Brain sex matters: estrogen in cognition and Alzheimer's disease

Abstract

Estrogens are the primary female sex hormones and play important roles in both reproductive and non-reproductive systems. Estrogens can be synthesized in non-reproductive tissues such as liver, heart, muscle, bone and the brain. During the past decade, increasing evidence suggests that brain estrogen can not only be synthesized by neurons, but also by astrocytes. Brain estrogen also works locally at the site of synthesis in paracrine and/or intracrine fashion to maintain important tissue-specific functions. Here, we will focus on the biology of brain estrogen and its impact on cognitive function and Alzheimer's disease. This comprehensive review provides new insights into brain estrogens by presenting a better understanding of the tissue-specific estrogen effects and their roles in healthy ageing and cognitive function.

Keywords: Alzheimer’s disease; Brain estrogen; Cognition.

Fig. 1. Estrogen synthesis in the ovary and brain

(A) Cell-specific estrogen synthesis in the ovary. Production of estrogens starts with the synthesis of pregnenolone from cholesterol, catalyzed by the cytochrome P450 side-chain cleavage enzyme (P450scc). Pregnenolone is then converted to progesterone by 3β-hydroxysteroid dehydrogenase (3β-HSD) in both thecal and granulosa cells. Progesterone is converted to androgens via cytochrome P450 17α-hydroxylase (P45017α) and 17β-hydroxysteroid dehydrogenase (17β-HSD) in thecal cells during the follicular phase. The conversion of E2 is catalyzed by aromatase (P450Arom) in granulosa cells. (B) Neurons express all enzymes required for estrogen synthesis to produce brain estrogen.