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

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

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Title: Soluble Gamma-secretase Modulators Attenuate Alzheimer's β-amyloid Pathology and Induce Conformational Changes in Presenilin 1
Author: Raven, Frank; Ward, Joseph F.; Zoltowska, Katarzyna M.; Wan, Yu; Bylykbashi, Enjana; Miller, Sean J.; Shen, Xunuo; Choi, Se Hoon; Rynearson, Kevin D.; Berezovska, Oksana; Wagner, Steven L.; Tanzi, Rudolph E.; Zhang, Can

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Citation: Raven, 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.
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Abstract: A 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.
Published Version: doi:10.1016/j.ebiom.2017.08.028
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652037/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:34492274
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