Alzheimer's disease: genesis of amyloid.
Much of the present knowledge on the genes and genetic processes involved in the genesis of amyloid formation in Alzheimer's disease (AD) has come directly or indirectly from the retrospective molecular and genetic analysis of amyloid beta-protein (A beta or beta A4) deposits and from the identification of genes involved in inherited susceptibility to the disease. This analysis shows that the release and aggregation of the A beta fragment from the amyloid precursor protein (APP) is involved in APP (AD1), chromosome 14 (AD3), 1 (AD4) and 19(AD2) families as well as in the sporadic forms of AD, suggesting that AD is a single disease with a common APP/A beta amyloid pathogenesis. Synthetic A beta protein readily forms beta sheets, filaments and amyloid at micromolar concentrations. The principle to inhibit this process has been worked out by our groups with A beta variants. The N-terminal and C-terminal A beta sequences, oxidative radicals, membrane integrity and metal ions also affect the aggregation of A beta. Amino acid substitutions within the A beta sequence, as occur in rodents, alter A beta release and change the degree to which oxidation of the peptides occurs. Transgenic approaches resulting in overexpression of human APP have confirmed that A beta sequence and concentration are critical prerequisites to amyloid deposition in vivo.
ZMBH, Center for Molecular Biology, University of Heidelberg, Germany.
K
K
Beyreuther
G
G
Multhaup
C L
CL
Masters
D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000682:Amyloid / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015195:Drug Design; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data
D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor