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.