Soluble Gamma-secretase Modulators Attenuate Alzheimer's ?-amyloid Pathology and Induce Conformational Changes in Presenilin 1.

ABSTRACT: A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the A?42 peptide, which is generated from amyloid-? precursor protein (APP) via cleavages by ?- and ?-secretase. We have developed a class of soluble 2-aminothiazole ?-secretase modulators (SGSMs) that preferentially decreases A?42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of ?-secretase modulation remain largely unknown. Here, a representative of this SGSM scaffold, SGSM-36, was investigated using animals and cells expressing FAD mutations. SGSM-36 preferentially reduced A?42 levels without affecting either ?- and ?-secretase processing of APP nor Notch processing. Furthermore, an allosteric site was identified within the ?-secretase complex that allowed access of SGSM-36 using cell-based, fluorescence lifetime imaging microscopy analysis. Collectively, these studies provide mechanistic insights regarding SGSMs of this class and reinforce their therapeutic potential in AD.

SUBMITTER: Raven F 

PROVIDER: S-EPMC5652037 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature