Estrogen In Alzheimer's Disease

Rena Li, PhD
Roskamp Research Institute (Sarasota, FL)
Year Awarded:
2009
Grant Duration:
April 1, 2009 to March 31, 2013
Disease:
Alzheimer's
Award Amount:
$399,761
Grant Reference ID:
A2009028
Award Type:
Standard
Award Region:
US Southwestern

Co-principal Investigators

Yong Shen, MD, PhD
Sun Health Research Institute (Sun City, AZ)

Estrogen And Its Receptors In BACE1 Regulation: From Cells To Mice

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.

Research Updates

During the past few years, Dr. Li’s and Dr. Shen’s team 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. Unfortunately, due to some difficulties of transferring Dr. Li’s research samples and supplies from her former employee, Banner Sun health Research Institute, it has caused a huge delay of the project.

Nevertheless, the team has worked together to re-isolate the full length of the BACE1 gene promoter, and developed 8 different mutations of the BACE1 promoter that are suspected to interfere with estrogen binding (within the three half sized estrogen response element (ERE) sites). Most importantly, they established stable cultured cell lines for each BACE1 promoter mutation, to be able to study in detail the effect on the binding of estrogen to the BACE1 promoter. Using the regenerated experimental described above, the team has confirmed the estrogen regulation on the BACE1 promoter via the ERE binding sites with and without estrogen dependency. They found that estrogen depletion causes up-regulation of BACE1 gene expression by measuring the amount of mRNA using real time PCR. Therefore, these results contribute to further understanding how the reduction of estrogen levels in menopausal and postmenopausal women may increase the risk of developing Alzheimer’s disease.

Publications

Long J, He P, Shen Y, Li R. (2012) New evidence of mitochondria dysfunction in the female Alzheimer's brain: deficiency of estrogen receptor-ƒÒ. Journal of Alzheimer's Disease.

McAllister C, Long J, Bowers A, Walker A, Cao P, Honda S-I, Harada N, Staufenbiel M , Shen Y, Li R. (2010) Genetic targeting aromatase in male amyloid precursor protein (APP) transgenic mice down-regulates beta-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment. PubMed Icon Google Scholar Icon

Li R, He P, Cui J, Staufenbiel M, Harada N, Shen Y. (2012) Brain endogenous estrogen levels determine responses to estrogen replacement therapy via regulation of BACE1 and NEP in female Alzheimer's transgenic mice. Molecular Neurobiology November 20 (Epub ahead of print)

Li R, Cui J, Jothishankar B, Shen J, He P, Shen Y. (2012) Early reproductive experiences in females make differences in cognitive function later in life. Journal of Alzheimer’s Disease. In press

Long J, He P, Shen Y, Li R. (2012) New evidence of mitochondria dysfunction in the female Alzheimer's brain: deficiency of estrogen receptor-ƒÒ. Journal of Alzheimer's Disease. PubMed Icon Google Scholar Icon

McAllister C, Long J, Bowers A, Walker A, Cao P, Honda S-I, Harada N, Staufenbiel M , Shen Y, Li R. (2010) Genetic targeting aromatase in male amyloid precursor protein (APP) transgenic mice down-regulates beta-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment. PubMed Icon Google Scholar Icon

Cui J, Shen Y, Li R. (2013) Estrogen synthesis and signaling pathways during ageing: from periphery to brain. Trends in Molecular Medicine, 19(3): 197-209. PubMed Icon Google Scholar Icon

Li R, He P, Cui J, Staufenbiel M, Harada N, Shen Y. (2013) Brain endogenous estrogen levels determine responses to estrogen replacement therapy via regulation of BACE1 and NEP in female Alzheimer's transgenic mice. Molecular Neurobiology. 47(3): 857-867. PubMed Icon Google Scholar Icon

Li R, Cui J, Jothishankar B, Shen J, He P, Shen Y. (2013) Early reproductive experiences in females make differences in cognitive function later in life. Journal of Alzheimer's Disease. 34: 589-594. PubMed Icon Google Scholar Icon

Wang H, Li R, Shen Y. (2013) Beta-secretase: its biology as a therapeutic target in diseases. Trends in Pharmacological Science. February 27, (Epub ahead of print).  PubMed Icon Google Scholar Icon

Li R, Shen Y. (2013) An old method facing a new challenge: re-visiting housekeeping protein as internal reference control for neuroscience research.  Life Science.  92(13):747-751. PubMed Icon Google Scholar Icon

He P, Cheng X, Staufenbiel M, Li R, Shen Y. (2013) Long-term treatment of thalidomide ameliorates amyloid-like pathology through Inhibition of beta-secretase in a mouse model of Alzheimer's disease. PLoS ONE. 8(2):e55091. PubMed Icon Google Scholar Icon

McAllister C, Long J, Bowers A, Walker A, Cao P, Honda S-I, Harada N, Staufenbiel M , Shen Y, Li R. (2010) Genetic targeting aromatase in male amyloid precursor protein (APP) transgenic mice down-regulates beta-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment. Journal of Neuroscience, 30:7326-7334. PubMed Icon Google Scholar Icon