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2017 Grants - Nott
Functional role of genetic variation in cell-specific pathogenesis of AD
Alexander Nott, Ph.D.
University of California, San Diego
San Diego, California
2017 Alzheimer's Association Research Fellowship (AARF)
Functional Role of Genetic Variation in Cell-Specific Pathogenesis of AD Do variations in certain regions of a person's DNA enhance one's risk for Alzheimer's disease?
With the exception of identical twins, every individual has a unique set of DNA (or genetic material). Differences in DNA can often make one person more susceptible or resistant to Alzheimer's disease. However, it remains uncertain exactly how DNA variations and dementia risk are linked. Certain small DNA regions, about 20 in total, have been identified as containing genetic variations that may affect one's risk for Alzheimer's. According to recent studies, these regions may occur within larger segments of DNA called enhancers — segments that help facilitate, either increasing or decreasing the process of gene expression, which ultimately regulates how much protein is made. Differences in where enhancer regions are located within the brain may alter gene expression in ways that could promote dementia. These differences, however, have not been clarified, as scientists have not yet mapped all the enhancer regions in the human brain.
Alexander Nott, Ph.D., and colleagues plan to study the relationships between DNA enhancers, gene expression and Alzheimer's disease risk. For this effort, they will acquire brain samples from people who had died with and without Alzheimer's. They will then isolate and examine two types of cells from these samples: nerve cells and microglia (the "immune" cells of the brain). Using state-of-the art sequencing technology, the researchers will map all the enhancer regions in the cells' DNA. They will then determine how differences in enhancer location affected gene transcription in the cells, and whether some of these differences may distinguish brains with Alzheimer's disease from brains without the disorder.
Dr. Nott's study will shed new light on how DNA variations between individuals can affect dementia risk. It may also help identify novel therapeutic targets for Alzheimer's.