Soluble gamma-secretase modulators attenuate Alzheimer's β-amyloid pathology and induce conformational changes in presenilin 1

A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the A beta 42 peptide, which is generated from amyloid-beta precursor protein (APP) via cleavages by beta- and gamma-secretase. We have developed a class of soluble 2-aminothiazole gamma-secretase modulators (SGSMs) that preferentially decreases A beta 42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of gamma-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 beta 42 levels without affecting either alpha- and beta-secretase processing of APP nor Notch processing. Furthermore, an allosteric site was identified within the gamma-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. (C) 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND licens