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

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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.

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Abbreviations

AD:

Alzheimer’s disease

ER:

Estrogen receptor

ERα:

Estrogen receptor alpha

ERβ:

Estrogen receptor beta

COMT:

Catechol-O-methyltransferase

ApoE:

Apolipoprotein E

Daxx:

Death domain-associated protein

NMDA:

N-methyl-D-aspartate

VDAC:

Voltage-dependent anion channel

IGF-1R:

Insulin-like growth factor I receptor

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Acknowledgments

The authors concede the support by the Pharmakon Neuroscience Research Network, Dhaka, Bangladesh.

Funding

This project was supported by the Pharmakon Neuroscience Research Network, Dhaka, Bangladesh.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Southeast University, Dhaka, Bangladesh

    Md. Sahab Uddin

  2. Pharmakon Neuroscience Research Network, Dhaka, Bangladesh

    Md. Sahab Uddin

  3. Graduate School of Innovative Life Science, University of Toyama, Gofuku 3190, Toyama, 930-8555, Japan

    Md. Motiar Rahman & Md. Sohanur Rahman

  4. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia

    Md. Jakaria

  5. School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy

    Md. Sarwar Hossain

  6. Department of Cell Biology and Neuroscience, Rowan University School of Osteopathic Medicine, Stratford, NJ, USA

    Ariful Islam

  7. Department of Pharmacy, Daffodil International University, Dhaka, Bangladesh

    Muniruddin Ahmed

  8. Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, India

    Bijo Mathew

  9. Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia

    Ulfat Mohammed Omar

  10. Immunology Unit, King Fahad Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia

    Ulfat Mohammed Omar

  11. Department of Biological Sciences, University of Limerick, Limerick, Ireland

    George E. Barreto

  12. Health Research Institute, University of Limerick, Limerick, Ireland

    George E. Barreto

  13. King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia

    Ghulam Md Ashraf

  14. Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia

    Ghulam Md Ashraf

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  1. Md. Sahab Uddin
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Contributions

MSU conceived the original idea and designed the outlines of the study. MSU, MMR, MJ, MSR, and MSH wrote the draft of the manuscript. MSU prepared the figures for the manuscript. AI, MA, BM, GEB, UMO, and GMA performed the literature review and aided in revising the manuscript. All authors have read and agreed to the final version of the manuscript.

Corresponding authors

Correspondence to Md. Sahab Uddin, George E. Barreto or Ghulam Md Ashraf.

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Uddin, M.S., Rahman, M.M., Jakaria, M. et al. Estrogen Signaling in Alzheimer’s Disease: Molecular Insights and Therapeutic Targets for Alzheimer’s Dementia. Mol Neurobiol 57, 2654–2670 (2020). https://doi.org/10.1007/s12035-020-01911-8

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  • DOI: https://doi.org/10.1007/s12035-020-01911-8

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