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CELLULAR MECHANISMS OF y-SECRETASE MODULATION AND EFFICACY OF COMBINATION TREATME

γ-分泌酶调节的细胞机制和联合治疗的功效

基本信息

批准号：
7568355
负责人：
EDWARD H. KOO
金额：
$ 36.13万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7568355
关键词：
AP40 Abeta synthesis Affect Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloid deposition Anti-Inflammatory Agents Anti-inflammatory Attenuated Biology Brain Chronic Collaborations Cultured Cells Curcumin Data Docosahexaenoic Acids Drug Compounding Drug effect disorder Drug user Epidemiology Event Exposure to Funding Future Generations Hippocampus (Brain)Human Ibuprofen In Vitro Membrane Mutation Non-Steroidal Anti-Inflammatory Agents Pathology Pathway interactions Pb clearance Peptides Pharmaceutical Preparations Preparation Principal Investigator Production Property Prostaglandin-Endoperoxide Synthase Protein Isoforms R-flurbiprofen Recombinants Reporting Risk Reduction Safety Site Slice Synaptic Transmission Synaptic plasticity System Testing Therapeutic Therapeutic Agents Toxic effect Transgenic Mice Transgenic Organisms Translating Virus atorvastatin cytotoxic disease phenotype gamma secretase in vivo insight interest member neurotoxic novel presenilin programs response secretase synaptic function

项目摘要

The amyloid hypothesis states that altered Abeta production or clearance leading to gradual accumulation of aggregated Abeta, which in turn initiates the cascade of events leading to Alzheimer's disease. Increasing evidence supports the concept that the highly amyloidogenic Abeta42 isoform is the pathogenic species. Consequently, selective targeting of Abeta42 may be an excellent anti-amyloid strategy for Alzheimer's therapeutics. In the current funding cycle, we have reported that a subset of nonsteroidal anti-inflammatory drugs (NSAIDs) selectively lower Abeta42 while increasing shorter Abeta species without altering overall Abeta levels, an activity which we term gamma-secretase modulating action. Further, these findings led us io hypothesize that this activity may in part explain the apparent AD risk reduction in chronic users of NSAIDs. Thus, NSAIDs represent the prototypic members of a class of gamma-secretase modulators [GSM) that selectively lower Abeta42 in vitro and in vivo. We also provided preliminary characterization of its potential mechanism of action, which we now believe is centered on the gamma-secretase complex itself, including the APR substrate. In the next funding cycle, we hypothesize that this gamma-secretase modulating activity may target the initial epsilon-cleavage site, which appears to precede and possibly predict the cleavage of various Abeta peptides at the gamma-site. We will test this hypothesis in cultured cells and with in vitro membrane preparations. Further, in studies in collaboration with Project 2, we will examine the biology of shorter Abeta peptides that are invariably increased by Abeta42 lowering agents. We will ask whether shorter Abeta peptides are neurotoxic and whether they modulate the toxicity and aggregability of Abeta42 peptide by testing synaptic transmission and synaptic plasticity following exposure to these peptides. Finally, we will test whether combination treatments with Abeta42 lowering GSMs and a second unrelated compound are superior to treatment with single agents in reducing amyloid levels and amyloid associated pathology in APP transgenic mice. We hypothesize that targeting multiple cellular pathways will ultimately be more efficacious than single targets. We hope that our studies will be translated to testing in AD subjects in the future if we can demonstrate synergy with combination treatments.

淀粉样蛋白假说认为改变β的产生或清除导致逐渐积累