Alterations in glucose metabolism occur in the brain in the early stage of Alzheimer's disease (AD), and menopausal women have more severe metabolic dysfunction and are more prone to dementia than men. Although estrogen deficiency-induced changes in glucose metabolism have been previously studied in animal models, their molecular mechanisms in AD remain elusive. To investigate this issue, double transgenic (APP/PS1) female mice were subjected to bilateral ovariectomy at 3 months of age and were sacrificed 1 week, 1 month and 3 months after surgery to simulate early, middle and late postmenopause, respectively. Our analysis demonstrated that estrogen deficiency exacerbates learning and memory deficits in this mouse model of postmenopause. Estrogen deficiency impairs the function of mitochondria in glucose metabolism. It is possible that the occurrence of AD is associated with the aberrant mitochondrial ERβ-mediated IGF-1/IGF-1R/GSK-3β signaling pathway. In this study, we established a potential mechanism for the increased risk of AD in postmenopausal women and proposed a therapeutic target for AD due to postmenopause.

阿尔茨海默病（AD）早期大脑中会发生葡萄糖代谢的改变，更年期女性的代谢功能障碍更严重，比男性更容易患痴呆症。尽管先前已经在动物模型中研究了雌激素缺乏引起的葡萄糖代谢变化，但它们在 AD 中的分子机制仍然难以捉摸。为了研究这个问题，双转基因 (APP/PS1) 雌性小鼠在 3 个月大时接受双侧卵巢切除术，并在手术后 1 周、1 个月和 3 个月分别处死以模拟绝经后早期、中期和晚期。我们的分析表明，雌激素缺乏会加剧这种绝经后小鼠模型的学习和记忆缺陷。雌激素缺乏会损害线粒体在葡萄糖代谢中的功能。AD的发生可能与线粒体ERβ介导的IGF-1/IGF-1R/GSK-3β信号通路异常有关。在这项研究中，我们建立了绝经后女性 AD 风险增加的潜在机制，并提出了绝经后 AD 的治疗靶点。