Update on the Neuroprotective Effect of Estrogen Receptor Alpha Against Alzheimer's Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and disordered cognition. Women have a higher AD incidence than men, indicating that the declining estrogen levels during menopause may influence AD pathogenesis. However, the mechanism underlying estrogen's neuroprotective effect is not fully clarified and is complicated by the presence of several distinct estrogen receptor (ER) types and the identification of a growing number of ER splice variants. Thus, a deeper analysis of ERs could elucidate the role of estrogen in age-related cognitive changes. Intracellular calcium signaling cascades play a pivotal role in ER alpha neuroprotection against AD. The ER alpha-mediated inhibition of Death domain-associated protein (Daxx) translocation and the combination of membrane ER alpha and caveolin in caveolae may protect against AD. Moreover, the voltage-dependent anion channel (VDAC)/ER alpha association may be important for maintaining channel inactivation and may be relevant in neuronal preservation against A beta injury. Additionally, ER alpha may prevent glutamate excitotoxic injury by A beta through estrogen signaling mechanisms. ER alpha and IGF-IR co-activation may mediate neuroprotection, and many other growth factors and intracellular signaling responses triggered by ER alpha may also play important roles in this process. Furthermore, details regarding the genes and mRNA variants of ER alpha that are expressed in different parts of the human organs have been clarified recently. Therefore, here we review the literature to clarify the neuroprotective role of ER alpha. This review focuses on the potential mechanisms mediated by ER alpha in the intracellular signaling events in nervous system cells, thereby clarifying ER alpha-mediated protection against AD.