons possibly through an effect on the membrane lipid peroxidation, impaired ion-motive ATPases, glucose and glutamate transporters making nerve cells vulnerable to the excitotoxic effects of glutamate [7]. (scirp.org)
  • Histopathological hallmarks include extracellular amyloid peptide (Aβ) deposition in neuritic plaques, and intracellular deposits of hyperphosphorylated Tau, causing formation of neurofibrillary tangles and finally neuronal death. (biomedcentral.com)
  • The principal component of the plaques, a neurotoxic, self-aggregating peptide known as amyloid β (Aβ), is generated by successive cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. (biomedcentral.com)
  • Although the etiology of AD remains unknown, a consensus has emerged on the amyloid hypothesis, which posits that increased production of soluble amyloid β (Aβ) peptide induces neuronal network dysfunctions and cognitive deficits. (sciencemag.org)
  • Although the etiology of AD remains unknown, a consensus has emerged on the amyloid hypothesis ( 1 ), which posits that the amyloid β (Aβ) peptide, a major constituent of the amyloid plaques, induces neuronal network dysfunctions and is therefore responsible for the alteration of cognitive functions ( 2 ). (sciencemag.org)
  • Biochemical characterizations and comparisons have revealed that many PSEN mutations alter γ-secretase activity to promote accumulation of toxic Aβ42 peptides. (biomedcentral.com)
  • One of the numerous important substrates of the γ-secretase is the amyloid-beta precursor protein (AβPP), a type-1 membrane-bound molecule that is degraded by the action of the β- and γ-secretases to yield the 40/42 amino acid amyloid-β (Aβ) peptides. (biomedcentral.com)
  • These are subsequently cleaved by γ-secretase at multiple sites in the transmembrane region, releasing small peptides, Aβ 1-40 and Aβ 1-42 , the major components of AD-associated amyloid fibrils. (biologists.org)
  • There is abundant evidence that at early stages of the disease, prior to Aβ amyloid plaque formation, Aβ peptides accumulate intraneuronally in the cerebral cortex and the hippocampus. (springer.com)
  • The experimental evidence would indicate that intracellular amyloid-β could originate both by intracellular biosynthesis and also from the uptake of amyloidogenic peptides from the extracellular milieu. (springer.com)
  • peptides derived from amyloid precursor protein, these fragments of amyloid beta are the main protein component of plaques, and probably a major cause for the their toxicity. (memory-key.com)
  • The peptides come in two forms: A-beta 42 and A-beta 40. (memory-key.com)
  • Amyloid beta peptides routinely circulate in the human bloodstream, where they are harmless. (memory-key.com)
  • the process by which APP is clipped by the beta form of secretase, then further clipped by gamma secretase, resulting in amyloid beta peptides. (memory-key.com)
  • One of those which is found outside the cell is made of amyloid beta peptides. (memory-key.com)
  • γ-Secretase inhibitors (GSIs) reduce amyloid-β (Aβ) peptides but inevitably increase the β-C-terminal fragment (β-CTF) of amyloid precursor protein (APP), potentially having undesirable effects on synapses. (jneurosci.org)
  • Amyloid beta (Abeta) plays an apolipoprotein-like role in helping to maintain cerebral cholesterol homeostasis, and Abeta peptides are found in atherosclerotic plaque. (lmreview.com)
  • Alpha-secretase is protective not only because it cleaves APP inside the amylolid beta (Abeta) sequence, splitting this sequence apart and thus preventing the formation of Abeta peptides, but also because it releases a soluble fragment called APPsα that is neuroprotective. (lmreview.com)
  • Beta-secretase cleavage frees the entire Abeta sequence, producing Abeta peptides which, if not quickly cleared when produced in or delivered to the brain, become potent neurotoxins that ultimately self-aggregate and deposit as amyloid plaque. (lmreview.com)
  • The amyloid precursor protein gene (APP) and its derivative peptides have important functions in the central nervous system. (scirp.org)
  • P. Panegyres and E. Atkins, "The Functions of the Amyloid Precursor Protein Gene and Its Derivative Peptides: I Molecular Biology and Metabolic Processing," Neuroscience and Medicine , Vol. 2 No. 2, 2011, pp. 120-131. (scirp.org)
  • ABCA1 promotes cellular cholesterol efflux to lipid-free apolipoprotein acceptors and also inhibits the production of neurotoxic beta-amyloid (Abeta) peptides in vitro. (edu.au)
  • Secreted amyloid β-proteins in a cell culture model include N-terminally extended peptides that impair synaptic plasticity. (nih.gov)
  • One of the most critical pathological features of Alzheimer's disease (AD) is the accumulation of β-amyloid (Aβ) peptides that form extracellular senile plaques in the brain. (meta.org)
  • The different Ab peptides are produced by the proteolytic cleavage of amyloid precursor protein (APP), a process that is largely mediated by the enzymes beta- and gamma-secretase. (clontech.com)
  • The cleavage of APP by both the beta- and gamma-secretases via the amyloidogenic pathway results in a number of Ab peptides that range from 36 to 43 amino acids in length. (clontech.com)
  • So to get A beta peptides the APP must be cut (more than once) at its carboy terminal end. (wordpress.com)
  • Then gamma secretase (another enzyme) cleaves C99 within the membrane forming the Abeta peptides, which constitute much of the senile plaque of Alzheimer's disease. (wordpress.com)
  • Alpha and beta secretase then work on CTFneta to produce shorter peptides, called Aneta-alpha, and Aneta-beta. (wordpress.com)
  • Hydrolysis of amyloid precursor protein-derived peptides by cysteine proteinases and extracts of rat brain clathrin-coated vesicles," Peptides 15(1):175-182 (1994). (patentgenius.com)
  • In Alzheimer's disease, beta-amyloid peptides in the brain aggregate into toxic oligomers and plaques, a process which is associated with neuronal degeneration, memory loss, and cognitive decline. (biomedcentral.com)
  • Nine peptides were derived from proteins that may not be γ-secretase substrates per se , but that are regulated in a γ-secretase-dependent manner. (biomedcentral.com)
  • While the majority of CSF proteomic studies to date follow the strategy of analyzing proteins digested with trypsin, endogenous peptides - the CSF peptidome - may also be a valuable source of biomarkers, particularly for studying biological events involving proteolytic processing. (biomedcentral.com)
  • Amyloid plaques are predominantly comprised of insoluble amyloid-beta (Aβ) peptides, mostly 40 or 42 amino acids in length, with Aβ42 being the most prevalent component [ 4 ]. (pubmedcentralcanada.ca)
  • This gene encodes a cell surface receptor and transmembrane precursor protein that is cleaved by secretases to form a number of peptides. (mybiosource.com)
  • Some of these peptides are secreted and can bind to the acetyltransferase complex APBB1/TIP60 to promote transcriptional activation, while others form the protein basis of the amyloid plaques found in the brains of patients with Alzheimer disease. (mybiosource.com)
  • The amyloid precursor protein (APP) is cleaved by β- and γ-secretases to generate toxic amyloid β (Aβ) peptides. (biomedcentral.com)
  • they represent the essential components of the gamma-secretase complex, which, by cleaving APP in concert with beta-secretase, leads to the production of the neurotoxic beta-amyloid peptides. (unipd.it)
  • Moreover, several gamma-secretase inhibitors block this same step in Notch processing, indicating that related protease activities are responsible for cleavage within the predicted transmembrane domains of Notch and APP. (nih.gov)
  • Gamma-Secretase Inhibitors: The Wrong Way Around? (sciencemag.org)
  • 39 comments on "Gamma-Secretase Inhibitors: The Wrong Way Around? (sciencemag.org)
  • This is actually good news for the amyloid hypothesis, although clearly bad news for gamma secretase inhibitors. (sciencemag.org)
  • INGELHEIM, Germany--(BUSINESS WIRE)--Boehringer Ingelheim and Vitae Pharmaceuticals, Inc., announced today that they have entered into a significant worldwide collaboration to research and develop beta-secretase (BACE) inhibitors for the treatment of Alzheimer's disease. (biospace.com)
  • Thus in patients, it is anticipated that inhibitors blocking BACE1 could prevent the build up of amyloid-beta plaques and help slow or stop the progression of disease. (biospace.com)
  • provide an overview of treatment of KRAS mutant cancers including directly targeting oncogenic KRAS protein by a virtual screening approach to discover novel KRAS inhibitors [1]. (eurekaselect.com)
  • One of the reasons Gleevec differs from other gamma-secretase inhibitors is that it probably does not inhibit gamma-secretase directly," says William Netzer, Ph.D., lead author of the current study. (alzinfo.org)
  • This review summarizes recent evidence for a role of γ-secretase in inflammatory diseases, and discusses the potential use of γ-secretase inhibitors as an effective future treatment option. (edu.au)
  • Therapeutically, the new structural details around the PS1 HL-1 loop in the E-S complex could accelerate the design of more potent and well-targeted γ-secretase modulators (GSMs), which have theoretical and practical advantages over γ-secretase inhibitors. (alzforum.org)
  • A novel recombinant cell line has been developed for screening inhibitors for Gamma-secretase activity via APP processing pathway.Cell Line Characterization: APP-C99 U2Os cells allow to perform a Betaays to evaluate the endogenous Gamma-secretase proteolityc process in living cells. (asone-int.com)
  • There's a new kid on the Alzheimer's block, and it may explain why the huge sums thrown at beta-secretase inhibitors by big pharma has been such an abject failure. (wordpress.com)
  • What's fascinating about all this, is that the work possibly explains why the huge amount of money big pharma has spend on beta secretase inhibitors has been such a failure. (wordpress.com)
  • One therapeutic strategy is to decrease the production of potentially toxic beta-amyloid species by the use of inhibitors or modulators of the enzymes that produce beta-amyloid from amyloid precursor protein (APP). (biomedcentral.com)
  • Inhibitors of β- and γ-secretases may prevent the deposition of Aβ in brain, whereas an activator of α-secretase (and Aβ-degrading enzymes) may inhibit the accumulation of Aβ with the same efficiency. (perfectmargin.com)
  • We proposed - and provided the first evidence - that holoPS undergoes autocatalytic endoproteolysis to generate the active heterodimer, first reconstituted PS and its 3 cofactors in mammalian cells, purified the protease to homogeneity, obtained the first 3D structure of the ycomplex by EM, conducted SILAC screens to identify several new substrates, and designed many gamma-secretase inhibitors, some of which are potent and much more APP-selective than compounds tried in humans. (grantome.com)
  • 4: Refining potent and selective Notch-sparing gamma-inhibitors and defining their mechanism. (grantome.com)
  • A deficiency in presenilin-1 (PS1) inhibits processing of APP by gamma-secretase in mammalian cells, and genetic interactions between Notch and PS1 homologues in Caenorhabditis elegans indicate that the presenilins may modulate the Notch signalling pathway. (nih.gov)
  • Recent evidence suggests that some such proteins are first processed to ectodomains by alpha secretases and subsequently cleaved by another Alzheimer's-associated protease complex, gamma secretase in its presenilin-complexed form. (wikipedia.org)
  • When it was learned that gamma-secretase, as part of a complex called presenilin , also processes the Notch protein , a lot of people were understandably worried about what an inhibitor might do on the side). (sciencemag.org)
  • γ-secretase is actually a protein complex containing presenilin, nicastrin, APH-1, and PEN-2. (wikipedia.org)
  • γ-secretase is a high-molecular-mass complex composed of presenilin-1 (PS1), nicastrin, APH-1 and Pen-2. (biologists.org)
  • Familial AD (FAD), on the other hand, is associated with mutations in amyloid precursor protein (APP) on chromosome 21, apolipoprotein E gene on chromosome 19, presenilin-1 (PS1) on chromosome 14 (14q24.3) and presenilin-2 (PS2) on chromosome 1. (biologists.org)
  • Presenilin 1 negatively regulates beta-catenin/T cell factor/lymphoid enhancer factor-1 signaling independently of beta-amyloid precursor protein and notch processing. (nih.gov)
  • In addition to its documented role in the proteolytic processing of Notch-1 and the beta-amyloid precursor protein, presenilin 1 (PS1) associates with beta-catenin. (nih.gov)
  • Substitution of charged (E84A, R87A) or polar (Q83A) residues in TM3 had no effect on complex assembly or activity.Substitution with a negatively charged side chain (His-to-Asp) or altering the structural location of the histidines also disrupted gamma-secretase binding and abolished functionality of APH1.These results suggest that the conserved transmembrane histidine residues contribute to APH1 function and can affect presenilin catalytic activity. (nih.gov)
  • Complexes involved in the gamma/epsilon-secretase-regulated intramembranous proteolysis of substrates such as the amyloid-beta precursor protein are composed primarily of presenilin (PS1 or PS2), nicastrin, anterior pharynx defective-1 (APH1), and PEN2. (nih.gov)
  • The γ secretase is a macromolecular enzyme complex composed of presenilin 1, 2 and other molecular constitutents essential for its function. (scirp.org)
  • γ-Secretase is a complex of four integral membrane proteins, with presenilin (PS) as the catalytic component. (pubmedcentralcanada.ca)
  • γ-Secretase is composed of four transmembrane proteins, Aph-1, Pen-2, Nicastrin (NCT) ( 4 - 10 ) and presenilin (PS), which is ostensibly the catalytic component of an unusual aspartyl protease ( 3 , 11 , 12 ). (pubmedcentralcanada.ca)
  • γ-secretase is a high molecular weight complex minimally composed of four components: presenilins (PS), nicastrin, anterior pharynx defective 1 (APH-1), and presenilin enhancer 2 (PEN-2). (meta.org)
  • Gamma-secretase is also a transmembrane protein that, as part of a larger complex including Presenilin-1 , cleaves APP. (clontech.com)
  • Presenilin-Dependent Gamma-Secretase Processing of Beta-Amyloid Precursor Protein at a Site Corresponding to the S3 Cleavage of Notch," EMBO Reports 2:835-841, 2001. (patentgenius.com)
  • Presenilin/gamma-secretase-mediated cleavage of the voltage-gated sodium channel beta2-subunit regulates cell adhesion and migration. (semanticscholar.org)
  • gamma-secretase is composed of four proteins - presenilin, nicastrin, PEN-2 and APH-1 - which must come together for cleavage activity. (vib.be)
  • The best characterized function of PRESENILIN (PSEN) proteins is in γ-secretase enzyme activity. (iospress.com)
  • Early Contextual Fear Memory Deficits in a Double-Transgenic Amyloid-[beta] Precursor Protein/Presenilin 2 Mouse Model of Alzheimer's Disease. (thefreelibrary.com)
  • NAM400 pre-treatment significantly reduced the gene expression of amyloid precursor protein and presenilin 1 in brain tissues. (bvsalud.org)
  • The aim of this study was to investigate the effects of human Presenilin 2 mutant (hPS2m) overexpression on the γ-secretase complex in the mitochondrial fraction. (bvsalud.org)
  • Presenilin 1 regulates the processing of .beta. (patentgenius.com)
  • To observe the effects of Huannao Yicong Formula (, HYF) on learning and memory and it's regulating effect on γ-secretase related anterior pharynx defective 1 (APH-1), presenilin enhancer-2 (PEN-2) signaling pathway, so as to discuss and further clarify the mechanism of HYF on Alzheimer's disease. (bvsalud.org)
  • Presenilin 1 and presenilin 2 are polytopic membrane proteins, whose genes are mutated in some individuals with Alzheimer's disease. (embl-heidelberg.de)
  • Presenilin 1 (PSN1) and presenilin 2 (PSN2) are membrane proteins, whose genes are mutated in some individuals with Alzheimer's disease. (embl-heidelberg.de)
  • The two conserved aspartates required for presenilin endoproteolysis and γ-secretase processing of APP and Notch are predicted to be within TM6 and TM7. (perfectmargin.com)
  • The presenilin proteins appear in a cell structure called the endoplasmic reticulum, which plays many roles in the normal activities of a cell. (elifesciences.org)
  • The discovery of presenilin (PS) as the first intramembrane aspartyl protease and the catalytic center of gamma-secretase occurred in Project 1. (grantome.com)
  • This grant originally discovered that presenilin is a hitherto unknown type of protein-cutting enzyme that plays a seminal role in Alzheimer's disease. (grantome.com)
  • amyloid Pathology and Induce Conformational Changes in Presenilin 1. (grantome.com)
  • Soluble forms of the amyloid precursor protein may inhibit the damaging effects of presenilin 1 mutations by influencing the effects of NF-kappa-B and calcium homeostasis induced by these mutations [10]. (scirp.org)
  • The early-onset AD is caused by missense genetic mutations in amyloid precursor protein (APP), presenilin (PS) 1 and 2, all impinging on APP processing and leading to an increase in A β 42 generation [ 4 ]. (biomedcentral.com)
  • Zoltowska KM, Maesako M, Meier J, Berezovska O. Novel interaction between Alzheimer's disease-related protein presenilin 1 and glutamate transporter 1. (harvard.edu)
  • Alpha secretases are a family of proteolytic enzymes that cleave amyloid precursor protein (APP) in its transmembrane region. (wikipedia.org)
  • That enzyme has been targeted for a long time now, since it's thought to be involved in the proteolytic processing that generates beta-amyloid, a hallmark of Alzheimer's. (sciencemag.org)
  • Amyloid-beta is generated from amyloid precursor protein (APP) by proteolytic processing by beta and gamma secretases. (biospace.com)
  • Aβ is generated by sequential proteolytic processing of the amyloid precursor protein (APP), a large type-I transmembrane protein [ 3 ]. (mdpi.com)
  • 1992) Production of the Alzheimer amyloid b protein by normal proteolytic processing. (springer.com)
  • In contrast, PS1Deltacat restores Notch-1 proteolytic cleavage and Abeta generation in PS1-deficient cells, indicating that PS1 function in modulating beta-catenin levels can be separated from its roles in facilitating gamma-secretase cleavage of beta-amyloid precursor protein and in Notch-1 signaling. (nih.gov)
  • Proteolytic shedding of cell surface proteins generates paracrine signals involved in numerous signaling pathways. (jneurosci.org)
  • γ-Secretase is a distinct proteolytic complex required for the activation of many transmembrane proteins. (edu.au)
  • Aβ is produced from the amyloid β-protein precursor (APP) as a result of sequential proteolytic cleavages first by β-secretase ( 1 ) and then by γ-secretase ( 2 ). (pubmedcentralcanada.ca)
  • Facile and Sensitive Assay for Monitoring Proteolytic Activities with Defined Specificities: Studies on Amyloid .beta. (patentgenius.com)
  • It is generally accepted that the main constituent of amyloid plaques is the 4 kD amyloid protein (βA4, also referred to as Aβ,β-protein and βAP) which is a proteolytic product of a precursor protein of much larger size. (google.com)
  • This hydrophobic polypeptide is the product of proteolytic cleavage of the amyloid precursor protein (APP). (biomedcentral.com)
  • The inhibition of BACE - an enzyme involved in the formation of amyloid-beta plaques which accumulate in the brains of patients with Alzheimer's disease - offers the potential to slow or even halt disease progression. (biospace.com)
  • Since beta-secretase (beta-site APP cleaving enzyme 1, or BACE1) cleavage is rate limiting for the production of amyloid-beta, inhibition of this enzyme represents an attractive strategy to ameliorate amyloid-beta plaque deposition in Alzheimer's disease. (biospace.com)
  • The two mutations occur in a gene called ADAM10 coding for an enzyme involved in processing the amyloid precursor protein which now becomes the second pathologically-confirmed gene for late-onset AD and the fifth AD gene overall. (seniorjournal.com)
  • A-beta results if APP is first cut into two segments by an enzyme called beta-secretase, and one of those segments is further cut by a gamma-secretase enzyme to release the toxic A-beta fragment. (seniorjournal.com)
  • However, processing of APP by an alpha-secretase enzyme one of which is ADAM10 cuts right through the A-beta region in APP. (seniorjournal.com)
  • A major concern of inhibiting the enzymes which produce Abeta (beta- and gamma-secretase) is that precursors of Abeta may accumulate and cause a rapid increase in Abeta production when enzyme inhibition discontinues. (nih.gov)
  • Inhibition of the γ-secretase enzyme that snips amyloid precursor protein (APP) to form Aβ has long been seen as a therapeutic option for Alzheimer disease, but finding a safe, effective inhibitor has proved frustrating. (alzforum.org)
  • Involving antigen-antibody binding, specific binding protein assay or specific ligand-receptor binding assay assay in which an enzyme present is a label heterogeneous or solid phase assay system (e.g., elisa, etc. (patentsencyclopedia.com)
  • If acted upon by the enzyme alpha-secretase, however, APP cleavage produces neuroprotective compounds. (lmreview.com)
  • Although both covalent cross-linking and mutating one of the active site aspartates (yielding a "catalytically dead" enzyme) were necessary to stably embed C83 into γ-secretase, Q112C might not allow full representation of the dynamics of γ-secretase. (alzforum.org)
  • γ-Secretase is a founding member of membrane-embedded aspartyl proteases that cleave substrates within transmembrane domains, and this enzyme is an important target for the development of therapeutics for Alzheimer's disease. (pubmedcentralcanada.ca)
  • As a crucial enzyme for Aβ production, γ-secretase is an appealing therapeutic target for AD. (meta.org)
  • beta Subunits of voltage-gated sodium channels are novel substrates of beta-site amyloid precursor protein-cleaving enzyme (BACE1) and gamma-secretase. (semanticscholar.org)
  • Numerous sources of endogenous regulation have been identified, and one of these is the relative abundance and regulation of splice variants of the β-secretase, BACE1 (β-site amyloid precursor protein cleaving enzyme 1). (springermedizin.de)
  • Given that processing of APP to Aβ and soluble APP alpha (sAPPα) contributes to disease phenotypes, we also investigated whether Fmr1 KO associates with nuclear export of the mRNAs for APP protein processing enzymes, including β-site amyloid cleaving enzyme (Bace1), A disintegrin and metalloproteinases (Adams), and presenilins (Psen). (elsevier.com)
  • 3: Toward greater structural resolution of the gamma-secretase complex Working with leading structural biologists, we will pursue the technically challenging but essential quest for the structure of gamma-secretase via: a) further cryo-EM analyses of 2D crystals;b) 3D x-ray crystallography of individual gamma-components (PS, Net, Pen-2);and c) attempted 3D x-ray crystallography of the purified holo-enzyme. (grantome.com)
  • Our research plan aims to decipher critical new details about how this enzyme coordinates with two other key enzymes in normal biology, what its fundamental structure is, and how its production of amyloid beta-protein can be controlled by certain lipids and prototype drugs. (grantome.com)
  • Remarkably, β-secretase (BACE1) mRNA, neuronal BACE1 protein at sites of focal inflammation and total BACE1 enzyme activity were increased in 3 month old APP transgenic mice, relative to age-matched non-transgenic mice. (biomedcentral.com)
  • Aβ is produced in the amyloidogenic pathway where amyloid precursor protein (APP) is cleaved by β-secretase APP-cleaving enzyme (BACE1) to liberate soluble APPβ (sAPPβ) and the intracellular β-carboxy-terminal fragment (βCTF) (2). (deepdyve.com)
  • We now showed that repression of PS1 transcription by JNK inhibitor SP600125 inhibited gamma-secretase mediated processing of amyloid precursor protein (APP) resulting in the accumulation of C99 fragment and the reduction of secreted Abeta40 level without altering the expression of nicastrin (NCT). (nih.gov)
  • Eli Lilly got a gamma-secretase inhibitor well into the clinic, before finding out that it was not only ineffective , but that it actually seemed to make the disease slightly worse. (sciencemag.org)
  • If all this does hang together, then a gamma-secretase inhibitor like Lilly's is the last thing you'd want to give Alzheimer's patients. (sciencemag.org)
  • In principle one could identify a gamma secretase inhibitor or modulator that did the same, but the risk of failure for this approach just increased considerably. (sciencemag.org)
  • To this end, we report the translation of the human in vivo stable-isotope-labeling kinetics (SILK) method to a rhesus monkey cisterna magna ported (CMP) nonhuman primate model, and use the model to test the mechanisms of action of a gamma-secretase inhibitor (GSI). (nih.gov)
  • The recent cancellation of a high-profile γ-secretase inhibitor clinical trial (see ARF related news story ) is the latest disappointment for approaches targeting this secretase. (alzforum.org)
  • In the current study, researchers at the Fisher Center and at Memorial Sloan-Kettering Cancer Center demonstrated that Gleevec and a similar compound called inhibitor 2 dramatically diminished the production of beta-amyloid in rat brain cell cultures and in cells containing defective genes that lead to an inherited form of Alzheimer's at an early age. (alzinfo.org)
  • During the course of our research efforts to develop a potent and selective gamma-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. (qub.ac.uk)
  • Compound 4 is a potent inhibitor of gamma-secretase (A beta 40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. (qub.ac.uk)
  • 2. The method of claim 1, further comprising the step of evaluating a candidate compound as an inhibitor of the EphA4 cleavage activity of .gamma. (patentgenius.com)
  • Functions as a protease inhibitor by blocking access of secretases to APP cleavage sites. (uniprot.org)
  • Starting from the idea that Alzheimer's disease might be slowed by inhibiting g - secretase, we have now identified an endogenous inhibitor that prevents gamma-secretase complex assembly and activity and thus might be targeted for therapy (Spasic et al. (vib.be)
  • Fifteen human healthy volunteers, divided into three groups, received a single dose of placebo or either 140 mg or 280 mg of the γ-secretase inhibitor semagacestat (LY450139). (biomedcentral.com)
  • The abundance of this fragment was increased in the presence of a γ-secretase inhibitor, but was not affected by M3 receptor activation. (biomedcentral.com)
  • Supporting this notion are studies demonstrating that deletion of the BACE1 gene in mice prevents the formation of amyloid-beta in cultured neurons and the brain. (biospace.com)
  • In addition, it has been shown that amyloid-beta-associated memory deficits, which occur in mutant mice overexpressing APP, are prevented when the BACE1 gene is deleted. (biospace.com)
  • Beta secretase, or BACE1 , is a transmembrane protein that contains two aspartate residues in its active site. (clontech.com)
  • The early and focal glial activation, in conjunction with upregulated BACE1 mRNA, protein and activity in the presence of its substrate APP, is proposed to represent the earliest sites of amyloid deposition, likely evolving into amyloid plaques. (biomedcentral.com)
  • Upon cleavage by alpha secretases, APP releases its extracellular domain - a fragment known as APPsα - into the extracellular environment in a process known as ectodomain shedding. (wikipedia.org)
  • extracellular expression of mutant ADAM9 (also known as MDC9 or meltrin gamma) lacking the membrane anchor domain has been suggested as one of many possible means of Alzheimer's prevention and treatment exploiting the alpha secretase pathway. (wikipedia.org)
  • BACE is a transmembrane protein with an extracellular aspartic acid protease domain. (wikipedia.org)
  • Although BACE cleaves the extracellular domains of several transmembrane proteins, its physiological function remains unknown. (wikipedia.org)
  • The accumulation of amyloid beta (Abeta) in Alzheimer's disease is caused by an imbalance of production and clearance, which leads to increased soluble Abeta species and extracellular plaque formation in the brain. (nih.gov)
  • APP is a ubiquitous membrane protein that is physiologically processed by site-specific proteolysis firstly by α- or β-secretases, releasing a large fragment called APP S that contains most of the extracellular sequences of APP, a small extracellular stub, the transmembrane region and the cytoplasmic tail of APP (`AICD'-APP intracellular domain). (biologists.org)
  • A recent report by the Nomenclature Committee of the International Society of Amyloidosis defined amyloid as "extracellular depositions of protein fibrils with characteristic appearance in electron microscope, typical X-ray diffraction pattern, and affinity for Congo red with concomitant green birefringence" [ 8 ]. (pubmedcentralcanada.ca)
  • Biochemical and genetic interaction screens have led to the identification of both extracellular and multiple intracellular binding partners, which seem to anchor the APP/APLP C-termini to a complex protein network at the cell surface, which may transduce various cellular responses [ 2 , 3 ]. (hindawi.com)
  • APP is a single transmembrane domain protein with a large extracellular domain, expressed at high level in the brain. (unipd.it)
  • extracellular senile plaques made of amyloid-β (Aβ) and intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated tau (2). (deepdyve.com)
  • This cleavage occurs within the predicted transmembrane domain, releasing the Notch intracellular domain (NICD), and is reminiscent of gamma-secretase-mediated cleavage of beta-amyloid precursor protein (APP), a critical event in the pathogenesis of Alzheimer's disease. (nih.gov)
  • Thus the targeting of gamma-secretase for the treatment of Alzheimer's disease may risk toxicity caused by reduced Notch signalling. (nih.gov)
  • A Partial Failure of Membrane Protein Turnover May Cause Alzheimer's Disease: a New Hypothesis Current Alzheimer Research. (jove.com)
  • Pubmed ID: 16472208 The amyloid hypothesis has dominated the thinking in our attempts to understand, diagnose and develop drugs for Alzheimer's disease (AD). (jove.com)
  • Senescence-accelerated mice (SAMP8) serve as a model for Alzheimer's disease (AD) as they exhibit early loss of memory and increased amyloid precursor protein (APP) expression. (biologists.org)
  • The drug, called Gleevec, was shown to lower production of a toxic substance called beta-amyloid that is thought to underlie the development of Alzheimer's disease. (alzinfo.org)
  • Researchers have been trying for years to develop effective treatments against Alzheimer's disease by preventing the brain damage caused by the toxic beta-amyloid. (alzinfo.org)
  • In this review the authors discuss the possible neuropathological role of intracellular amyloid-β accumulation in Alzheimer's disease (AD) pathology. (springer.com)
  • 1992) Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. (springer.com)
  • 1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. (springer.com)
  • Production of ACT increases in brains with Alzheimer's disease, and this strongly increases the build-up of amyloid proteins. (memory-key.com)
  • There is accumulating evidence that it is these, rather than amyloid fibrils, that are the principal pathogenic species in Alzheimer's disease. (memory-key.com)
  • Although brain amyloid-β (Aβ) plaque is a pathological hallmark of Alzheimer's disease (AD), actual correlation with memory dysfunction is quite weak. (jneurosci.org)
  • measuring a protein biomarker complex in said fluid sample and correlating the measurement with mild cognitive impairment or Alzheimer's disease status. (patentsencyclopedia.com)
  • The other main neuropathologic hallmarks of Alzheimer's disease are the neurofibrillary tangles of tau protein. (google.com)
  • Alzheimer's disease is not normally a hereditary disease, although cases linked to genetics share a common problem: a mutation in the genes that code for the presinilin proteins. (google.com)
  • Signaling Pathways: Amyloid Plaque and Neurofibrillary Tangle Formation in Alzheimer's Disease. (google.com)
  • Conversely, PS1 specifically represses LEF-dependent transcription in a dose-dependent manner.The hyperproliferative response can be reversed by reintroducing PS1 expression or overexpressing axin, but not a PS1 mutant that does not bind beta-catenin (PS1Deltacat) or by two different familial Alzheimer's disease mutants.Thus, PS1 adds to the molecules that are known to regulate the rapid turnover of beta-catenin. (nih.gov)
  • The hyperproliferative response can be reversed by reintroducing PS1 expression or overexpressing axin, but not a PS1 mutant that does not bind beta-catenin (PS1Deltacat) or by two different familial Alzheimer's disease mutants. (nih.gov)
  • A substantial amount of research has been conducted on ADAM-10, a member of the ADAM family of proteins (ADAM =a disintegrin and metalloproteinase) that, among other functions, acts as an alpha-secretase and has been shown to prevent amyloid plaque formation in an Alzheimer's disease mouse model. (lmreview.com)
  • Despite its key role in the molecular pathology of Alzheimer's disease (AD), the physiological function of amyloid precursor protein (APP) is unknown. (frontiersin.org)
  • Accumulation of amyloid plaque is a common feature not only in Alzheimer's disease (AD), Creutzfeldt-Jakob Disease (aka Mad Cow disease), and the dementias associated with Parkinson's disease and Huntington's disease, but in the aging brain, brain injury, and certain chronic low grade infections, such as Lyme disease. (lmreview.com)
  • Soluble fragments of the amyloid precursor protein (APP) generated by α- and β-secretases, sAPPα and sAPPβ, have been postulated as promising new cerebrospinal fluid (CSF) biomarkers for the clinical diagnosis of Alzheimer's disease (AD). (biomedcentral.com)
  • J. Kang and B. Müller-Hill, "Differential Splicing of Alzheimer's Disease Amyloid A4 Precursor RNA in Rat Tissues," Nature, Vol. 325, 1987, pp. 733-736. (scirp.org)
  • T. E. Golde, S. Estus, M. Usiak, L. H. Younkin and S. G. Younkin, "Expression of B Amyloid Protein Precursor mRNAs: Recognition of a Novel Alternatively Spliced Form and Quantitation in Alzheimer's Disease Using PCR," Neuron, Vol. 4, 1990, pp. 253-267. (scirp.org)
  • Accumulation of the amyloid β-protein (Aβ) is one of the defining pathological features of Alzheimer's disease. (pubmedcentralcanada.ca)
  • Amyloid precursor protein proteolysis is critical for the development of Alzheimer's disease, a neurodegenerative disease associated with accumulation of amyloid plaques. (meta.org)
  • Alzheimer's disease (AD) is a chronic neurodegenerative disease associated with accumulation of amyloid plaques, which are comprised of amyloid beta. (meta.org)
  • Loss of GPR3 reduces the amyloid plaque burden and improves memory in Alzheimer's disease mouse models. (neurotree.org)
  • Genetic determinants of white matter hyperintensities and amyloid angiopathy in familial Alzheimer's disease. (neurotree.org)
  • Although the amyloid precursor protein (APP) and its proteolysis are regarded as key elements of the pathology of Alzheimer's disease, the physiological function of APP is not well understood and mice lacking App and the related gene Aplp2 die early postnatally without any obvious histopathological abnormalities. (phoenixpeptide.com)
  • Identification of the Alzheimer's disease amyloid precursor protein (APP) and its homologue APLP2 as essential modulators of glucose and insulin homeostasis and growth. (phoenixpeptide.com)
  • The 68 kDa human beta-secretase in brains of Alzheimer's disease patients contains heparan sulfate glycoconjugate,"Neurobiol. (patentgenius.com)
  • sub.1 -Antichymotrypsin in the Brain Amyloid Deposits of Alzheimer's Disease," Cell, 52:487-501 (1988). (patentgenius.com)
  • Increased Neuronal Endocytosis and Protease Delivery to Early Endosomes in Sporadic Alzheimer's Disease: Neuropathologic Evidence for a Mechanism of Increased .beta. (patentgenius.com)
  • Accumulation of β-amyloid protein (Aβ) is a key neuropathologic feature of Alzheimer's disease. (primarypsychiatry.com)
  • While the clinical diagnosis of Alzheimer's disease depends on recognition of typical cognitive deficits and behavioral disturbances, the neuropathologic hallmarks of the disease depend on detection of intra-cellular neurofibrillary tangles and extra-cellular amyloid plaques in the brain. (primarypsychiatry.com)
  • 2 The "amyloid hypothesis" is the most widely embraced theory for the causation of Alzheimer's disease and posits that the deposition of amyloid is an early crucial event that in turn leads to a cascade of other neuropathologic changes that culminate in the final full-blown disease. (primarypsychiatry.com)
  • One of the keys to understanding the mystery of Alzheimer's disease is elucidating the role of β-amyloid protein (Aβ). (primarypsychiatry.com)
  • HYF can decrease the levels of APP, Aβ, Aβand the activity of γ-secretase in hippocampus of Alzheimer's disease model mice. (bvsalud.org)
  • HYF can improve the learning and memory ability by inhibiting the activity of γ-secretase through the CREB/PEN-2 signaling pathway, and this may be one of the therapeutic mechanisms of HYF in Alzheimer's disease. (bvsalud.org)
  • Cleavage of the amyloid precursor protein by enzymes commonly referred to as β- and γ-secretase constitute an important process in the pathogenesis of Alzheimer's disease (AD). (springermedizin.de)
  • Holsinger RM, McLean CA, Beyreuther K, Masters CL, Evin G (2002) Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease. (springermedizin.de)
  • Tyler SJ, Dawbarn D, Wilcock GK, Allen SJ (2002) alpha- and beta-secretase: profound changes in Alzheimer's disease. (springermedizin.de)
  • Holsinger RM, McLean CA, Collins SJ, Masters CL, Evin G (2004) Increased beta-secretase activity in cerebrospinal fluid of Alzheimer's disease subjects. (springermedizin.de)
  • Beta-Amyloid-positive "neuritic plaque" in cerebral cortex as seen in a post-mortum specimen taken from an Alzheimer's disease patient. (antibodiesinc.com)
  • Nicastrin (NCSTN) is a component of the gamma-secretase complex and therefore potentially a candidate risk gene for Alzheimer's disease. (gcu.ac.uk)
  • Amyloid-β-protein (Aβ), the key component of senile plaques in Alzheimer's disease (AD) brain, is produced from amyloid precursor protein (APP) by cleavage of β-secretase and then γ-secretase. (biomedcentral.com)
  • Imaging agents capable of assessing amyloid-beta (Aβ) content in vivo in the brains of Alzheimer's disease (AD) subjects likely will be important as diagnostic agents to detect Aβ plaques in the brain, to help test the amyloid cascade hypothesis of AD, and as an aid to assess the efficacy of anti-amyloid therapeutics currently under development and in clinical trials. (pubmedcentralcanada.ca)
  • Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase specificity. (perfectmargin.com)
  • Amyloid precursor protein (APP), implicated in Alzheimer's disease, is a transmembrane protein of undetermined function. (hindawi.com)
  • 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 Alzheimer's disease. (google.com)
  • wherein X is CH 2 , O or S. The compounds inhibit gamma secretase without affecting Notch signalling, and hence find use in the treatment or prevention of Alzheimer's disease. (google.com)
  • Alzheimer's Disease (AD) is characterized by the abnormal deposition of amyloid in the brain in the form of extra-cellular plaques and intra-cellular neurofibrillary tangles. (google.com)
  • These protein clumps, known as amyloid plaques, are a key focus of research into Alzheimer's disease. (elifesciences.org)
  • Mutations in genes for proteins called presenilins cause an earlier onset form of Alzheimer's disease, in which symptoms can develop in people who are in their 40s or 50s. (elifesciences.org)
  • 2007). Expression of APP pathway mRNAs and proteins in Alzheimer's disease. (enacademic.com)
  • Mutations in critical regions of Amyloid Precursor Protein, including the region that generates amyloid beta, are known to cause familial susceptibility to Alzheimer's disease. (enacademic.com)
  • A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. (enacademic.com)
  • 1991). Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. (enacademic.com)
  • 2005). Crystallization and preliminary crystallographic studies of the copper-binding domain of the amyloid precursor protein of Alzheimer's disease. (enacademic.com)
  • Secretase: Implication for Alzheimer's Disease Pathogenesis. (grantome.com)
  • The pathogenesis of Alzheimer's disease (AD) is due, at least in part, to the formation in brain of insoluble protein deposits known as amyloid plaques. (biomedcentral.com)
  • Age, Amyloid precursor protein, Amyloid-β, Human brain Alzheimer's disease (AD) is the most common form of dementia accounting for an estimated 60%-80% of all cases (1). (deepdyve.com)
  • Alzheimer's disease is mainly characterized by specific hallmarks such as amyloid plaques, formed by insoluble A β 42 aggregates, and neurofibrillary tangles (NFTs), due to Tau hyperphosphorylation inducing microtuble disassemble. (biomedcentral.com)
  • I myself was involved in a program to target the secretase enzymes (the other end is clipped by beta-secretase) even before anyone was sure what enzymes they were. (sciencemag.org)
  • Secretases are enzymes that "snip" pieces off a longer protein that is embedded in the cell membrane. (wikipedia.org)
  • The process leading to the generation of A-beta which accumulates in characteristic plaques in the brains of AD patients begins when the amyloid precursor protein (APP) is cut into smaller proteins by enzymes called secretases. (seniorjournal.com)
  • Vassar, R. and Citron, M. (2000) Abeta-generating enzymes: recent advances in beta- and gamma-secretase research. (springer.com)
  • Enzymes called secretases snip it apart into three protein fragments, two of which are released outside the cell and one inside. (memory-key.com)
  • APP can be cleaved and processed by either alpha- or beta-secretase enzymes. (lmreview.com)
  • (In grad school neta is how we pronounced the Greek letter eta, which looks like a script N). The authors call the enzymatic activity forming them neta-secretase (clearly not all the enzymes which do this have been identified at this point). (wordpress.com)
  • The abundance of the APP processing enzymes Adam9 and Psen1 mRNA, which code for a minor alpha-secretase and gamma-secretase, respectively, were selectively enriched in wild type cytoplasm. (elsevier.com)
  • The resulting theory is that the disease is caused by amyloid toxicity, which impairs memory and triggers deposition of the microtubule associated protein, Tau, as neurofibrillary tangles. (jove.com)
  • The effects of EOs on pathological targets of AD and dementia including amyloid deposition (Aβ), neurofibrillary tangles (NFTs), cholinergic hypofunction, oxidative stress and glutamatergic abnormalities were focused. (frontiersin.org)
  • The Tau hypothesis states the Tau mutation is the cause, is the original cause of the disease and then the other symptom, neuronal loss and then deposition of amyloidal beta are both the consequence of this Tau mutation. (coursera.org)
  • The biological changes refer to the presence of neurofibrillary entanglement, senile plaques, amyloid deposition and synaptic loss in the brain. (mdpi.com)
  • Positron emission tomography (PET) imaging studies of amyloid deposition in human subjects with several Aβ imaging agents are currently underway. (pubmedcentralcanada.ca)
  • Amyloid deposition was assessed by immunohistochemistry, thioflavine S staining and western blot experiments. (biomedcentral.com)
  • Foci of activated micro- and astroglia were already detected at age 3 months, before any amyloid deposition. (biomedcentral.com)
  • Alzheimer disease (AD) is characterized by brain depositions of the beta amyloid (Beta-A). The Beta-A is the amyloid precursor protein (APP) digestion product, which is released from the cell after Beta-secretase and Gamma-secretase proteolysis. (asone-int.com)
  • PS1 and PS2 are homologous transmembrane proteins, and along with nicastrin, form high molecular mass multimeric protein complexes involved in the intramembranous proteolysis of several proteins including beta amyloid precursor protein (β-APP) and Notch receptor. (biolegend.com)
  • An understanding of the mechanism of γ-secretase proteolysis requires a detailed description of the three-dimensional organization of its transmembrane domains. (pubmedcentralcanada.ca)
  • In this context, we hypothesize that the differential localization of distinct gamma-secretase complexes and substrates at the cell surface and endosomes is part of the mechanism defining specificity in intramembrane proteolysis. (vib.be)
  • The notion of attenuating γ-secretase cleavage of APP via the APP adaptor proteins, Dab and Numb, is particularly attractive with regard to therapeutic potential, given that side effects of γ-secretase inhibition owing to impaired proteolysis of other γ-secretase substrates, e.g. (biomedcentral.com)
  • Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets. (embl-heidelberg.de)
  • This study represents an example of a potential role for intramembrane proteolysis in the maturation of a viral protein. (embl-heidelberg.de)
  • Presenilins have been shown to influence limited proteolysis of amyloid beta protein precursor (APP), Notch and ErbB4, and have been proposed to be gamma-secretases that perform the terminal cleavage of APP. (embl-heidelberg.de)
  • The ragged NH 2 - and COOH-termini of the native Aβ amyloid indicates that a complex mechanism of proteolysis is involved in its biogenesis. (google.com)
  • Signalling through the receptor protein Notch, which is involved in crucial cell-fate decisions during development, requires ligand-induced cleavage of Notch. (nih.gov)
  • GSK-3 is an important kinase involved in many biochemical properties including: neurological disorders, diabetes, cancer and signaling pathways such as WNT/beta-catenin and NOTCH as well as others. (theflow.org)
  • There have been several attempts to explain that result - the compound wasn't potent enough, it didn't to the right things to gamma-secretase, or it was the side effects for Notch signaling that caused the trouble. (sciencemag.org)
  • γ-secretase plays a critical role in developmental signalling by the transmembrane receptor Notch, freeing the cytoplasmic tail of Notch to travel to the cell nucleus to act as a transcription factor. (wikipedia.org)
  • In this study, we compared the histopathologic and biochemical profiles of ten FAD cases expressing independent PSEN mutations and determined the degradation patterns of amyloid-β precursor protein (AβPP), Notch, N-cadherin and Erb-B4 by γ-secretase. (biomedcentral.com)
  • The risk of side effects from γ-secretase inhibition is high, in part because this secretase also cuts Notch, an essential protein for numerous biological functions. (alzforum.org)
  • A paper in yesterday's Nature online offers a new tack for this field by reporting the discovery of a γ-secretase activating protein (GSAP) that acts specifically to promote the binding of γ-secretase to APP, but not to Notch. (alzforum.org)
  • Unfortunately, while they block gamma-secretase, they also appear to block another protein called Notch-1 that is essential for proper functioning of the nervous and immune systems. (alzinfo.org)
  • Gleevec also blocks the activities of gamma-secretase but, as Fisher Center researchers have now shown, it does not inhibit Notch-1. (alzinfo.org)
  • Subchronic dosing with either GSI rather impaired normal cognition in 3-month-old Tg2576 mice, with no inhibition on the processing of other γ-secretase substrates, such as Notch, N-cadherin, or EphA4, in the brain. (jneurosci.org)
  • Two of the most widely known and studied of these substrates are the amyloid precursor protein (APP) and the Notch receptor, which are precursors for the generation of amyloid-β (Aβ) and the Notch intracellular domain (NICD), respectively. (edu.au)
  • γ-Secretase is an aspartyl transmembrane protease that cleaves a number of type I membrane protein substrates, including APP and Notch, in the middle of their transmembrane domains in a poorly understood process of hydrolysis within a hydrophobic environment ( 3 ). (pubmedcentralcanada.ca)
  • Optimization based on potency, Notch/amyloid-beta precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). (qub.ac.uk)
  • A number of type-I transmembrane proteins including Notch, p75NTR, CD44, ErbB4, neuregulin-1, and alcadein undergo a similar secretase mediated processing leading to ectodomain shedding and generation of intracellular domains (ICD's) [ 5 ]. (hindawi.com)
  • Building on more than 1,600 compounds we've synthesized, we will develop SARs for inhibiting APP vs. Notch, and for the most selective compounds, assess cleavage of other gamma-substrates and test them in mice. (grantome.com)
  • Moreover, although APP is normally processed to secreted and membrane-bound fragments, sAPPbeta and CTFbeta, by BACE, and the latter is subsequently processed by gamma-secretase to Abeta and CTFgamma, this pathway mostly yields Abeta of 40 residues, and increases in the levels of the amyloidogenic 42-residue Abeta (Abeta42) are seen in the majority of the mutations linked to the disease. (jove.com)
  • Multiple Abeta-lowering therapies are currently in development: an important goal is to characterize the molecular mechanisms of action and effects on physiological processing of Abeta, as well as other amyloid precursor protein (APP) metabolites, in models which approximate human Abeta physiology. (nih.gov)
  • Exacerbated ROS/RNS production results in macrophage activation in the arteries and glial activation in the brain, both of which promote beta-secretase processing of APP and Abeta formation-a potentially vicious cycle. (lmreview.com)
  • While the specific mechanisms of beta-amyloid's involvement in neuropathology remain to be fully characterized, the preponderance of evidence indicates that beta-amyloid (Abeta) accumulation plays a significant role in AD, promoting inflammation and oxidative stress, and increasing the aging brain's vulnerability to functional impairment and neuronal atrophy. (lmreview.com)
  • Advances in diagnosis and palliative treatment of AD, and other age-related neuropathologies involving the accumulation of soluble Abeta and amyloid-beta plaque, have done nothing to lessen their rapidly escalating incidence in the United States. (lmreview.com)
  • The transient expression of ABCA7 in human embryonic kidney cells significantly stimulated cholesterol efflux (fourfold) to apolipoprotein E (apoE) discoidal lipid complexes but not to lipid-free apoE or apoA-I. ABCA7 also significantly inhibited Abeta secretion from Chinese hamster ovary cells stably expressing human amyloid precursor protein (APP) or APP containing the Swedish K670M671-->N670L671 mutations when compared with mock-transfected cells. (edu.au)
  • We showed that all NCSTN-BAC haplotypes expressed nicastrin protein and rescued gamma-secretase activity and amyloid beta (Abeta) production in NCSTN-BAC(+)/Ncstn(-/-) lines. (gcu.ac.uk)
  • EGCG prevents certain apoptotic (pre-programmed) cell death through inhibiting the elevation of Abeta (a protein involved with Alzheimer's and also involved with DS) via inhibition of beta and gamma-secretases. (blogspot.com)
  • abstract = "Fragile X mental retardation protein (FMRP) binds to and regulates the translation of amyloid-β protein precursor (App) mRNA, but the detailed mechanism remains to be determined. (elsevier.com)
  • The α-secretase gene has not been conclusively identified but is believed to be a metalloproteinase. (wikipedia.org)
  • R. L. Neve, E. A. Finch and L. R. Dawes, "Expression of the Alzheimer Amyloid Precursor Gene Transcripts in the Human Brain," Neuron, Vol. 1, 1988, pp. 669-667. (scirp.org)
  • One substrate of γ-secretase is encoded by the gene AMYLOID BETA A4 PRECURSOR PROTEIN (A βPP/APP ) that is a fAD mutation locus. (iospress.com)
  • The APP (for amyloid precursor protein) contains anywhere from 563 to 770 amino acids in 5 distinct transcripts made by alternate splicing of the single gene. (wordpress.com)
  • Embryonic stem cell-derived neurons as a cellular system to study gene function: lack of amyloid precursor proteins APP and APLP2 leads to defective synaptic transmission. (phoenixpeptide.com)
  • The purpose of this study is to investigate whether nicotinic acid (NA) and nicotinamide (NAM) reduce the Alzheimer disease (AD)-related gene expression in brain tissues of amyloid beta (Aβ)-injected mice. (bvsalud.org)
  • Protein products of the regenerating islet-derived (REG) gene family are important regulators of many cellular processes. (bvsalud.org)
  • This subtle phenotype is probably due to compensatory effects mediated by two other members of the APP gene family: amyloid-precursor-like protein-1 and -2 (APLP1 and APLP2). (hindawi.com)
  • Genomic organization of the human amyloid beta-protein precursor gene "Gene" 87:257-263. (enacademic.com)
  • 1993). Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice "Nat Genet" 5:22-30. (enacademic.com)
  • Beta-amyloid builds up in the brains of those with the disease, forming sticky patches called plaque and killing off healthy cells. (alzinfo.org)
  • Herein the aspects of the possible impact of intracellular amyloid-β in human AD pathology are discussed, as well as recent observations from a rat transgenic model with a phenotype of intracellular accumulation of Aβ fragments in neurons of the hippocampus and cortex, without plaque formation. (springer.com)
  • an experimental drug now in human clinical trials for treatment of mild-to-moderate Alzheimer's, Alzhemed works by binding with amyloid beta to prevent plaque formation. (memory-key.com)
  • It's speculated that the creation of amyloid plaque is a byproduct of a misregulation in normal APP processing. (memory-key.com)
  • Amyloid plaque and atherosclerotic plaque have much in common. (lmreview.com)
  • 4 In mice bred to over-express APP in neurons, concomitant over-expression of ADAM-10 causes increased production of APPsα, reduced formation of amyloid plaque, and a reduction in cognitive deficits. (lmreview.com)
  • And as was said, the pathological hall markers of this disease is one neurofibrillary tangle inside the cell and the other one is amyloid plaque or in another way called senile plaque. (coursera.org)
  • So this is in the senile plaque or called amyloid plaque and then these are the small molecule of amyloid beta to form these big aggregates. (coursera.org)
  • Preventing this release might provide a means to reduce gamma-secretase activity and thus amyloid plaque formation. (vib.be)
  • In the last 25 years research have moved from the first identification of Aβ as a significant component of the senile plaque of patients with the disease to an advanced understanding of many of the basic metabolic pathways that control the production of this protein. (primarypsychiatry.com)
  • The ability to quantify regional Aβ plaque load in the brains of living human subjects has provided a means to begin to apply this technology as a diagnostic agent to detect regional concentrations of Aβ plaques and as a surrogate marker of therapeutic efficacy in anti-amyloid drug trials. (pubmedcentralcanada.ca)
  • Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternat. (nih.gov)
  • this demonstrates an alternative degradation pathway for CNS amyloid precursor protein during gamma-secretase inhibition. (nih.gov)
  • This suggests that GSAP inhibition could be a promising therapeutic approach to lowering amyloid levels while avoiding toxic side effects. (alzforum.org)
  • Inhibition of beta secretase activity results in accumulation of CTFneta and Aneta-alpha. (wordpress.com)
  • We previously showed that inhibition of the GTPase dynamin reduced APP internalization and increased release of sAPPα, apparently by prolonging the interaction between APP and α-secretases at the plasma membrane. (biomedcentral.com)
  • Surface levels of ADAM10 were unaffected by activation of protein kinase C (PKC) or M3 receptors, indicating that receptor-coupled shedding of the ADAM substrate APP is unlikely to be mediated by inhibition of ADAM10 endocytosis in this cell line. (biomedcentral.com)
  • We observed a wide variation in type, number and distribution of amyloid deposits and neurofibrillary tangles. (biomedcentral.com)
  • The vast majority of FAD, resulting from mutations in the AβPP and PSEN genes, share the neuropathology observed in sporadic AD (SAD) which typically includes amyloid plaques and cerebral amyloid angiopathy, as well as neurofibrillary tangles (NFT) composed of hyperphosphorylated tau. (biomedcentral.com)
  • In the brains of Alzheimer's patients there are millions of small structures called "neurofibrillary tangles", made up primarily of a protein named tau . (randombio.com)
  • As Ab self-aggregates into oligomers and forms plaques, it is accompanied by neurofibrillary tangles (NFT) containing hyperphosphorylated microtubule-associated protein tau (MAPT). (clontech.com)
  • AD is characterized histopathologically by the presence and abundance of two different abnormal aggregated proteins, amyloid plaques and neurofibrillary tangles, in brain tissue ( Fig 1 ) [ 3 ]. (pubmedcentralcanada.ca)
  • Neurofibrillary tangles (NFTs) are composed mainly of hyperphosphorylated forms of the microtubule-associated protein, tau [ 5 ]. (pubmedcentralcanada.ca)
  • Phosphorylated GSK3β increased significantly with age, a possible precursor for neurofibrillary tangle production, although phosphorylated tau was undetectable. (deepdyve.com)
  • So instead of generating the toxic A-beta fragment, cleavage with alpha-secretase produces a protein fragment that has been reported to protect and stimulate the generation of neurons in brain. (seniorjournal.com)
  • He and colleagues characterized GSAP by using co-immunoprecipitations, showing that it binds both the γ-secretase complex and the membrane-bound, β-secretase-cleaved C-terminal fragment of APP. (alzforum.org)
  • Here, we have developed a novel approach based on Gaussia princeps luciferase protein-fragment complementation assay to quantitively investigate protein partitioning to cholesterol and sphingomyelin-rich domains, sometimes called 'lipid rafts', in intact living cells with a high-spatial resolution. (portlandpress.com)
  • Here we functionally characterise a non-protein coding product of the family, the long noncoding RNA (lncRNA) REG1CP that is transcribed from a DNA fragment at the family locus previously thought to be a pseudogene. (bvsalud.org)
  • The beta -amyloid protein precursor (APP) is cleaved by beta -secretase, producing a soluble derivative of the protein and a membrane anchored 99-amino acid carboxy-terminal fragment (C99). (mybiosource.com)
  • Alternatively, APP may be cleaved within its Aβ domain by α-secretases, precluding the formation of Aβ, and releasing sAPPα, a large soluble N-terminal fragment, from the cell surface. (biomedcentral.com)
  • γ-Secretase then cleaves βCTF to produce Aβ and a C-terminal fragment (2-3), primarily after APP has undergone endocytosis (4). (deepdyve.com)
  • Many people had assumed that such mutations somehow turned gamma-secretase loose to do its amyloid-forming work earlier and more thoroughly, but Jie Shen and Raymond Kelleher's work had been pointing at the opposite conclusion: that these mutations inactivated gamma-secretase, and that this inactivation was a risk factor for Alzheimer's. (sciencemag.org)
  • Now in this new paper, they've generated mice with two of the most common such mutations, and they find that (1) their gamma-secretase activity is indeed impaired, and (2) they show Alzheimer's-type pathology in their brains - in fact, some of the most human-like pathology that has yet been seen in a rodent model. (sciencemag.org)
  • Nevertheless, a few exceptional FAD mutations and the presence of large amounts of amyloid deposits in a group of cognitively normal elderly patients suggest that the disease process is more complex. (jove.com)
  • In the report from Massachusetts General Hospital (MGH), which will appear in the October 16 issue of Neuron and has been released online, the investigators from the MassGeneral Institute for Neurodegenerative disease (MGH-MIND) describe how the two mutations in ADAM10 increase generation and accumulation of the toxic amyloid beta (A-beta) protein in the brains of a mouse model of AD. (seniorjournal.com)
  • Since ADAM10 was already known to be important to alpha-secretase processing of APP, along with having a role in early brain development, the researchers set out to investigate how the observed mutations might lead to the pattern of neurodegeneration characteristic of AD. (seniorjournal.com)
  • Jaehong Suh, PhD, of the MGH-MIND Genetics and Aging Research Unit, lead author of the Neuron article, says, 'Our current study shows that reducing ADAM10 activity by these AD-associated mutations delivers a 'one-two punch' to the brain one, decreasing neuroprotective alpha-secretase cleavage products and two, increasing neurotoxic A-beta protein accumulation. (seniorjournal.com)
  • These observations imply that missense mutations in PSEN genes can alter a range of key γ-secretase activities to produce an array of subtly different biochemical, neuropathological and clinical manifestations. (biomedcentral.com)
  • As PS1 has been shown to play a critical role in facilitating γ-secretase activity, and mutations in this protein are associated with familial AD (FAD), we have cloned it from SAMP8 mouse hippocampus and compared its sequence with those of other species. (biologists.org)
  • We present a case for an alternative interpretation of published data on the role of γ-secretase activity and fAD-associated mutations in AD pathology. (iospress.com)
  • Tg2576 mice (Tg(APPSWE)2576Kha), which express human [beta]-amyloid precursor proteins (hAPP) containing the K670N and M671L mutations on a 129S6 genetic background, were purchased from Taconic Farms, Inc. (Hudson, NY, USA) [11]. (thefreelibrary.com)
  • Among other roles in the cell, secretases act on the amyloid-beta precursor protein (APP) to cleave the protein into three fragments. (wikipedia.org)
  • APP is cleaved by three secretases known as α, β, and γ secretase which act on APP at different sites producing various fragments of differing amino acid length. (scirp.org)
  • Another set of carboxy terminal fragments (CTFs) called CTFneta is formed from the amyloid precurosr protein (APP). (wordpress.com)
  • We and others have shown that these diseases are frequently caused by the accumulation neurotoxic proteins or protein fragments. (cam.ac.uk)
  • amyloid precursor protein c-terminal fragments and the generation of amyloid .beta. (patentgenius.com)
  • 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. (biomedcentral.com)
  • Both the amyloidogenic and nonamyloidogenic pathways, that is, the cleavages of APP by β - and α -secretases, respectively, liberate the soluble ectodomain of APP (ectodomain shedding) and retain the C-terminal fragments (CTF) (CT99 and CT83, resp. (hindawi.com)
  • A minor portion of APP s is released by a β-secretase, which cleaves near the NH 2 -terminus of Aβ and produces COOH-terminal fragments (CTFs) which contain the whole Aβ domain. (google.com)
  • 2003). Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity, and memory. (enacademic.com)
  • ADDLs are a form of amyloid beta, but differ from plaques in that they are very much smaller, are soluble and diffuse between brain cells until they find vulnerable synapses. (memory-key.com)
  • Cellular Actions of Beta-amyloid Precursor Protein and Its Soluble and Fibrillogenic Derivatives. (google.com)
  • However, the capacity of these soluble proteins to assemble has not been explored and could be relevant. (biomedcentral.com)
  • Cleavage by α- and β-secretase also generates soluble forms of APP, named sAPPα and sAPPβ, respectively, which are present in human CSF [ 4 , 5 ] and have been postulated as potential new AD biomarkers. (biomedcentral.com)
  • Alternatively, α -secretases cleave APP within the Aβ domain, precluding Aβ formation and releasing the soluble ectodomain, sAPPα. (biomedcentral.com)
  • In the nonamyloidogenic pathway, α-secretase cleaves APP within Aβ to release soluble APPα (sAPPα) therefore precluding the production of Aβ (5). (deepdyve.com)
  • In addition to APP, γ-secretase also cleaves many other type I transmembrane (TM) protein substrates. (meta.org)
  • PURPOSE: Presenilins are functionally important components of γ-secretase, which cleaves a number of transmembrane proteins. (bvsalud.org)
  • α-secretase cleaves the majority of APP in the middle of the Aβ region of APP. (biomedcentral.com)
  • Most APP s is released by a putative α-secretase which cleaves within the Aβdomain (between residues Lys 16 and Leu 17 ) to release (α-APP s and precludes the release of intact Aβ. (google.com)
  • This echoes Karran and Hardy's paper (A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease. (sciencemag.org)
  • Hardy, J. (1999) The shorter amyloid cascade hypothesis. (springer.com)
  • And then A-beta hypothesis stating the A-beta is the primary cause of the disease and then the aggravation of tau and the neural loss are the consequence of A-beta aggregation. (coursera.org)
  • Cell death hypothesis says that synaptic and neuronal loss is the primary cause of the disease and then the aggregation of tau and A-beta are the consequence of synaptic and neuron loss. (coursera.org)
  • So let's look at the A-beta hypothesis more closely. (coursera.org)
  • The current amyloid hypothesis of AD states that the imbalance between Aβ generation and Aβ clearance is the basis of AD neuropathogenesis. (biomedcentral.com)
  • However, the relative failures of Aβ-centric therapeutics suggest that the amyloid hypothesis is incomplete and/or that the treatments were given too late in the course of AD, when neuronal damages were already too extensive. (sciencemag.org)
  • Scientists at the Fisher Center and other research institutes had previously shown that the brain toxin beta-amyloid is produced when a large protein called APP, or amyloid precursor protein, is chopped into smaller pieces by scissor-like proteins called beta-secretase and gamma-secretase. (alzinfo.org)
  • The cleavage is performed by α, β, and γ secretases in the brain. (google.com)
  • Normally, tau proteins serve to stabilize microtubules in the neurons in the brain, and are essential for axonal growth and development. (google.com)
  • Amyloid precursor protein (APP) is a transmembrane protein concentrated in the plasma (outer) membrane of brain cells, including neurons, glial cells, the cells lining the perivascular channels that drain into the CNS, and the endothelial cells of the blood brain barrier. (lmreview.com)
  • So this protein normally under physiological conditions is highly expressed in our neurons and in brain region. (coursera.org)
  • Oral administration of 4 significantly reduced A beta 40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs. (qub.ac.uk)
  • Quantify human Amyloid Beta (1-x) and human Amyloid Beta Oligomers (82E1 specific) in serum, plasma, CSF, brain tissue extract, or cell culture media. (clontech.com)
  • However, with the progress in medical technology, in vivo detection of pathological changes in the brain directly via advanced imaging techniques (magnetic resonance imaging (MRI) and positron emission tomography (PET)) and indirectly via biomarkers in cerebrospinal fluid (CSF) (tau, phosphorylated tau and 42 amino acid isoform of beta-amyloid protein (Aβ42)), is made possible nowadays [ 2 , 3 ]. (mdpi.com)
  • Aβ42 injection was confirmed by Western blot analysis of Aβ42 protein in brain tissue. (bvsalud.org)
  • Matsumoto et al, "Human brain beta-secretase contains heparan sulfate glycoconjugates," Neurosci. (patentgenius.com)
  • Composition of white matter bovine brain coated vesicles: evidence that several components influence .beta. (patentgenius.com)
  • A Novel Brain Cysteine Protease Forms and SDS Stable Complex with the .beta. (patentgenius.com)
  • secretase-like specificity," Brain Research, 750:11-19 (1997). (patentgenius.com)
  • This article discusses the current status of various strategies aimed at reducing amyloid burden in the brain. (primarypsychiatry.com)
  • These criteria depend in part on such factors as the age-adjusted density of certain types of amyloid-containing plaques (neuritic vs. diffuse) in specific sampled brain areas. (primarypsychiatry.com)
  • In AD, the Aβ component far outweighs the other amyloid-related protein components, such as NFTs, on a total mass basis in most brain regions [ 9 ]. (pubmedcentralcanada.ca)
  • Purification and cloning of amyloid precursor protein β-secretase from human brain. (perfectmargin.com)
  • The rate of amyloid accumulation is a combination of the rates of formation, aggregation and egress from the brain. (google.com)
  • A hallmark of this condition is progressive loss of memory, accompanied by a buildup of hard clumps of protein between the brain cells. (elifesciences.org)
  • Untangling the effects of amyloid plaques and presenilins on brain cells in humans is challenging. (elifesciences.org)
  • This kind of damage to brain cells did not depend on amyloid plaques. (elifesciences.org)
  • Our extensive supporting data include robust co-IP of endogenous a- and gamma-secretases from wt brain and the sequential alpha/gamma processing of an APP substrate. (grantome.com)
  • Examination of the cerebrospinal fluid (CSF) indicates that the full length and truncations of the Notch1 protein are reduced in AD patients hinting at an accumulation in the brain parenchyma. (biomedcentral.com)
  • 8 Presenilins are a set of proteins that are part of the gamma secretase complex, which helps cleave APP to form Aβ. (google.com)
  • In this work, we have used a combination of different sequence database search methods to identify a new family of proteins homologous to presenilins. (embl-heidelberg.de)
  • During CME, plasma membrane proteins are packaged into clathrin-coated vesicles which are internalized into the cell and fuse with early/sorting endosomes. (deepdyve.com)
  • Amyloid β Oligomers Disrupt Blood-CSF Barrier Integrity by Activating Matrix Metalloproteinases. (neurotree.org)
  • 2007) Protein Phosphatase 2A Methyltransferase Links Homocysteine Metabolism with Tau and Amyloid Precursor Protein Regulation. (clontech.com)
  • We then discuss the main ideas regarding the role of γ-secretase and the PSEN genes in this disease. (iospress.com)
  • Here we show that glutamatergic neurons differentiated from ESCs lacking both genes reveal a decreased expression of the vesicular glutamate transporter 2 (VGLUT2) both at the mRNA and protein level, as well as a reduced uptake and/or release of glutamate. (phoenixpeptide.com)
  • A number of genes of small risk for AD were identified in genome-wide association studies (GWAS), including genes coding for proteins involved in endocytosis, PICALM, BIN-1, and sorLA (sorting protein-related receptor) (20). (deepdyve.com)
  • Despite substantial progress in establishing the full identity of γ-secretase ( 7 - 9 , 13 , 14 ) and the step-wise assembly of the γ-secretase complex ( 7 , 15 , 16 ), the molecular structure of the protease complex or even any of its individual components remains unknown. (pubmedcentralcanada.ca)
  • β-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. (perfectmargin.com)
  • Three secretase subtypes referred to as alpha, beta, and gamma have been identified based upon the region of amyloid protein precursor they cleave. (curehunter.com)
  • Remarkably it is very difficult (for me at least) to find out just at what amino acids of the amyloid precursor protein(s) the 3 secretases (alpha, beta, gamma) cleave. (wordpress.com)
  • Sustained levels of antibodies against Aβ in amyloid-rich regions of the CNS following intravenous dosing in human APP transgenic mice. (nih.gov)
  • Transgenic mice overexpressing the london mutant of amyloid precursor protein, APP [V717I], robustly recapitulate the amyloid pathology of AD. (biomedcentral.com)
  • In the current application, we plan to elucidate the impact of a high protein diet on the profile of gut hormones released postprandially in obese subjects and the underlying changes at the neuronal (vagal afferent) level that take place in response to a high protein diet in a relevant experimental model. (bioportfolio.com)
  • Amyloid Beta is a derivative of the Amyloid Precursor Protein (APP), which is a protein that is believed to modulate neuronal excitability, synaptic plasticity, synaptogenesis, and neurite outgrowth. (google.com)
  • Early beta amyloid accumulation within neurons is the trigger for the onset of memory decline in Alzheimer's. (memory-key.com)
  • Tiny toxic proteins only discovered a few years ago, they attack specific synapses rather than the neurons themselves. (memory-key.com)
  • 3 Eventually, the degenerate neurons become clumped into the amyloid plaques which are insoluble and unable to be broken down by the body. (google.com)
  • Beta-amyloid and Its Damaging Effects on Neurons. (google.com)
  • There is some suggestion that this process might make use of amyloid precursor protein (APP) , a large protein that is often found in the growing tips of neurons where it may participate in synaptogenesis (the formation of new synapses) or cell adhesion. (randombio.com)
  • Blocking gamma-secretase cleavage of APP in wild-type neurons resulted in a similar decrease of VGLUT2 expression, whereas VGLUT2 levels could be restored in App-/-Aplp2-/- neurons by a construct encompassing the C-terminal intracellular domain of APP. (phoenixpeptide.com)
  • Matrix Metalloproteinase-9 (MMP-9) Is Synthesized in Neurons of the Human Hippocampus and Is Capable of Degrading the Amyloid-.beta. (patentgenius.com)
  • However, numerous treatment strategies are being tested that are aimed at each step of the amyloid pathway-from its initial liberation, to its early aggregation, and finally to the eventual formation of insoluble β-pleated sheets. (primarypsychiatry.com)
  • Amyloid Precursor Protein Secretases" is a descriptor in the National Library of Medicine's controlled vocabulary thesaurus, MeSH (Medical Subject Headings) . (ucdenver.edu)
  • AL amyloid imaging and therapy with a monoclonal antibody to a cryptic epitope on amyloid fibrils. (nih.gov)
  • APP is cleaved by gamma-secretase that releases the APP intracellular domain (AICD) in the cytoplasm. (hindawi.com)
  • They also showed that both compounds lowered levels of beta-amyloid that accumulate in the brains of live adult guinea pigs that produce beta-amyloid chemically identical to that made by people. (alzinfo.org)
  • PD and DLB are characterized by aggregation of the synaptic protein α-synuclein, and there is compelling evidence to suggest that progression of these diseases is associated with the trans-cellular spread of pathogenic α-synuclein through the brains of afflicted individuals. (bvsalud.org)
  • On the other hand, the function of this ubiquitously expressed protein in healthy brains remains poorly understood. (frontiersin.org)
  • To achieve this, alterations of γ-secretase complex expression and activity were detected in the mitochondrial fraction derived from brains of NSE/hPS2m Tg mice and Non-Tg mice. (bvsalud.org)
  • Aβ40 and Aβ42 were significantly increased in old brains, while APP and secretase expression was unaffected by age. (deepdyve.com)
  • The wide spectrum of γ-secretase substrates has made analyses of the pathology of γ-secretase-related diseases and underlying mechanisms challenging. (edu.au)
  • These observations have resulted in … a focus on γ-secretase activity and Aβ as we attempt to understand the molecular basis of AD pathology. (iospress.com)
  • Hence, it is striking to see that very few studies have extensively characterized, from anatomy to behavior, the alterations associated with pre-amyloid stages in mouse models of AD amyloid pathology. (sciencemag.org)
  • An increased amount or mutation(s) in PS1, which alters the stoichiometric balance of the γ-secretase complex, may be the cause of aberrant or increased processing of APP, resulting in Aβ accumulation leading to loss of memory. (biologists.org)
  • PS2M1 mice express human PS2 proteins containing the N141I mutation on a C57BL/6JJcl background (purchased from Immuno-Biological Laboratories Co, Ltd., Fujioka, Japan) [22, 23]. (thefreelibrary.com)
  • The common rats or mice we used in our lab, they do not naturally have accumulation of amyloid with age. (coursera.org)
  • Since KRAS proteins must be associated to the plasma membrane for their function, targeting KRAS plasma membrane localization represents a logical and potentially tractable therapeutic approach [2]. (eurekaselect.com)
  • Therefore, an increase in α-secretase activity is an attractive therapeutic target for AD treatment. (mdpi.com)
  • In this regard, it has been suggested that highly-selective antibodies can be administered as therapeutic agents targeting pathogenic proteins. (bvsalud.org)
  • Despite our lack of full knowledge concerning the identity of APP α-secretase, it is clear that the activation of these proteases may offer new therapeutic methods. (perfectmargin.com)
  • Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool. (neurotree.org)
  • The cleavage of the APP cytoplasmic tail by γ-secretase generates AICD, which contains the strongly conserved YENPTY-motif. (biomedcentral.com)
  • A paper in Neuron from Harvard/Mass General/Brigham & Women's says that we may have been thinking about gamma-secretase the wrong way around. (sciencemag.org)
  • There is some evidence suggest this protein can have function, or can have a role in neuron upgrowth and extension. (coursera.org)
  • Amyloid precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapse s of neuron s. (enacademic.com)
  • Besides their involvement in the pathogenesis of Alzheimer's, these proteins also have other functional roles in the cell. (wikipedia.org)
  • In addition to the debate as to how g-secretase may be involved in AD, a paper by De Strooper (Lessons from a failed γ-secretase Alzheimer trial. (sciencemag.org)
  • Acx H, Serneels L, Radaelli E, Muyldermans S, Vincke C, Pepermans E, Müller U, Chávez-Gutiérrez L, De Strooper B . Inactivation of γ-secretases leads to accumulation of substrates and non-Alzheimer neurodegeneration. (neurotree.org)
  • This isn't idle chatter as Aneta-alpha, and Aneta-beta are found in the dystrophic neurites in an Alzheimer mouse model (human work is sure to follow). (wordpress.com)
  • Manipulations of PSEN1 and PSEN2 have been separately studied in Alzheimer disease (AD) and cancer because both involve substrates of γ-secretase. (bvsalud.org)
  • La más común es ocasionada por la enfermedad de Alzheimer, que se define como un trastorno neurodegenerativo que produce una alteración progresiva de la memoria y de otras habilidades mentales, por una pérdida de volumen en los lóbulos temporales, en especial en las áreas mediales como el hipocampo y la corteza entorrinal. (bvsalud.org)
  • Fukumoto H, Cheung BS, Hyman BT, Irizarry MC (2002) Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. (springermedizin.de)
  • Clearly, amyloid deposits are an invariable feature of AD. (jove.com)
  • The dissociated tau protein becomes tangled and deposits inside the cell. (google.com)
  • This presents more binding sites (higher B max ) for aggregated Aβ binding relative to NFT binding sites for ligands with high binding affinities for these protein deposits. (pubmedcentralcanada.ca)
  • Thus, alpha-secretase cleavage precludes amyloid beta formation and is considered to be part of the non-amyloidogenic pathway in APP processing. (wikipedia.org)
  • Vascular alterations in PDAPP mice after anti-Aβ immunotherapy: Implications for amyloid-related imaging abnormalities. (nih.gov)
  • Endopeptidases that are specific for AMYLOID PROTEIN PRECURSOR. (curehunter.com)
  • Therefore Greengard and colleagues set out to understand how it blocked the secretase complex so they could develop a better drug. (alzforum.org)
  • First author Gen He added a radiolabeled, photoactivatable nitrogen group to imatinib, then incubated this derivative with a membrane preparation containing the γ-secretase complex. (alzforum.org)
  • 2. The method of claim 1, wherein the protein biomarker complex comprises transthyretin and prostaglandin-H2 D-isomerase. (patentsencyclopedia.com)
  • 7. The method of claim 1, wherein the correlating step comprises comparing an amount of said protein biomarker complex with a reference value in a control sample. (patentsencyclopedia.com)
  • will no doubt agree that this work from Yigong Shi's group represents a tour de force in applying cryoEM to the structure of the γ-secretase complex with either of two key substrates cross-linked to it. (alzforum.org)
  • 1: A new cell biological model of secretase processing We have discovered that contrary to current concepts, alpha- (ADAM 10), beta- and gamma-secretases exist in part in a large protein complex that can mediate efficient sequential processing of substrates. (grantome.com)
  • 2: The complex regulation of gamma-secretase by membrane lipids. (grantome.com)
  • β-Amyloid inhibits E-S potentiation through suppression of cannabinoid receptor 1-dependent synaptic disinhibition. (nih.gov)
  • cDNA cloning and tissue distribution of five human EPH-like receptor protein-tyrosine kinases", Dept of Immunology Amen Center, CA 91320-1789, Oncogene 1995 897-905. (patentgenius.com)
  • This binding is competed early in the secretion pathway by Rer1p, a membrane receptor that retrieves proteins from the Golgi back to the ER. (vib.be)
  • In this study, by overexpressing AICD in mouse neuroblastoma cell lines, we have demonstrated the alteration in the expressions of two proteins, patched homolog 1 (PTCH1), a receptor for sonic hedgehog signaling, and transient receptor potential cation channel subfamily C member 5 (TRPC5), a component of receptor-activated nonselective calcium permeant cation channel. (hindawi.com)
  • The amyloid precursor protein (APP or AβPP) has a receptor-like structure with a large ectodomain, a membrane spanning region and a short cytoplasmic tail. (google.com)
  • Therefore, regulation of PS1 transcription modulates gamma-secretase activity. (nih.gov)
  • Several such proteins, notably ADAM10, have been identified as possessing alpha-secretase activity. (wikipedia.org)
  • constitutive activity occurs mainly at the cell surface and is independent of regulatory mechanisms inside the cell, while regulated activity occurs mainly in the golgi and is dependent on the activity of protein kinase C. Alpha-secretase activity in the golgi is thought to compete directly with the beta-secretase pathway for APP substrates during membrane protein maturation. (wikipedia.org)
  • The activity of alpha secretases has been implicated in the regulation of learning and memory formation. (wikipedia.org)
  • Alpha-secretase activity of the disintegrin metalloprotease ADAM 10. (wikipedia.org)
  • So, is there anything that increases gamma-secretase activity? (sciencemag.org)
  • Thus, we believe that increasing ADAM10 activity might help to alleviate both genetic and environmental AD risk factors that increase the toxic beta-secretase processing of APP. (seniorjournal.com)
  • We found that α-secretase activity is significantly elevated in the presence of FAs with short chain length and in the presence of polyunsaturated FAs, whereas variations in the phospholipid headgroups, as well as the double-bond position, have little or no effect on α-secretase activity. (mdpi.com)
  • Overall, our study shows that local lipid membrane composition can influence α-secretase activity and might have beneficial effects for AD. (mdpi.com)
  • Drug researchers have been searching for compounds that inhibit these secretases, because blocking their activity would halt production of beta-amyloid. (alzinfo.org)
  • In this model, the intracellular amyloid-β phenotype is accompanied by increased MAPK/ERK activity and tau hyperphosphorylation. (springer.com)
  • In contrast, changes to either of two highly conserved histidines (H171A, H197A) located in TM5 and TM6 negatively affected PS1 cleavage and altered binding to other secretase components, resulting in decreased amyloid generating activity. (nih.gov)
  • This cell line has been validated using different inhibitory compounds for Gamma-secretase (positive controls) and Beta-secretase activity (negative controls). (asone-int.com)
  • Synaptic activity prompts .gamma. (patentgenius.com)
  • 1. A method of screening for compounds which affect the cleavage activity of EphA4 by .gamma. (patentgenius.com)
  • and (iv) identifying the candidate compounds selected in step (iii) as compounds which affect the cleavage activity of EphA4 by .gamma. (patentgenius.com)
  • Decreasing the amount of Rer1p led to an increase in gamma-secretase activity. (vib.be)
  • Holoprotein multimerization may be required for the endoproteolysis that activates PSENs' γ-secretase activity. (iospress.com)
  • Based on these observations, these results indicate that alteration of γ-secretase activity in cells upon overexpression of hPS2m is tightly linked to mitochondrial dysfunction under the specific physiological and pathological conditions of AD. (bvsalud.org)
  • We performed molecular biological analyses to determine the levels of inflammatory and amyloid-related proteins and molecules, cytokines, Aβ, and secretases activity. (biomedcentral.com)
  • Tau, a microtubule-associated protein essential for protein transport, becomes hyper-phosphorylated in AD due to the activity of a number of kinases including glycogen synthase kinase3β (GSK3β) (7). (deepdyve.com)
  • Secretase Activity in Live Cells. (harvard.edu)
  • Secretase Activity in Living Cells. (harvard.edu)
  • In contrast, β1B lacks a transmembrane domain and is a secreted protein. (semanticscholar.org)
  • In both cases, the initial cleavage is followed by an additional cleavage by gamma-secretase. (lmreview.com)
  • Although ADAM10 is a major alpha-secretase involved in non-amyloidogenic processing of the amyloid precursor protein, several additional substrates have been identified, most of them in vitro. (mdc-berlin.de)
  • Our results indicate a significant functional role of APP and amyloid precursor-like protein 2 (APLP2) in the development of synaptic function by the regulation of glutamatergic neurotransmission. (phoenixpeptide.com)
  • For fast synaptic transmission, there are two types of synapses: type I synapses use glutamate as the neurotransmitter and are excitatory, whereas type II synapses use gamma-amino butyric acid (GABA) as the major neurotransmitter and are inhibitory. (hindawi.com)
  • Glutamate activates ion channel family receptors and G protein coupled receptors which modulate excitatory synaptic transmission through transduction pathways [1]. (scirp.org)
  • Aβ is derived from β-amyloid precursor protein (APP) through sequential cleavage by β- and γ-secretases. (meta.org)
  • It reveals a previously unknown mechanism by which the toxic substance beta-amyloid is controlled, and opens up a new area of research for developing drugs for the treatment of Alzheimer's. (alzinfo.org)
  • Phosphorylation of proteins by GSK-3 can result in their targeting to the proteasome and subsequent degradation. (theflow.org)
  • Evidence for a nonsecretory, acidic degradation pathway for amyloid precursor protein in 293 cells," J. Biol. (patentgenius.com)