Due to the critical role of gamma-secretase in the generation of A? peptides, which are believed to be essential in Alzheimer's disease (AD) pathogenesis, gamma-secretase inhibitors have emerged as potential drug targets for AD. However, the wide spectrum of gamma-secretase substrates and the differential activities of the two major A? species, A?40 and A?42, in amyloid pathology have made gamma-secretase based therapy a formidable challenge. The combination of current understanding of the gamma-secretase biology with the recently failed clinical trial calls for the need to develop gamma-secretase inhibitors that specifically block A?42 production while leaving A?40 and other substrates intact. We have identified a series of compounds that exhibit these characteristics and they act through a distinct mechanism from that of A?42 gamma-secretase modulators. The overarching goal of this application is to elucidate the mechanism of action and therapeutic efficacy of A?42-specific gamma-secretase inhibition using an integrated approach of chemical biology, cell biology and animal models. We will develop a series of photoactivatable analogs to probe the molecular mechanisms of different mode of A?42 inhibition. We will determine their specificity and compare these with other classes of gamma-secretase inhibitors using novel cellular assays and in mice. Lastly, we will test the efficacy of A?42 specific inhibition on synaptic function and cognition in an AD knock-in mouse model. Overall, this proposal uses innovative approaches and model systems to address a topic highly significant in AD pathogenesis and therapeutic development.

Public Health Relevance

Overwhelming evidence support a critical role of A?42 in AD pathogenesis. Accordingly, inhibition of gamma-secretase for A?42 production has emerged as an appealing therapeutic strategy for AD. This proposal directly addresses the mechanisms and functional role of A?42-specific inhibition in synaptic plasticity and learning and memory. It will greatly facilitate the understanding and development of ?-secretase-based AD therapy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Corriveau, Roderick A
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Sloan-Kettering Institute for Cancer Research
New York
United States
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Frost, Georgia R; Wong, Eitan; Li, Yue-Ming (2017) Versatility of presenilin 1. Proc Natl Acad Sci U S A 114:6885-6887
Fried, Eric S; Li, Yue-Ming; Gilchrist, M Lane (2017) Phase Composition Control in Microsphere-Supported Biomembrane Systems. Langmuir 33:3028-3039
Frost, Georgia R; Li, Yue-Ming (2017) The role of astrocytes in amyloid production and Alzheimer's disease. Open Biol 7:
Gertsik, Natalya; Am Ende, Christopher W; Geoghegan, Kieran F et al. (2017) Mapping the Binding Site of BMS-708163 on ?-Secretase with Cleavable Photoprobes. Cell Chem Biol 24:3-8
Lian, Hong; Litvinchuk, Alexandra; Chiang, Angie C-A et al. (2016) Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease. J Neurosci 36:577-89
Gilchrist, M Lane; Ahn, Kwangwook; Li, Yue-Ming (2016) Imaging and Functional Analysis of ?-Secretase and Substrate in a Proteolipobead System with an Activity-Based Probe. Anal Chem 88:1303-11
Lian, Hong; Roy, Ethan; Zheng, Hui (2016) Protocol for Primary Microglial Culture Preparation. Bio Protoc 6:
Crump, Christina J; Murrey, Heather E; Ballard, T Eric et al. (2016) Development of Sulfonamide Photoaffinity Inhibitors for Probing Cellular ?-Secretase. ACS Chem Neurosci 7:1166-73
Lian, Hong; Roy, Ethan; Zheng, Hui (2016) Microglial Phagocytosis Assay. Bio Protoc 6:
Lian, Hong; Zheng, Hui (2016) Signaling pathways regulating neuron-glia interaction and their implications in Alzheimer's disease. J Neurochem 136:475-91

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