Molecular insights into the potential effects of selective estrogen receptor β agonists in Alzheimer's and Parkinson's diseases.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders. Pathologically, AD and PD are characterized by the accumulation of misfolded proteins. Hence, they are also called as proteinopathy diseases. Gender is considered as one of the risk factors in both diseases. Estrogens are widely accepted to be neuroprotective in several neurodegenerative disorders. Estrogens can be produced in the central nervous system, where they are called as neurosteroids. Estrogens mediate their neuroprotective action mainly through their actions on estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). However, ERα is mainly involved in the growth and development of the primary and secondary sexual organs in females. Hence, the activation of ERα is associated with undesired side effects such as gynecomastia and increase in the risk of breast cancer, thromboembolism, and feminization. Therefore, selective activation of ERβ is often considered to be safer. In this review, we explore the role of ERβ in regulating the expression and functions of AD- and PD-associated genes. Additionally, we discuss the association of these genes with the amyloid-beta peptide (Aβ) and α-synuclein mediated toxicity. Ultimately, we established a correlation between the importance of ERβ activation and the process underlying ERβ's neuroprotective mechanisms in AD and PD.