Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Medicine, General & Internal, Medicine, Research & Experimental, General & Internal Medicine, Research & Experimental Medicine, Alzheimer's disease, beta-amyloid, beta-amyloid precursor protein, gamma-secretase, gamma-secretase modulator, Notch, TRANSGENIC MOUSE MODEL, PRECURSOR PROTEIN, SYNAPTOTAGMIN 1, IN-VIVO, A-BETA, DISEASE, APP, DEPOSITION, INHIBITOR, MEMBRANE, β-amyloid, β-amyloid precursor protein, γ-secretase, γ-secretase modulator, Allosteric Site, Alzheimer Disease, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Animals, CHO Cells, Cells, Cultured, Cricetulus, Disease Models, Animal, Enzyme Inhibitors, Humans, Mice, Mice, Transgenic, Neurons, Presenilin-1, Protein Conformation, 1103 Clinical Sciences, 1117 Public Health and Health Services, 3202 Clinical sciences, 4202 Epidemiology

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.