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Alzheimer's Disease Research - Current Award

Dr. Rena Li

Rena Li, Ph.D.

Sun Health Research Institute
Sun City, AZ

Title: Estrogen And Its Receptors In BACE1 Regulation: From Cells To Mice
Non-Technical Title: Estrogen In Alzheimer’s Disease

Co-Investigator(s):
Yong Shen, M.D., Ph.D.
Sun Health Research Institute

Duration: April 1, 2009 - March 31, 2012
Award Type: Standard
Award Amount: $399,761


Summary:

Reduction of estrogen in postmenopausal women might cause a higher risk of developing Alzheimer's disease (AD). Studies show that inhibition of beta-secretase (BACE1) might play a major role in preventing AD. Our study on estrogen and estrogen receptors in BACE1 regulation will not only provide better understanding of molecular mechanisms of estrogen in preventing AD, but also provide scientific evidence for new drug development.

Details:


Reduction of sex hormone levels in menopausal women is associated with several major health risks, including bone loss and increased risk of Alzheimer’s disease (AD). Increase in brain amyloid plaque formation by accumulations of beta-amyloid peptide is one of major landmarks for AD. We recently discovered that the enzyme activity of beta-secretase (BACE1), a key enzyme for beta-amyloid production, is significantly increased in AD brains. However, it is not known whether alteration of estrogen during menopause may contribute to the increase of BACE1 in female AD patients or whether estrogen treatment can reduce BACE1 activity in order to prevent AD. To better understand the effect of estrogen on BACE1 regulation, we will use a genetic approach to define whether estrogen regulates BACE1 level activity and whether the effect of estrogen on the BACE1 gene is dependent on estrogen receptors. The three specific research aims of this proposal are: (1) to determine whether estrogen deficiency will result in changes in levelsof brain BACE1, (2) to examine whether estrogen regulates BACE1 promoter activity, and (3) to examine whether the regulation of BACE1 promoter activity by estrogen is estrogen receptor dependent.

Progress Updates:

Reduction of sex hormone levels in menopausal and postmenopausal women is associated with several major health risks, including increased risk of Alzheimer's disease (AD). We recently discovered that the enzymatic activity of b-secretase (BACE1), a key enzyme for AD disease development, is significantly increased in AD brains. However, it is not known whether alteration of estrogen levels during menopause contributes to the increase of levels of BACE1 in female AD patients or whether estrogen plays a role in BACE1 activity.

During the past few years, we have developed a new animal line which combines the genetic inhibition of estrogen production by "knocking out" the gene for estrogen synthase aromatase (represented by Ar-/-), with the over-expression of a mutant AD gene, called amyloid precursor protein or APP.

In the past year, we have conducted research experiments to test a central hypothesis that estrogen can reduce BACE1 transcription activity via interaction with estrogen receptors, and the resulting decrease in BACE1 in turn affects APP processing. We have made some progress in the proposed three research aims: (1) our preliminary data shows that the mRNA (gene expression) levels of the BACE1 gene in the brains of APP/Ar+/- mice are altered by sex hormones; (2) using cell cultures, we have identified estrogen regulatory sites on the BACE1 gene promoter; and (3) we are currently working on determining estrogen's effect on BACE1 gene promoter activity and possible estrogen receptor-dependent activity on the BACE1 promoter.