Estrogen receptor α: a critical role in successful female cognitive aging.

Due to potential health risks, current recommendations are that individuals who wish to use hormone therapy to treat menopausal symptoms do so for the shortest period of time possible. In our investigation into how short-term use of estrogens in midlife following loss of ovarian function exerts long-term effects on female cognitive aging in rodents, we discovered a link between the ability of previous exposure to estradiol to enhance memory in the long term and its ability to increase estrogen receptor α (ERα) levels in the hippocampus, a brain area important for memory. Follow-up studies in model systems implicate a role for ERα in enhanced cognitive function independent of ovarian or exogenously administered estrogens. Results are consistent with clinical studies in which brain ERα levels in older women and men are related to cognitive functioning and risk of cognitive decline is associated with polymorphisms in the gene that transcribes ERα. Research in preclinical models reveals mechanisms through which ERα can be activated and affect cognition in the absence of ovarian estrogens, including ligand-independent activation via insulin-like growth factor-1 signaling and activation by brain-derived neuroestrogens. This report reviews preclinical and clinical data that collectively point to the importance of ERα in cognition and highlights the need to differentiate the role of estrogen receptors from their classical ligands as we seek approaches to facilitate successful cognitive aging.