The healthy cell bias of estrogen action through regulating glucose metabolism and mitochondrial function: Implications for prevention of Alzheimer's disease

Editors' introduction Brinton provides a comprehensive review of the effects of estradiol on glycolytic enzymes and glucose metabolism in the brain and in neurons. Her analysis reveals a large body of corroborating evidence converging on the conclusion that estradiol promotes enhanced utilization of glucose in the brain, thereby helping neurons to meet the energy demands of neuronal activation. Seeing as how dysfunction of glucose metabolism and neuronal biogenetics are antecedents to Alzheimer's disease (AD), it is reasonable to speculate how the effects of estrogens on glucose metabolism might help stave off the disease. Her studies show, however, that as neurons become compromised such as in the context of aging and/or disease, the effects of estrogens can become deleterious and ultimately lead to the activation of apoptotic pathways and neuronal death. Hence the hypothesis that as neurons age and become increasingly stressed or compromised, the net effect of estrogens on oxidative metabolism and neuronal survival shifts from positive to negative. This healthy cell bias may explain some of the recent negative clinical results, and in particular how estrogenic therapy administered around the time of the perimenopause can be beneficial whereas the same therapy administered late in life and in the context of a developing pathology could be detrimental and result in significant cognitive decline.