The Impact of Estrogen and Estrogen-Like Molecules in Neurogenesis and Neurodegeneration: Beneficial or Harmful?

Abstract

Estrogens and estrogen-like molecules can modify the biology of several cell types. Estrogen receptors alpha (ERα) and beta (ERβ) belong to the so-called classical family of estrogen receptors, while the G protein-coupled estrogen receptor 1 (GPER-1) represents a non-classical estrogen receptor mainly located in the plasma membrane. As estrogen receptors are ubiquitously distributed, they can modulate cell proliferation, differentiation, and survival in several tissues and organs, including the central nervous system (CNS). Estrogens can exert neuroprotective roles by acting as anti-oxidants, promoting DNA repair, inducing the expression of growth factors, and modulating cerebral blood flow. Additionally, estrogen-dependent signaling pathways are involved in regulating the balance between proliferation and differentiation of neural stem/progenitor cells (NSPCs), thus influencing neurogenic processes. Since several estrogen-based therapies are used nowadays and estrogen-like molecules, including phytoestrogens and xenoestrogens, are omnipresent in our environment, estrogen-dependent changes in cell biology and tissue homeostasis have gained attention in human health and disease. This article provides a comprehensive literature review on the current knowledge of estrogen and estrogen-like molecules and their impact on cell survival and neurodegeneration, as well as their role in NSPCs proliferation/differentiation balance and neurogenesis.

Keywords: 17β-estradiol; Alzheimer’s disease; ERα/β; GPER1/GPR30; Parkinson’s disease; bisphenol A; hormone replacement therapy; neural stem/progenitor cells.

FIGURE 1

Molecules with estrogenic activity. Classification of the various molecules and compounds that display estrogenic activity.

FIGURE 2

Endogenous estrogen regulates the proliferation and differentiation of NSPCs. Endogenous estrogen binds to both classical and non-classical ERs. Transactivation of the epidermal growth factor receptor (EGFR) via GPER-1 promotes the formation of dimers or heterodimers between nuclear receptors through (i) the activation of protein kinase A (PKA), (ii) an increase in the intracellular Ca²⁺ concentration, and (iii) the subsequent activation of the non-receptor tyrosine kinase (Src) and matrix metalloproteinases (MMP). EGFR promotes the downstream activation of the small GTPase (RAS)/phosphatidylinositol 3-kinase (PI3K) and the extracellular-signal-related kinase (ERK)/protein kinase B (also known as Akt) signaling pathways, which, in turn, phosphorylate of nuclear receptors, denoting the end of the non-genomic pathway. Alternatively, estrogens can directly bind to dimerized nuclear receptors (ERα/β) to activate the ERK/Akt pathways and promote their own phosphorylation. The genomic pathway involves the translocation of phosphorylated ER dimers into the nucleus for controlling the expression of genes associated with cell survival/proliferation, neurogenesis, and oligodendrogenesis.

FIGURE 3

Estrogen-like molecules activate the classical estrogen signaling cascade and alternative pathways. Phytoestrogens and xenoestrogens bind to classical and non-classical ERs to enhance or disrupt estrogenic activity. Alternatively, xenoestrogens are capable of promoting ER dimers phosphorylation through the Frizzled/GSK3β/β-catenin signaling axis. Question marks denote the absence of a well-established axis between phosphorylated ERs dimers and soluble AMP-activated protein kinase (AMPK), sirtuin-1 (SIRT1), and extracellular-signal-related kinase (ERK). Once phosphorylated, ERs dimers translocate to the nucleus to begin the genomic pathway, controlling the expression of genes associated with cell survival/proliferation, neurogenesis, and oligodendrogenesis.