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2008 Grants - Hegde
Ameliorating Harmful Abeta Effects on Synaptic Plasticity and Memory
Ashok N. Hegde, Ph.D.
Wake Forest University
Winston-Salem, North Carolina
2008 Investigator-Initiated Research Grant
Nerve cells use tiny gaps called synapses to send and receive messages. Memory formation may depend, in part, on a phenomenon called long-term potentiation (LTP), a kind of "increased sensitivity" that develops with repeated sending and receiving of a message across a synapse. In Alzheimer's disease, a tiny protein fragment called beta-amyloid may impair LTP and synaptic function, thereby contributing to cognitive problems associated with the disease.
Current research has found that the synaptic proteasome can help maintain synaptic health. This proteasome is a type of cellular garbage disposal that degrades unwanted proteins around the synapses. Evidence suggests that the proteasome does not function properly in people with Alzheimer's.
In preliminary studies with cultured cells, Ashok N. Hedge, Ph.D., and colleagues found that beta-amyloid prevents LTP by inhibiting the production of proteins vital to the health of synapses. Furthermore, the researchers believe that by regulating the activities of the synaptic proteasome, they can prevent amyloid-induced blockage of LTP.
For this proposed grant, Dr. Hedge's team will further study the effects of beta-amyloid on synaptic function and LTP. Using cultured cells, they hope to verify that beta-amyloid inhibits the production of proteins critical for LTP. Then, using mice engineered to develop Alzheimer-like symptoms, the team will administer drugs designed to regulate the function of the synaptic proteasome. Dr. Hedge and colleagues hope to prove that these drugs will block the negative effects of beta-amyloid on LTP and long-term memory.
Results of this study could shed new light on how beta-amyloid causes synaptic damage and cognitive loss. The effort could also help identify novel therapeutic strategies for preventing Alzheimer's.