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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS076117-04
Application #
8663323
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Corriveau, Roderick A
Project Start
2011-06-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
$554,411
Indirect Cost
$135,417
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Lian, Hong; Zheng, Hui (2016) Signaling pathways regulating neuron-glia interaction and their implications in Alzheimer's disease. J Neurochem 136:475-91
Xu, Yin; Martini-Stoica, Heidi; Zheng, Hui (2016) A seeding based cellular assay of tauopathy. Mol Neurodegener 11:32
Martini-Stoica, Heidi; Xu, Yin; Ballabio, Andrea et al. (2016) The Autophagy-Lysosomal Pathway in Neurodegeneration: A TFEB Perspective. Trends Neurosci 39:221-34
Gilchrist, M Lane; Ahn, Kwangwook; Li, Yue-Ming (2016) Imaging and Functional Analysis of γ-Secretase and Substrate in a Proteolipobead System with an Activity-Based Probe. Anal Chem 88:1303-11
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
Justice, Nicholas J; Huang, Longwen; Tian, Jin-Bin et al. (2015) Posttraumatic stress disorder-like induction elevates β-amyloid levels, which directly activates corticotropin-releasing factor neurons to exacerbate stress responses. J Neurosci 35:2612-23
Lian, Hong; Yang, Li; Cole, Allysa et al. (2015) NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer's disease. Neuron 85:101-15
Gertsik, Natalya; Chau, De-Ming; Li, Yue-Ming (2015) γ-Secretase Inhibitors and Modulators Induce Distinct Conformational Changes in the Active Sites of γ-Secretase and Signal Peptide Peptidase. ACS Chem Biol 10:1925-31
Dang, Shangyu; Wu, Shenjie; Wang, Jiawei et al. (2015) Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH. Proc Natl Acad Sci U S A 112:3344-9
Gertsik, Natalya; Chiu, Danica; Li, Yue-Ming (2014) Complex regulation of γ-secretase: from obligatory to modulatory subunits. Front Aging Neurosci 6:342

Showing the most recent 10 out of 23 publications