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2015 Grants - Rodrigues
P2Y1 Receptor-CRMP2 Controls Synaptic Loss and Memory Impairment in Early Alzheimer’s Disease
Ricardo Jorge Rodrigues, Ph.D.
Center for Neuroscience and Cell Biology (CNCB)
2015 New Investigator Research Grant
Does abnormal activation of a developmental signaling pathway promote nerve cell damage and memory loss in early-stage Alzheimer’s disease?
Nerve cells in the brain communicate with one another using specialized structures called synapses, which send chemical messages across tiny channels between cells. Synapses tend to become damaged in early Alzheimer’s disease, a process that hinders cell-to-cell communication and leads to memory loss and other forms of cognitive decline. Research has shown that a protein fragment called beta-amyloid tends to accumulate around synapses in the hippocampus, a brain region important for learning and memory; and that this accumulation may promote synaptic damage in early Alzheimer’s. However, scientists do not know exactly how beta-amyloid and synaptic deficits are linked.
Ricardo Jorge Rodrigues, Ph.D., and colleagues have been examining the molecular chain of events – or “signaling pathways” that may underlie synaptic damage during Alzheimer’s disease. Using mice engineered to develop Alzheimer’s-like brain changes, the researchers found that a certain signaling pathway that is normally active only during brain development, gets abnormally “re-activated” by beta-amyloid in Alzheimer’s disease. This signaling pathway involves a protein called P2Y1 receptor (P2Y1R) which becomes overactive and can abnormally modify other proteins involved in maintaining the structure of synapses. The researchers hypothesize that this pathway gets re-activated in a misguided attempt to recover brain function, but instead leads to the damage and loss of nerve cell synapses. For their current studies, Dr. Rodrigues and colleagues will examine P2Y1R pathways in detail using both nerve cells grown in laboratory dishes and Alzheimer’s-like mice.
The results of this effort could shed new light on how beta-amyloid promotes nerve cell damage and the development of Alzheimer’s disease at its earliest stages. These findings could also point to novel targets for dementia prevention strategies.