Grant: Project Grant

This proposal focuses on a new treatment for Alzheimer's disease using a drug that blocks the activity of a glutamate receptor in the brain, called mGlu5, which is now extensively implicated in contributing to the cause of Alzheimer's disease, the most prevalent neurodegenerative illness in older adults. A hallmark of Alzheimer's disease is the deposition of an insoluble protein called ß-amyloid (Aß42) in plaques in the brain. Soluble Aß42 oligomers are believed to be one of the primary mediators involved in the early stages of the development of Alzheimer's disease. The present proposal focuses on how both Aß42 oligomers and spinophilin (a protein found in neurons that we have identified to interact with mGlu5) contribute to pathological mGlu5 activity in Alzheimer's disease. Aß42 oligomers bind to the outer surface of mGlu5 to send pathological cell signals that impair cognition in a mouse model of Alzheimer's disease, and spinophilin binds to the inner surface of mGlu5 to negatively regulate memory and learning. We have demonstrated that the genetic deletion of mGlu5 results in improved memory and reduces neuronal pathology in Alzheimer mice. We propose here to: 1) examine how Aß42 oligomers regulate mGlu5 signaling, 2) whether blocking mGlu5 with a drug called CTEP can prevent/reverse cognitive decline and pathological changes in Alzheimer's disease mice, and 3) whether the genetic deletion of spinophilin results in reversal of the cognitive impairment of Alzheimer's disease mice and reduces the associated brain pathology. Our goal is to understand the mechanism by which mGlu5 contributes to Alzheimer's pathology and to repurpose the mGlu5 antagonist CTEP for the treatment of Alzheimer's disease.