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

描述（由申请人提供）：该项目探讨了mGluR 5拮抗剂是治疗阿尔茨海默病的可行治疗策略的假设。我们实验室的发现表明，mGluR 5拮抗剂降低了阿尔茨海默病小鼠模型中Abeta的表达。我们在这项R21申请中的目标是响应PAS-10-151“阿尔茨海默病药物发现赠款”，提供体内概念验证证据，证明mGluR 5拮抗剂是一种可行的治疗策略，可减少TgCRND 8小鼠（阿尔茨海默病小鼠模型）中的Abeta和随后的学习和记忆缺陷。具体而言，我们将测试mGluR 5拮抗剂非诺班的疗效，非诺班是一种已通过I期和II期临床试验的非专利孤儿药，可用于治疗AD，CTEP是一种具有长半衰期和高口服生物利用度的mGluR 5实验性负变构调节剂。总之，这些研究将提供非诺班和CTEP在WT和TgCRND 8同窝仔中关于AD生物标志物和认知表型的疗效的临床前数据。

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.