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2012 Grants - Li
Abeta Increases Glutamatergic Excitation and Induces Epileptiform Activity
Shaomin Li, M.D., Ph.D
Brigham and Women's Hospital
2012 New Investigator Research Grant
According to recent studies, up to 15 percent of people with Alzheimer's disease develop epileptic seizures, and the percentage is even higher in people with inherited, early onset Alzheimer's. Evidence indicates that the protein fragment beta-amyloid may promote such seizure activity. Beta-amyloid has already been implicated in dementia-related cognitive decline and brain cell damage. But the mechanisms underlying amyloid's role in seizures remains unclear.
In preliminary studies, Shaomin Li, M.D., Ph.D., and colleagues have found that beta-amyloid hinders the proper transportation of glutamate in neurons. Glutamate is a neurotransmitter (or chemical messenger) that helps brain cells communicate with one another through tiny channels called synapses. But when beta-amyloid altered glutamate movement in Dr. Li's cells, the neurotransmitter overaccumulated at the synapses. Too much glutamate can lead to a toxic process called excitotoxicity, in which overstimulation of the synapse causes synaptic damage and memory loss. Dr. Li's team also described recent experiments with rats, in which the injection of toxic beta-amyloid clumps called oligomers helped elicit seizure activity in the animals. Collectively, these findings suggest that amyloid-induced excitotoxicity is responsible for the increased seizure risk in people with Alzheimer's.
For their proposed study, Dr. Li and colleagues will use rodent models to confirm the link between excitotoxicity and seizures. They will also look for molecular mechanisms that may underlie this association. One such mechanism, the researchers hypothesize, may involve oligomers binding to cell membranes and preventing the activities of molecules that help transport glutamate. The team will also test the efficacy of drug compounds to prevent glutamate-induced synaptic damage and epileptic seizures—especially those that occur early in the course of Alzheimer's.