2005 New Investigator Research Grant

Estrogen is of particular interest in Alzheimer research because the hormone has been shown to have neuroprotective properties. Clinical trials of estrogen-progestin or estrogen therapy have not, however, been promising, as the treatment appeared to increase the risk of developing cognitive impairment. In order to understand this apparent contradiction, investigators have begun to look more closely at estrogen’s activity in the brain and its possible connection to other molecules associated with Alzheimer’s disease.

A certain form of the protein called apolipoprotein E (ApoE) is a risk factor for Alzheimer’s disease. While some forms of the protein have little or no impact on Alzheimer’s disease risk, people who have the ApoE-e4 variant are more likely to develop the disease. In estrogen treatment trials, women who carried ApoE-e4 had generally lower performance on cognitive tests than women who have other forms of the protein.

Jun Ming Wang, Ph.D., and colleagues will explore the relationship between estrogen and ApoE-e4. In the brain there are two types of receptors, or cell-surface “docking sites,” to which estrogen can bind, the alpha and the beta receptor. The researchers have observed that when estrogen binds to cells that have predominantly the alpha form of the receptor, those cells produce more ApoE. In contrast, when estrogen binds to cells mostly harboring the beta receptor, then ApoE production is suppressed.

The researchers will study these factors in mice that are genetically altered to produce human ApoE-e4. The investigators will use modified estrogen-like molecules that bind specifically to either one receptor or the other and measure the effects on ApoE-e4 production. The findings may demonstrate the potential benefit of a modified estrogen therapy in people with Alzheimer’s disease or demonstrate the necessity of limiting such a therapy to individuals who do not carry ApoE-e4.