ABSTRACT
Alzheimer’s disease (AD) is characterized by the abnormal cortical deposition of a set of peptides referred to as amyloid beta peptides (Aß). Although the exact etiology of AD remains questionable, several lines of biochemical, anatomical and genetic evidence suggest that the Aß peptides at least contribute to the pathogenesis of AD. While beta-site APP Cleaving Enzyme depletion appears mostly innocuous for the mice, the knockout of PS is lethal in embryo suggesting that either Aß exerts a vital embryonic function in mammals or, alternatively, that presenilins (PS)-dependent Gama-secretase targets other proteins involved in important cell functions. The blockade of PS-dependent Aß production by several inhibitors that physically interact with PS has rapidly demonstrated its theoretical limits as potential therapeutic mean. Altogether, our data demonstrate the theoretical possibility of designing selective blockers of the Aß-producing pathway without triggering unexpected deleterious side-effects.
