Raven, FrankWard, Joseph F.Zoltowska, KatarzynaWan, YuBylykbashi, EnjanaMiller, Sean J.Shen, XunuoChoi, Se HoonRynearson, Kevin D.Berezovska, OksanaWagner, Steven L.Tanzi, RudolphZhang, Can2017-12-062017Raven, F., J. F. Ward, K. M. Zoltowska, Y. Wan, E. Bylykbashi, S. J. Miller, X. Shen, et al. 2017. “Soluble Gamma-secretase Modulators Attenuate Alzheimer's β-amyloid Pathology and Induce Conformational Changes in Presenilin 1.” EBioMedicine 24 (1): 93-101. doi:10.1016/j.ebiom.2017.08.028. http://dx.doi.org/10.1016/j.ebiom.2017.08.028.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34492274A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the Aβ42 peptide, which is generated from amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. We have developed a class of soluble 2-aminothiazole γ-secretase modulators (SGSMs) that preferentially decreases Aβ42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of γ-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 Aβ42 levels without affecting either α- and β-secretase processing of APP nor Notch processing. Furthermore, an allosteric site was identified within the γ-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.en-USAlzheimer's diseaseβ-amyloidβ-amyloid precursor proteinγ-secretaseγ-secretase modulatorNotchJournal Article2017-12-0610.1016/j.ebiom.2017.08.028