Estrogen regulation of glucose metabolism and mitochondrial function: therapeutic implications for prevention of Alzheimer's disease

Abstract

Estrogen-induced signaling pathways in hippocampal and cortical neurons converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis and citric acid cycle-driven oxidative phosphorylation and ATP generation. Data derived from experimental and clinical paradigms investigating estrogen intervention in healthy systems and prior to neurodegenerative insult indicate enhanced neural defense and survival through maintenance of calcium homeostasis, enhanced glycolysis coupled to the citric acid cycle (aerobic glycolysis), sustained and enhanced mitochondrial function, protection against free radical damage, efficient cholesterol trafficking and beta amyloid clearance. The convergence of E(2) mechanisms of action onto mitochondrial is also a potential point of vulnerability when activated in a degenerating neural system and could exacerbate the degenerative processes through increased load on dysregulated calcium homeostasis. The data indicate that as the continuum of neurological health progresses from healthy to unhealthy so too do the benefits of estrogen or hormone therapy. If neurons are healthy at the time of estrogen exposure, their response to estrogen is beneficial for both neuronal survival and neurological function. In contrast, if neurological health is compromised, estrogen exposure over time exacerbates neurological demise. The healthy cell bias of estrogen action hypothesis provides a lens through which to assess the disparities in outcomes across the basic to clinical domains of scientific inquiry and on which to predict future applications of estrogen and hormone therapeutic interventions sustain neurological health and to prevent age-associated neurodegenerative diseases such as Alzheimer's. Overall, E(2) promotes the energetic capacity of brain mitochondria by maximizing aerobic glycolysis (oxidative phosphorylation coupled to pyruvate metabolism). The enhanced aerobic glycolysis in the aging brain would be predicted to prevent conversion of the brain to using alternative sources of fuel such as the ketone body pathway characteristic of Alzheimer's.

Figure 1. Estrogen (E₂) promotes glycolysis and glycolytic coupled tricarboxylic acid cycle (TCA) function, mitochondrial respiration and ATP generation to prevent switch to ketone bodies as an alternative fuel source

E₂ increases key enzymes in the glycolytic pathway to promote generation of pyruvate and its conversion by pyruvate dehydrogenase (PDH) to acetyl-CoA to initiate and sustain the TCA cycle. Under metabolically challenging conditions (i.e. starvation, aging and neurodegeneration) neurons can utilize acetyl-CoA generated from ketone body metabolism (ketolysis), produced by the liver or under conditions of starvation in neighboring glial cells. This latter pathway is much less efficient and can inhibit residual glycolysis. In AD there is a generalized shift towards use of an alternative fuel, ketone bodies, and away from glycolytic energy production. E₂ enhances the glycolytic/pyruvate/acetyl-CoA pathway to generate electrons required for oxidative phosphorylation and ATP generation to sustain utilization of glucose as the primary fuel source for the brain.