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2015 Grants - Dai
Role of O-GlcNAcylation in Tau Pathology and Cognitive Function
Chun-Ling Dai, Ph.D.
Research Foundation for Mental Hygiene, Inc. at New York State Institute for Basic Research
Staten Island, New York
2014 Dale Schenk Alzheimer's Association Research Roundtable Grant Award
(2015 New Investigator Research Grant)
How do changes in the brain’s ability to use glucose for energy affect the formation of tau tangles and decline in brain function during Alzheimer’s disease?
The primary source of energy for the brain is glucose, the main sugar in the blood. Levels of glucose in the brain and inside individual cells are carefully regulated. One way that cells monitor glucose levels is by attaching a chemical derived from glucose (beta-N-acetylglucosamine, abbreviated GlcNac) to proteins. This process is known as O-GlcNAcylation. In people with Alzheimer’s disease, the brain’s ability to use glucose is impaired, and this impairment is accompanied by reduced O-GlcNAcylation. Declines in the brain’s ability to use glucose for energy may contribute to brain changes associated with disease progression.
Tau is a protein at the focus of research into the mechanisms of Alzheimer’s disease. In Alzheimer’s disease, tau becomes abnormally modified leading to the formation of tau tangles, a hallmark feature of Alzheimer’s disease in the brain. It remains unknown if there is a relationship between impaired glucose use and the formation of toxic tau tangles inside nerve cells.
Using mice genetically altered to have reduced O-GlcNAcylation, Chun-Ling Dai, Ph.D., and colleagues have found evidence that this decrease is associated with declines in brain function. Their current studies will use molecular methods to reduce O-GlcNAcylation in nerve cells and study how this affects the formation and accumulation of abnormal tau protein. The researchers will also use certain compounds to increase levels of O-GlcNAcylation in nerve cells to determine if this can prevent the build-up of abnormal tau and the subsequent declines in brain function.
The studies by Dr. Dai and colleagues will shed new light on how impairments in glucose metabolism in the brain are linked with the formation of tau tangles and with declines in brain function. A better understanding of these molecular mechanisms can provide researchers novel targets for the future development of disease-modifying treatments.