Wild-type Presenilin 1 Protects against Alzheimer Disease Mutation-induced Amyloid Pathology

Abstract Mutations in presenilin 1 (PS1) lead to dominant inheritance of early onset familial Alzheimer disease (FAD). These mutations are known to alter the γ-secretase cleavage of the amyloid precursor protein, resulting in increased ratio of Aβ42/Aβ40 and accelerated amyloid plaque pathology in transgenic mouse models. To investigate the factors that drive the Aβ42/Aβ40 ratio and amyloid pathogenesis and to investigate the possible interactions between wild-type and FAD mutant PS1, which are co-expressed in transgenic animals, we expressed the PS1 M146V knock-in allele either on wild-type PS1 (PS1M146V/+) or PS1 null (PS1M146V/–) background and crossed these alleles with the Tg2576 APP transgenic mice. Introduction of the PS1 M146V mutation on Tg2576 background resulted in earlier onset of plaque pathology. Surprisingly, removing the wild-type PS1 in the presence of the PS1 M146V mutation (PS1M146V/–) greatly exacerbated the amyloid burden; and this was attributed to a reduction of γ-secretase activity rather than an increase in Aβ42. Our findings establish a protective role of the wild-type PS1 against the FAD mutation-induced amyloid pathology through a partial loss-of-function mechanism.