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2016 Grants - Gamsby
Tauopathy and Circadian Dysfunction
Joshua Gamsby, Ph.D.
University of South Florida
2016 New Investigator Research Grant
Can abnormal tau protein hinder brain function by disrupting normal sleep patterns?
Circadian rhythms are natural biological changes that occur in animals over an approximately twenty-four hour cycle. These changes usually respond to the amount of light and darkness in an environment and they involve daily patterns of sleeping, eating and other processes. Circadian rhythms are controlled by genes and proteins that make up the body’s “circadian clock.” For people with Alzheimer’s disease, these genes and proteins tend to become dysfunctional, promoting sleep disorders and other problems associated with the disease. However, the causes of circadian dysfunction and the effects it may have on Alzheimer’s disease are not well understood.
In Alzheimer’s and other neurodegenerative diseases, a protein called tau becomes abnormally modified and can accumulate in the brain leading to toxic effects on nerve cells. In recent studies, Joshua Gamsby, Ph.D., and colleagues found that mice engineered to develop accumulation of abnormal tau protein in the brain were wakeful in periods when they would be expected to be sleeping. They also found that the mice had unusual brain levels of a protein called BMAL1, which helps regulate the circadian clock. These abnormalities occurred, in part, within the hippocampus — a brain region that is involved in learning and memory and is especially vulnerable to damage in early Alzheimer’s disease. Such findings suggest that tau-related circadian rhythm disorders may be linked to Alzheimer’s.
For their current studies, Dr. Gamsby and colleagues will perform a series of experiments in these mice to better clarify how tau-related diseases (called tauopathies) may affect the circadian clock and its regulatory protein, BMAL1. They will then test whether inhibiting casein kinase-1 (CK1), another protein involved in the circadian clock, can lower harmful tau levels in the brain, possibly reversing sleep disorders and improving cognitive function.
Dr. Gamsby’s research may help clarify the molecular basis of sleep disorders in early Alzheimer’s disease. It could also lead to novel therapies for improving sleep that could have an impact on slowing or preventing the progression of Alzheimer’s disease.