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2017 Grants - Myeku
Stopping Tau Propagation by Receptor-Mediated Synaptic Proteolysis
Natura Myeku, Ph.D.
Columbia University Medical Center
New York, New York
2017 Alzheimer’s Association Research Grant (AARG)
Can activation of proteasomes help stop the movement of abnormal tau protein between nerve cells in Alzheimer’s disease?
Tau protein normally functions to help support nerve cell structure and transport nutrients within the cell. In Alzheimer’s, tau protein can become abnormally modified and clump into “tangles” in the brain, one of the characteristic features of the disease. 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. In previous experiments, Natura Myeku, Ph.D. and colleagues found that as abnormal tau moves throughout the brain, it interferes with the function of special structures called “proteasomes” which break down and clear damaged or abnormal proteins from nerve cells. More research is needed to understand if the effects of tau on proteasome function contribute to abnormal brain changes associated with Alzheimer’s disease.
Dr. Myeku and colleagues hypothesize that a vicious cycle occurs in which abnormal tau interferes with proteasome function, which subsequently leads to the accumulation and spread of tau tangles. To test this hypothesis, the researchers will collect abnormal tau from brain tissue of people who had Alzheimer’s and administer it into the brains of mice. They will specifically administer the abnormal tau to brain regions important for memory and known to be affected in the early stages of Alzheimer’s disease. They will measure the movement of tau between nerve cells over several months and determine the effects on proteasome function and the animals’ memory. Some of the mice will be treated with a molecule that increases activation of proteasomes to see if this can prevent tau spread and improve cognitive function.
The results of these studies could shed new light on how abnormal tau accumulates and moves throughout the brain in Alzheimer’s disease. Importantly, this work could help determine if drugs that activate proteasome function can prevent or reduce the formation of tau tangles and potentially slow or stop Alzheimer’s progression.