Study on the mechanism of amyloid betaprotein deposition in Alzheimer's disease brain

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We have biochemically purified Abeta from brains of two unrelated familial Alzheimer's disease (FAD) pedigrees with the APP717 mutation (Val to lle) and from two sporadic AD brains and characterized them by means of mass spectrometry and EIA assay. We observed two types of Abeta, the short-tail form (Abeta1-40) and the long-tail form (Abeta1-42/43) in sporadic AD brains (Mori, H., Takio, K., Ogawara, M.& Selkoe, D.J., Mass spectrometry of purified amyloid beta protein in Alzheimer's disease, J.Biol.Chem., 267 : 17082-17086,1992). We examined Abeta in FAD brains and sporadic AD brains, and found that the ratio of the long-tail form of Abeta (Abeta1-42/43) to total Abeta was increased in FAD brains. These in vivo results were confirmed in vitro using cultured cells transfected with three kinds of APP cDNAs bearing the APP717 mutations (Val to lle, Gly of Phe).Taken together with the hypothesis that Abeta1-42/43 functions as a "seed" that increases the kinetics of amyloid fibril formation (Jarrett, J.T.& Lansbury, P.T.Jr.(1993) Cell 73,1055-1058), we conclude that the APP717 missense mutation promotes the increased accumulation of Abeta1-42/43 in the brain, which results in the enhancement of amyloid fibril formation from soluble Abeta. These findings provide a causal relationship between this FAD genotype and the pathological phenotype of Abeta deposition and senile plaque fromation.