科研之友
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摘要
Rodent models show decreased neuronal responses to estradiol (E2) during aging (E2-desensitization) in association with reduced neuronal estrogen receptor (ER)-alpha, but little is known about age changes of E2-dependent astrocytic neurotrophic support. Because elevated expression of astrocyte glial fibrillary acidic protein (GFAP) is associated with impaired neurotrophic activity and because the GFAP promoter responds to ER alpha, we investigated the role of astrocytic ER alpha and ER beta in impaired astrocyte neurotrophic activity during aging. In vivo and in vitro, ER alpha was increased greater than 50% with age in astrocytes from the cerebral cortex of male rats (24 vs 3 months), whereas ER beta did not change. In astrocytes from 3-month-old males, experimentally increasing the ER alpha to ER beta ratio induced the aging phenotype of elevated GFAP and impaired E2-dependent neurite outgrowth. In 24-month-old male astrocytes, lowering ER alpha reversed the age elevation of GFAP and partially restored E2-dependent neurite outgrowth. Mixed glia (astrocytes to microglia, 3: 1) of both sexes also showed these age changes. In a model of perimenopause, mixed glia from 9-to 15-month rats showed E2 desensitization: 9-month regular cyclers retained young-like ER alpha to ER beta ratios and neurotrophic activity, whereas 9-month noncyclers had elevated ER alpha and GFAP but low E2-dependent neurotrophic activity. In vivo, ER alpha levels in cortical astrocytes were also elevated. The persisting effects of ovarian acyclicity in vitro are hypothesized to arise from steroidal perturbations during ovarian senescence. These findings suggest that increased astrocyte ER alpha expression during aging contributes to the E2 desensitization of the neuronal responses in both sexes.
- 出版日期2013-6
