ACCELERATED AMYLOID DEPOSITION IN THE BRAINS OF TRANSGENIC MICE COEXPRESSING MUTANT PRESENILIN-1 AND AMYLOID PRECURSOR PROTEINS

Missense mutations in two related genes, termed presenilin 1 (PS1) and presenilin 2 (PS2), cause dementia in a subset of early-onset familia r Alzheimer's disease (FAD) pedigrees. In a variety of experimental in vitro and in vivo settings, PAD-linked presenilin variants influence the processing of the amyloid precursor protein (APP), leading to elev ated levels of the highly fibrillogenic A beta 1-42 peptides that are preferentially deposited in the brains of Alzheimer Disease (AD) patie nts. In this report, we demonstrate that transgenic animals that coexp ress an PAD-linked human PS1 variant (A246E) and a chimeric mouse/huma n APP harboring mutations linked to Swedish PAD kindreds (APP swe) dev elop numerous amyloid deposits much earlier than age-matched mice expr essing APP swe and wild-type Hu PS1 or APP swe alone. These results pr ovide evidence for the view that one pathogenic mechanism by which PAD -linked mutant PS1 causes AD is to accelerate the rate of beta-amyloid deposition in brain.