Phenylpiperidine-type γ-secretase modulators target the transmembrane domain 1 of presenilin 1

Abstract

Amyloid‐β peptide ending at the 42nd residue (Aβ42) is implicated in the pathogenesis of Alzheimer's disease (AD). Small compounds that exhibit selective lowering effects on Aβ42 production are termed γ‐secretase modulators (GSMs) and are deemed as promising therapeutic agents against AD, although the molecular target as well as the mechanism of action remains controversial. Here, we show that a phenylpiperidine‐type compound GSM‐1 directly targets the transmembrane domain (TMD) 1 of presenilin 1 (PS1) by photoaffinity labelling experiments combined with limited digestion. Binding of GSM‐1 affected the structure of the initial substrate binding and the catalytic sites of the γ‐secretase, thereby decreasing production of Aβ42, possibly by enhancing its conversion to Aβ38. These data indicate an allosteric action of GSM‐1 by directly binding to the TMD1 of PS1, pinpointing the target structure of the phenylpiperidine‐type GSMs. There is a Have you seen? (November 2011) associated with this Article.