Testing Direct Effects of mGluR5 Inhibition in an Alzheimer's Disease Mouse Model

描述（由申请人提供）：本项目探讨mGluR5拮抗剂是治疗阿尔茨海默病的可行治疗策略的假设。我们实验室的研究结果表明，mGluR5拮抗剂可降低阿尔茨海默病小鼠模型中β的表达。为了响应PAS-10-151“阿尔茨海默病药物发现拨款”，我们在R21申请中的目标是提供体内概念验证证据，证明mGluR5拮抗剂是一种可行的治疗策略，可以减少TgCRND8小鼠（阿尔茨海默病小鼠模型）的Abeta和随后的学习和记忆缺陷。具体来说，我们将测试mGluR5拮抗剂非诺巴姆的疗效，非诺巴姆是一种非专利孤儿药，已通过I期和II期临床试验，可以与CTEP一起用于治疗AD， CTEP是一种实验性的mGluR5负变构调节剂，具有较长的半衰期和高的口服生物利用度。总的来说，这些研究将为非诺巴姆和CTEP在WT和TgCRND8幼崽AD生物标志物和认知表型方面的有效性提供临床前数据。

DESCRIPTION (provided by applicant): This project explores the hypothesis that mGluR5 antagonists are a viable therapeutic strategy to treat Alzheimer's disease. Findings from our laboratory indicate that mGluR5 antagonists reduce the expression of Abeta in mouse models of Alzheimer's disease. Our goal in this R21 application, in response to PAS-10-151 "Grants for Alzheimer's Disease Drug Discovery", is to provide in vivo proof-of-concept evidence that mGluR5 antagonists are a viable therapeutic strategy to reduce Abeta and ensuing learning and memory deficits in TgCRND8 mice, a mouse model of Alzheimer's disease. Specifically, we will test the efficacy of the mGluR5 antagonist fenobam, which is an off-patent, orphan drug that has passed Phase I and Phase II clinical trials and that could be repurposed for the treatment of AD, with CTEP, an experimental negative allosteric modulator of mGluR5 with a long half-life and high oral bioavailability. In aggregate, these studies will provide pre-clinical data on the efficay of fenobam and CTEP in regards to AD biomarkers and cognitive phenotypes in WT and TgCRND8 littermates.