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

ABSTRACT: Amyloid-? peptide ending at the 42nd residue (A?42) is implicated in the pathogenesis of Alzheimer's disease (AD). Small compounds that exhibit selective lowering effects on A?42 production are termed ?-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 ?-secretase, thereby decreasing production of A?42, possibly by enhancing its conversion to A?38. 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.

SUBMITTER: Ohki Y 

PROVIDER: S-EPMC3243616 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature