Menopause and mitochondria: windows into estrogen effects on Alzheimer's disease risk and therapy.
Menopause and mitochondria: windows into estrogen effects on Alzheimer's disease risk and therapy.
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更年期和线粒体：雌激素对阿尔茨海默氏病风险和治疗的影响。
DOI：
10.1016/s0079-6123(10)82003-5
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发表时间：
2010
影响因子：
--
通讯作者：
Brinton RD
中科院分区：
文献类型：
--
作者：
Henderson VW;Brinton RD
代谢紊乱和氧化应激是阿尔茨海默病发病机制的早期事件。雌激素的多方面作用包括通过对线粒体的作用改善大脑代谢状况和减少氧化应激，这表明女性在中年和绝经后晚期接触内源性和外源性雌激素可能会对阿尔茨海默病的风险和症状产生有利的影响。这一预测得到了临床文献的部分支持。正如预期的那样，卵巢切除术引起的提前绝经可能会增加认知脆弱性；然而，在其他情况下，绝经年龄与阿尔茨海默病风险之间，或者自然绝经与记忆丧失之间没有明确的联系。此外，在老年绝经后女性中，开始含雌激素的激素治疗会增加患痴呆症的风险，并且可能不会改善阿尔茨海默病的症状。正如“关键窗口”或“健康细胞”假说所表明的那样，早期雌激素暴露可能会带来更好的结果。一些观察结果表明，激素治疗对阿尔茨海默病风险的影响确实会因开始年龄、接近更年期的时间或女性的健康状况而改变。然而，潜在的方法学偏差在解释观察结果时需要谨慎。正在进行的大型临床试验（雌二醇早期与晚期干预试验 [ELITE]；Kronos 早期雌激素预防研究 [KEEPS]）的预期结果将有助于确定中年雌激素治疗是否可以改善中年认知技能，但不能确定中年雌激素暴露是否会改变晚年阿尔茨海默病风险。雌激素对线粒体的影响预示着雌激素与阿尔茨海默病的潜在相关性。然而，实验室模型是阿尔茨海默病发病机制和进展的不精确体现，因此很难推测雌激素暴露的净效应。研究需求包括更好地预测不良认知结果、激素治疗相关风险的生物标志物以及监测大脑功能和疾病进展的工具。
Metabolic derangements and oxidative stress are early events in Alzheimer’s disease pathogenesis. Multifaceted effects of estrogens include improved cerebral metabolic profile and reduced oxidative stress through actions on mitochondria, suggesting that a woman’s endogenous and exogenous estrogen exposures during midlife and in the late postmenopause might favorably influence Alzheimer risk and symptoms. This prediction finds partial support in the clinical literature. As expected, early menopause induced by oophorectomy may increase cognitive vulnerability; however, there is no clear link between age at menopause and Alzheimer risk in other settings, or between natural menopause and memory loss. Further, among older postmenopausal women, initiating estrogen-containing hormone therapy increases dementia risk and probably does not improve Alzheimer’s disease symptoms. As suggested by the “critical window” or “healthy cell” hypothesis, better outcomes might be expected from earlier estrogen exposures. Some observational results imply that effects of hormone therapy on Alzheimer risk are indeed modified by age at initiation, temporal proximity to menopause, or a woman’s health. However, potential methodological biases warrant caution in interpreting observational findings. Anticipated results from large, ongoing clinical trials (Early versus Late Intervention Trial with Estradiol [ELITE]; Kronos Early Estrogen Prevention Study [KEEPS]) will help settle whether midlife estrogen therapy improves midlife cognitive skills but not whether midlife estrogen exposures modify late life Alzheimer risk. Estrogen effects on mitochondria adumbrate the potential relevance of estrogens to Alzheimer’s disease. However, laboratory models are inexact embodiments of Alzheimer pathogenesis and progression, making it difficult to surmise net effects of estrogen exposures. Research needs include better predictors of adverse cognitive outcomes, biomarkers for risks associated with hormone therapy, and tools for monitoring brain function and disease progression.