Estrogen Signaling in Alzheimer’s Disease: Molecular Insights and Therapeutic Targets for Alzheimer’s Dementia Md. Sahab Uddin 1,2 & Md. Motiar Rahman 3 & Md. Jakaria 4 & Md. Sohanur Rahman 3 & Md. Sarwar Hossain 5 & Ariful Islam 6 & Muniruddin Ahmed 7 & Bijo Mathew 8 & Ulfat Mohammed Omar 9,10 & George E. Barreto 11,12 & Ghulam Md Ashraf 13,14 Received: 20 December 2019 /Accepted: 23 March 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020 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 post- menopausal 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. Keywords Estrogen . Alzheimer ’s disease . Estrogen signaling . Estrogen-related factors . Estrogen receptors . Estrogen-metabolizing enzymes Abbreviations AD Alzheimer’ s disease ER Estrogen receptor ERα Estrogen receptor alpha * Md. Sahab Uddin msu-neuropharma@hotmail.com; msu_neuropharma@hotmail.com * George E. Barreto gesbarreto@gmail.com; George.Barreto@ul.ie * Ghulam Md Ashraf ashraf.gm@gmail.com; gashraf@kau.edu.sa 1 Department of Pharmacy, Southeast University, Dhaka, Bangladesh 2 Pharmakon Neuroscience Research Network, Dhaka, Bangladesh 3 Graduate School of Innovative Life Science, University of Toyama, Gofuku 3190, Toyama, 930-8555, Japan 4 The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia 5 School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy 6 Department of Cell Biology and Neuroscience, Rowan University School of Osteopathic Medicine, Stratford, NJ, USA 7 Department of Pharmacy, Daffodil International University, Dhaka, Bangladesh 8 Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, India 9 Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia 10 Immunology Unit, King Fahad Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia 11 Department of Biological Sciences, University of Limerick, Limerick, Ireland 12 Health Research Institute, University of Limerick, Limerick, Ireland 13 King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia 14 Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia https://doi.org/10.1007/s12035-020-01911-8 Molecular Neurobiology (2020) 57:2654–2670 /Published online: 15 April 2020