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 familial Alzheimer's disease (FAD) pedigrees with the APP717 mutation (Val --> Ile) and from two sporadic Alzheimer's disease (AD) brains and characterized them by means of mass spectrometry and enzyme-linked immunosorbent 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 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 --> Ile, Gly, or Phe). Taken together with the hypothesis that A beta 1-42/43 functions as a ''seed'' that increases the kinetics of amyloid fibril formation (Jarrett, J. T., and Lansbury, P. T., Jr. (1993) Cell 73, 1055-1058), we conclude that the APP717 missense mutation does not create new A beta species but promotes the increased accumulation of A beta 1-42/43 in the brain, which results in the enhancement of amyloid fibril formation from soluble A beta. These findings provide a causal relationship between this FAD genotype and the pathological phenotype of A beta deposition and senile plaque formation.