INCREASED AMYLOID-BETA-42(43) IN BRAINS OF MICE EXPRESSING MUTANT PRESENILIN-1

MUTATIONS in the genes encoding amyloid-beta precursor protein (APP)(1 ), presenilin 1 (PS1)(2) and presenilin 2 (PS2)(3,4) are known to caus e early-onset, autosomal dominant Alzheimer's disease. Studies of plas ma and fibroblasts from subjects with these mutations have established that they all alter amyloid beta-protein (beta APP) processing, which normally leads to the secretion of amyloid-beta protein (relative mol ecular mass 4,000; M(r) 4K; similar to 90% A beta 1-40, similar to 10% A beta 1-42(43)), so that the extracellular concentration of A beta 4 2(43) is increased(5). This increase in A beta 42(43) is believed to b e the critical change that initiates Alzheimer's disease pathogenesis because A beta 42(43) is deposited early and selectively in the senile plaques that are observed in the brains of patients with all forms of the disease. To establish that the presenilin mutations increase the amount of A beta 42(43) in the brain and to test whether presenilin mu tations act as true (gain of function) dominants, we have now construc ted mice expressing wild-type and mutant presenilin genes. Analysis of these mice showed that overexpression of mutant, but not wild-type, P S1 selectively increases brain A beta 42(43). These results indicate t hat the presenilin mutations probably cause Alzheimer's disease throug h a gain of deleterious function that increases the amount of A beta 4 2(43) in the brain.