What do we learn from a few familial Alzheimer's disease cases?
Alzheimer's disease is the most common form of dementia. About 90% of the cases occur sporadically whereas in 10% of the cases mutations were found within three different genes. Mutations in the gene encoding the beta-Amyloid precursor protein (beta APP) are located in the ultimate neighborhood of the three proteases (secretases) involved in proteolytic processing of beta APP. These mutations cause an increased production of the long form of Amyloid beta-peptide (A beta) the major component of Amyloid plaques. In contrast to the 40 amino acid form (A beta 40), the 42 amino acid form (A beta 42) aggregates more rapidly, kills cultured neurons more efficiently, and precipitates preferentially in amyloid plaques. Interestingly, mutations in the Presenilin genes which are responsible for more then 40% of all familial AD cases also cause enhanced production of the elongated form of A beta. Therefore mutations in three different genes directly effect A beta production in a pathological manner, which strongly supports the amyloid cascade hypothesis.
Haass
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C
Central Institute for Mental Health, Department of Molecular Biology, Mannheim, Federal Republic of Germany.
Baumeister
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R
D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D010450:Endopeptidases / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D017354:Point Mutation; D053764:Presenilin-1; D017433:Protein Structure, Secondary
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human