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2017 Grants - Rodriguez
Attenuating Aβ-Driven Hyperexcitability and Tau Spread
Gustavo Rodriguez, Ph.D.
Columbia University Medical Center
New York, New York
2017 Alzheimer’s Association Research Fellowship to Promote Diversity (AARF-D)
Does beta-amyloid alter nerve cell activity in a way that promotes the movement of abnormal tau throughout the brain?
Alzheimer’s disease is characterized by the build-up of the beta-amyloid (Aβ) protein into “plaques” and the tau protein into “tangles” in the brain. Recent evidence suggests that abnormal tau protein can move from one nerve cell to another, possibly contributing to the progression of brain changes associated with Alzheimer’s disease. While research has focused on the patterns of tau accumulation in different brain regions associated with cognitive function, the actual mechanisms that initially trigger the movement of tau between nerve cells are not known.
Gustavo Rodriguez, Ph.D. and colleagues have genetically engineered mice to accumulate beta-amyloid and abnormal tau proteins in brain regions affected in the earliest stages of Alzheimer’s disease. They will use novel methods to identify nerve cells with abnormally high levels of electrical activity (hyperexcitability) in these living mice. Their goal is to determine if the level of nerve cell hyperexcitability directly relates to the rate that abnormal tau spreads throughout the brain. They will then treat the mice with molecules called Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) that allow very specific regulation of nerve cell activity. The researchers hypothesize that suppressing the nerve cell hyperexcitability induced by beta-amyloid will prevent the spread of toxic tau in the brain. They will also measure the animals’ memory abilities before and after the treatment to determine if it can effectively prevent or reverse cognitive decline.
The results of this work could shed new light on how abnormal nerve cell activity may trigger or accelerate the movement of tau tangles throughout the brain in Alzheimer’s. These studies could also help determine if drugs that regulate nerve cell activity may help slow disease progression and preserve memory function in the earliest stages of Alzheimer’s disease.