Estrogen and its Receptors in BACE1 Regulation: From Cells to Mice

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.

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 levels of 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.