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Brain Endogenous Estrogen Levels Determine Responses to Estrogen Replacement Therapy via Regulation of BACE1 and NEP in Female Alzheimer’s Transgenic Mice

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Abstract

Estrogens have been found to improve memory and reduce risk of dementia, although conflicting results such as failure of estrogen replacement therapy for treatment of Alzheimer's disease (AD) also has been reported. Only recently, our published human brain studies showed a depletion of brain estrogen in women with AD, while other studies have demonstrated cognitive impairment believed to be caused by inhibition of endogenous estrogen synthesis in females. To investigate whether the shortage of brain estrogen alters the sensitivity of response to estrogen replacement therapy, we have used genetic and surgical animal models to examine the response of estrogen treatment in AD neuropathology. Our studies have shown that early treatment with 17β-estradiol (E2) or genistein could reduce brain amyloid levels by increasing Aβ clearance in both APP23 mice with genetic deficiency of aromatase (APP/Ar+/−), in which the brains contain nondetectable levels of estrogen, and in APP23 mice with an ovariectomy (APP/OVX), in which the brains still contain certain levels of estrogen. However, only APP/Ar+/− mice showed a great reduction in brain amyloid plaque formation after E2 or genistein treatment along with downregulation of β-secretase (BACE1) mRNA and protein expression. Our results suggest that early and long-term usage of E2 and/or genistein may prevent AD pathologies in a dependent manner on endogenous brain estrogen levels in aged females.

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Acknowledgments

This work was supported by grants from the Alzheimer's Association IIRG-07-59510, American Health Assistance Foundation Grant G2006-118, NIH R01AG032441, and NIH R01AG025888. We thank Mr. Alex Bishop for editing and proofreading the manuscript.

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Authors and Affiliations

  1. Center for Hormone Advanced Science and Education, Roskamp Institute, 2040 Whitfield Ave., Sarasota, FL, 34243, USA

    Rena Li, Ping He & Jie Cui

  2. Center for Advanced Therapeutic Strategies for Brain Disorders, Roskamp Institute, Sarasota, FL, 34243, USA

    Ping He & Yong Shen

  3. Novartis Pharma Ltd., Nervous System Research, 4002, Basel, Switzerland

    Matthias Staufenbiel

  4. School of Medicine, Fujita Health University, Aichi, 470-1192, Japan

    Nobuhiro Harada

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  1. Rena Li
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Correspondence to Rena Li.

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Li, R., He, P., Cui, J. et al. Brain Endogenous Estrogen Levels Determine Responses to Estrogen Replacement Therapy via Regulation of BACE1 and NEP in Female Alzheimer’s Transgenic Mice. Mol Neurobiol 47, 857–867 (2013). https://doi.org/10.1007/s12035-012-8377-3

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