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2009 Grants - Ming Wang
ER-Isoform Specific Estrogen Therapy in ApoE/Alzheimer Mice
Jun Ming Wang, Ph.D.
University of Mississippi Medical Center
2009 Investigator-Initiated Research Grant
Variations in the ApoE gene are known to influence the risk of Alzheimer's disease. Individuals with the ApoE epsilon4 variant are at higher risk as compared to individuals with other variants. Indeed, the ApoE epsilon4 gene variant is the most prevalent genetic risk factor for late-onset Alzheimer's disease. Current evidence supports the concept that the ApoE epsilon4 variant is associated with higher levels of the protein fragment beta-amyloid, and higher levels of the product of beta-amyloid aggregation, amyloid plaque.
Some studies have suggested that the hormone estrogen acting in the brain may reduce the risk of Alzheimer's disease, although this idea has not been proven. Recent research has also found evidence that estrogen regulates the expression of the ApoE gene. Jun Ming Wang, Ph.D. and colleagues are studying the biochemical mechanisms by which estrogen may influence the expression of ApoE and beta-amyloid. The researchers have found that one type (isoform) of estrogen receptor increases ApoE expression while the other isoforms decrease ApoE expression.
Dr. Wang and colleagues plan to extend their studies of estrogen receptor isoforms and how they influence ApoE expression. The researchers will use mice that have been genetically altered to express specific estrogen receptor isoforms as well as Alzheimer-like pathology. Experiments with these animals will allow them to determine which estrogen receptor isoform increases ApoE expression, and whether this effect causes increases in beta-amyloid or amyloid plaque, or other effects associated with Alzheimer pathology. The researchers will also study cognitive function in these animals to document the functional consequences of different estrogen receptor isoforms. These studies will help to determine whether drugs that bind to specific isoforms of the estrogen receptor warrant further study as potential treatments for Alzheimer's disease, especially in individuals with the ApoE epsilon4 gene variant.