APP717 MISSENSE MUTATION AFFECTS THE RATIO OF AMYLOID-BETA PROTEIN SPECIES (A-BETA-1-42 43 AND A-BETA-1-40) IN FAMILIAL ALZHEIMERS-DISEASE BRAIN/

We have biochemically purified A beta from brains of two unrelated fam ilial Alzheimer's disease (FAD) pedigrees with the APP717 mutation (Va l --> Ile) and from two sporadic Alzheimer's disease (AD) brains and c haracterized them by means of mass spectrometry and enzyme-linked immu nosorbent assay, We observed two types of amyloid beta protein (A beta ), the short-tail form (A beta 1-40) and the long tail form (A beta 1- 42/43), in sporadic AD and FAD brains, and found that the ratio of the long-tail form of A beta (A beta 1-42/43) to total A beta was increas ed in FAD brains. These in vivo results were confirmed in vitro using cultured cells transfected with three kinds of APP cDNAs bearing the A PP717 mutations (Val --> Ile, Gly, or Phe). Taken together with the hy pothesis that A beta 1-42/43 functions as a ''seed'' that increases th e kinetics of amyloid fibril formation (Jarrett, J. T., and Lansbury, P. T., Jr. (1993) Cell 73, 1055-1058), we conclude that the APP717 mis sense mutation does not create new A beta species but promotes the inc reased accumulation of A beta 1-42/43 in the brain, which results in t he enhancement of amyloid fibril formation from soluble A beta. These findings provide a causal relationship between this FAD genotype and t he pathological phenotype of A beta deposition and senile plaque forma tion.