Cardiometabolic health, menopausal estrogen therapy and the brain: How effects of estrogens diverge in healthy and unhealthy preclinical models of aging

Abstract

Research in preclinical models indicates that estrogens are neuroprotective and positively impact cognitive aging. However, clinical data are equivocal as to the benefits of menopausal estrogen therapy to the brain and cognition. Pre-existing cardiometabolic disease may modulate mechanisms by which estrogens act, potentially reducing or reversing protections they provide against cognitive decline. In the current review we propose mechanisms by which cardiometabolic disease may alter estrogen effects, including both alterations in actions directly on brain memory systems and actions on cardiometabolic systems, which in turn impact brain memory systems. Consideration of mechanisms by which estrogen administration can exert differential effects dependent upon health phenotype is consistent with the move towards precision or personalized medicine, which aims to determine which treatment interventions will work for which individuals. Understanding effects of estrogens in both healthy and unhealthy models of aging is critical to optimizing the translational link between preclinical and clinical research.

Keywords: Cardiovascular; Cognition; Cortex; Estradiol; Estrogen; Hippocampus; Memory; Menopause; Metabolism.

Fig. 1.. Mechanisms by which impacts of estrogens on the brain and cognition may diverge under conditions of cardiometabolic health and disease.

First, status of cardiovascular and metabolic health alters mechanisms by which estrogens act directly on memory systems of the brain (blue arrows) including the hippocampus (1) and cortex (2). Second, cardiovascular and metabolic health impact mechanisms by which estrogens act directly on cardiometabolic systems (red arrows), which subsequently impact the brain (3, 4).

Fig. 2.. Hypothesized model by which effects of estrogens on the hippocampus and memory diverge in healthy and unhealthy females.

If individuals are healthy when treatment with estrogens is initiated, estrogens can act through a functional ubiquitin / proteasome system to protect hippocampal ERα from degradation. Once elevated levels are achieved, they will persist, creating a positive feedback loop and prolonged enhanced cognition. If individuals are unhealthy when treatment with estrogens is initiated, estrogens are unable to act to protect ERα in the hippocampus from degradation and has no effect on levels of ERα – a critical factor in the ability of estrogens to impact memory. Created with BioRender.com.

Fig. 3.. Hypothesized model by which effects of estrogens on cortical synaptic plasticity and neurovascular coupling diverge in healthy and unhealthy females.

Learning and memory are dependent on proper synaptic plasticity mechanisms, which are directly and indirectly determined, among other mechanisms, by neuronal activity and metabolism, mechanisms mutually dependent on each other too. In turn, neurovascular coupling (NVC) depends and has effects on neuronal activity and metabolism and relies on the proper function of endothelial cells of the brain vasculature. It is known that cessation of endogenous circulating estrogens, even in healthy conditions, has detrimental effects on NVC, neuronal activity, and synaptic plasticity (blue thunderbolts) that are ultimately responsible for overall impaired cognition. While hormone therapy early after menopause prevents or reverts many of those deficits (green blunt arrows), it is unknown whether the neuroprotective effect of estrogens therapy is able to overcome the presence of prior history of cardiovascular or metabolic disease in unhealthy aging conditions at menopause (red thunderbolts).

Fig. 4.. Hypothesized model by which effects of estrogens in the vasculature diverge in healthy versus unhealthy arteries.

If arteries are healthy when treatment with estrogens is initiated, estrogens activate both the G protein-coupled receptor (GPER) and estrogen receptor alpha (ERα) to induce vasodilation and decrease oxidative stress, blood pressure, arterial stiffness, and vascular remodeling. These protective effects in the vasculature positively impact the brain and cognition. If arteries are unhealthy due to hypertension or other cardiovascular diseases when treatment with estrogens is initiated, GPER and ERα expression and/or signaling are downregulated so the vascular effects as well as downstream impact on the brain are reduced. Created with BioRender.com.

Fig. 5.. Hypothesized model by which effects of estrogens on the central regulation of glucose homeostasis and subsequent implications for hippocampal function diverge under conditions of healthy and unhealthy aging.

Insulin resistance caused by high fat diet impairs downstream signaling pathways necessary for beneficial influence of estrogens on central regulation of glucose homeostasis, hippocampal LTP, and hippocampus-dependent cognitive function. High fat diet impairs glucose regulation through modulation of the hypothalamic neurons, and high fat diet will impair the PI3K pathway in both these neurons in the hypothalamus and neurons in the hippocampus to affect sensitivity to estrogens.