[Molecular basics of Alzheimer's disease].
Studies of molecular mechanisms for Alzheimer's Disease have led to the two major achievements. First, genes with mutations causing Alzheimer's Disease (presenilin genes PSI, PS2 and APP) or bearing a risk factor polymorphism (ApoE) for Alzheimer's Disease were described. Second, the new type of proteases and mechanisms of regulation of cellular differentiation and development by processes of intramembrane proteolysis were identified. These mechanisms, apparently, are universal for various cell types and organisms. Presenilin is a catalytic component of tetra-protein complex (epsilon-/gamma-secretase) cleaving type I transmembrane proteins. Other recently discovered aspartate proteases, IMPAS/SPP, cleave type II transmembrane proteins. Processing of transmembrane proteins by cellular intramembrane proteases results in production of signal peptides, transcriptional factors and short hydrophobic proteins (fragments of transmembrane domains), which may have a physiological function or play a key role in patogenic events associated with ageing (e.g., beta-amyloid formation in Alzheimer's Disease). To date approximately 160 mutations in PSI gene, more than 10 mutations in PS2 gene and 21 mutations in APP gene were described. Early preclinical diagnostics of some early forms of Alzheimer's Disease became possible. Since patogeneses of early and late onset forms of Alzheimer's Disease are similar, identification of molecular or epigenetic factors affecting primary molecular mechanisms (intramembrane or membrane associated proteolysis) underlying the disease may ultimately contribute to development of rational therapy for Alzheimer's Disease.
Grigorenko
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Rogaev
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D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000032:analysis / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010447:Peptide Hydrolases / Q000032:analysis / Q000378:metabolism; D053763:Presenilins / Q000235:genetics / Q000378:metabolism*; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D053763:Presenilins; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D053829:Amyloid Precursor Protein Secretases; D010447:Peptide Hydrolases