Huaxi Xu, Ph.D.
The Rockefeller University

Gonadal Steroid Regulation of ß-Amyloid Generation: Cellular Mechanisms and Animal Models.

Alzheimer's disease (AD) occurs when large numbers of neurons - the cells which make up the brain, die over many years. These cells are in the areas of the brain which are responsible for forming and storing memories and for performing higher thought processes. This is why AD affects memory and the ability to think in patients afflicted with the disease. The neurons are believed to die as the result of the toxic accumulation of deposits in the brain called amyloid. This amyloid is normally produced and secreted by neurons. However, in AD, neurons seem to make greater quantities, and thus larger toxic amounts are deposited in the brains of patients. The deposits are referred to as plaques and appear to be directly responsible for the death of the neurons in their vicinity.

The best hope researchers may have to slow or prevent AD is to interfere with the molecules which are responsible for forming amyloid inside neurons. Unfortunately, these molecules have not yet been discovered, so scientists have to pursue other leads. One lead was provided when it was discovered that women, who had been taking estrogen as part of a long term program of postmenopausal estrogen replacement, were less likely to get AD, and those who did eventually get AD, got it at much older ages. Our group was the first to show that estrogen may actually prevent or delay AD by slowing the secretion of amyloid from neurons. In order to understand how estrogen exerts these anti-amyloid effects we have proposed to study how estrogen regulates the precursor protein from which amyloid is derived. It is clear from previous work that estrogen exerts many effects in the brain and we would like to further pursue the link that we and others have established between estrogen treatment and the reduction in toxic secreted amyloid mice which have been genetically modified to produce high levels of human amyloid. Our preliminary results showed that estrogen may reduce brain amyloid production in these animals. In addition, we recently found that the male gonadal hormone, testosterone, may have a similar amyloid-reducing effect, thereby impacting on AD risk in elderly men who have declining testosterone levels. Our long term goal is to understand the detailed mechanism by which estrogen/testosterone exerts this effect, scientists may be able to design even more effective drugs to halt and possibly reverse the effects of AD.

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