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

• Published in: EBioMedicine 2017-10, Vol.24 (C), p.93-101
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Notch; Research Paper; β-amyloid; β-amyloid precursor protein; γ-secretase; γ-secretase modulator
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2017.08.028

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. •A novel class soluble 2-aminothiazole γ-secretase modulators (SGSMs) are characterized as potential therapeutics for AD.•A representative compound, SGSM-36, preferentially decreases Aβ42 levels using animal and cell models of AD.•An allosteric site was identified within γ-secretase to be accessible by SGSM-36. Alzheimer's disease (AD) is a devastating neurodegenerative disorder and there is currently no treatment to slow or halt disease progression. Considerable evidence shows that the primary pathological event leading to AD is the production and accumulation of Aβ42 peptide. We have developed a class of soluble 2-aminothiazole γ-secretase modulators (SGSMs) that preferentially decreases Aβ42 levels. The presented studies have primarily elucidated the mechanisms by which our SGSMs decrease Aβ42 levels and attenuate β-amyloid pathology. The results of these experiments will be useful toward the ongoing efforts toward the development of an effective therapy for the treatment and prevention of AD.