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2017 Grants - Schmidt
RAGE, DIAPH1, Microglia, and Alzheimer’s Disease
Ann-Marie Schmidt, M.D.
New York University School of Medicine
New York, New York
2017 Zenith Fellows Award Program
How do immune cells from the blood enter and interact with specific brain cells to affect the progression of Alzheimer’s disease?
One of the characteristic features of Alzheimer’s disease is inflammation in the brain. Inflammation is controlled by the immune system, and the primary immune cells in the brain are known as microglia. Microglia are important for clearing toxic proteins such as beta-amyloid and abnormal tau from the brain, but when microglia become overactivated during Alzheimer’s disease, this clearance function may be impaired.
In Alzheimer’s disease, the interaction of two molecules called receptor for advanced glycation end products (RAGE) and mammalian diaphanous 1 (DIAPH1) may promote overactivation of microglia leading to increased inflammation and impaired clearance of beta-amyloid. In addition, immune cells from the blood called monocytes can enter the brain and also have the RAGE protein on their surfaces. It is not yet known how activation of RAGE and the interaction of microglia and monocytes in the brain may contribute to Alzheimer’s disease.
Ann-Marie Schmidt, M.D., and colleagues hypothesize that activation of the RAGE/DIAPH1 pathway may contribute to brain changes associated with Alzheimer’s disease in two ways: first by direct effects on microglia function and second via monoyctes which enter the brain and amplify inflammation. To better understand how each cell type affects the disease process, Dr. Schmidt will selectively block RAGE on either microglia or monocytes, and measure beta-amyloid levels in the brain, nerve cell function, and mouse cognitive abilities. The researchers will also use nerve cells grown in laboratory dishes to test the effectiveness of novel drugs designed to block the RAGE-DIAPH1 interaction.
The results of this work could shed new light on how immune cells in the brain and body may contribute to the development of Alzheimer’s disease. Importantly these studies could identify new drugs that target the RAGE-DIAPH1 pathway and could potentially be developed as therapies to slow or prevent Alzheimer’s disease.