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Estrogen Signaling in Alzheimer’s Disease: Molecular Insights and Therapeutic Targets for Alzheimer’s Dementia

Uddin MS1,2Rahman MM3Jakaria M4Rahman MS3Hossain MS5Islam A6Ahmed M7Mathew B8Omar UM9,10Barreto GE11,12Ashraf GM13,14.

Mol Neurobiol. 2020 Apr 15. doi: 10.1007/s12035-020-01911-8. [Epub ahead of print]

 

Abstract

Estrogens play a crucial physiological function in the brain; however, debates exist concerning the role of estrogens in Alzheimer’s disease (AD). Women during pre-, peri-, or menopause periods are more susceptible for developing AD, suggesting the connection of sex factors and a decreased estrogen signaling in AD pathogenesis. Yet, the underlying mechanism of estrogen-mediated neuroprotection is unclarified and is complicated by the existence of estrogen-related factors. Consequently, a deeper analysis of estrogen receptor (ER) expression and estrogen-metabolizing enzymes could interpret the importance of estrogen in age-linked cognitive alterations. Previous studies propose that hormone replacement therapy may attenuate AD onset in postmenopausal women, demonstrating that estrogen signaling is important for the development and progression of AD. For example, ERα exerts neuroprotection against AD by maintaining intracellular signaling cascades and study reported reduced expression of ERα in hippocampal neurons of AD patients. Similarly, reduced expression of ERβ in female AD patients has been associated with abnormal function in mitochondria and improved markers of oxidative stress. In this review, we discuss the critical interaction between estrogen signaling and AD. Moreover, we highlight the potential of targeting estrogen-related signaling for therapeutic intervention in AD.

Conclusions

The complexity in the understanding of AD pathophysiology and lack of proper treatments led scientists to investigate new pathogenic factors in AD etiology. The connection between sex and Alzheimer’s incidence recommends a neuroprotective role of estrogen against the pathogenesis of the AD. Interestingly, developing the drugs that have action via estrogen effects, estrogen-metabolizing enzyme expression, or ERs expression has great potential to treat neurodegenerative conditions. However, the interaction between estrogen signaling and AD pathogenesis along with anti-AD drugs should be assessed by further studies.