The Impact of Estradiol on Neurogenesis and Cognitive Functions in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is described as cognitive and memory impairments with a sex-related epidemiological profile, affecting two times more women than men. There is emerging evidence that alternations in the hippocampal neurogenesis occur at the early stage of AD. Therapies that may effectively slow, stop, or regenerate the dying neurons in AD are being extensively investigated in the last few decades, but none has yet been found to be effective. The regulation of endogenous neurogenesis is one of the main therapeutic targets for AD. Mounting evidence indicates that the neurosteroid estradiol (17β-estradiol) plays a supporting role in neurogenesis, neuronal activity, and synaptic plasticity of AD. This effect may provide preventive and/or therapeutic approaches for AD. In this article, we discuss the molecular mechanism of potential estradiol modulatory action on endogenous neurogenesis, synaptic plasticity, and cognitive function in AD.

Keywords: Brain; Cell therapy; Dementia; Hormone; Neurodegeneration; Neurogenesis.

Fig. 1

Schematic diagram of two different estradiol (E2) signal transduction pathways: (1) In nuclear-initiated steroid signaling, E2 binds estrogen receptors (ERs) located in the nucleus and cytoplasm, which, in turn, binds to the DNA at estrogen-response element (ERE). This activates cyclic adenosine monophosphate response element-binding protein (CREB)-regulated gene transcription and promotes neuronal survival. (2) In membrane-initiated steroid signaling, plasma membrane estrogen receptor (mER) and G-protein coupled estrogen receptors (GPER) activate various intracellular cascades (e.g., PI3K-Akt and MAPK signaling pathways) resulting in CREB-mediated transcription for cell survival. AC adenylyl cyclase, CaMK Ca²⁺-calmodulin kinase, CREB cyclic response element-binding protein, DAG diacylglycerol, ER estrogen receptor, ERK extracellular signal-regulated kinase, IP3 inositol trisphosphate 3, PI3K phosphatidylinositol-3-kinase, PKC protein kinase C, MAPK mitogen-activated protein kinase. Diagram is summarized findings of in vivo and in vitro experimental animal studies

Fig. 2

Schematic representation of how estradiol (E2) increases neurogenesis through BDNF and NPY in different brain regions, such as the hippocampus, amygdala, and hypothalamus. In brief, E2 induces the BDNF and NPY synthesis and promotes neurogenesis. Neurogenesis inhibits anxiety and seizures and improves learning and appetite metabolism. Diagram is summarized findings of in vivo and in vitro experimental animal studies