Soluble Gamma-secretase Modulators Attenuate Alzheimer's β-amyloid Pathology and Induce Conformational Changes in Presenilin 1
Autor: | 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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Rok vydání: | 2017 |
Předmět: |
Aging
Notch Protein Conformation Cells beta-amyloid precursor protein Clinical Sciences CHO Cells Neurodegenerative γ-secretase Transgenic Mice Cricetulus Alzheimer Disease Acquired Cognitive Impairment Presenilin-1 2.1 Biological and endogenous factors Animals Humans Aetiology Enzyme Inhibitors γ-secretase modulator gamma-secretase Neurons gamma-secretase modulator Cultured Amyloid beta-Peptides Animal β-amyloid beta-amyloid Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Alzheimer's disease Brain Disorders Alzheimers disease β-amyloid precursor protein Neurological Disease Models Public Health and Health Services Dementia Amyloid Precursor Protein Secretases Allosteric Site |
Popis: | 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. |
Databáze: | OpenAIRE |
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