Estrogen regulation of glucose metabolism and mitochondrial function: therapeutic implications for prevention of Alzheimer's disease.
Estrogen regulation of glucose metabolism and mitochondrial function: therapeutic implications for prevention of Alzheimer's disease.
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DOI：
10.1016/j.addr.2008.06.003
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发表时间：
2008-10
影响因子：
16.1
通讯作者：
Brinton, Roberta Diaz
中科院分区：
文献类型：
--
作者：
Brinton, Roberta Diaz
关键词：
海马和皮质神经元中雌激素诱导的信号传导途径会聚在线粒体上，以增强线粒体功能并维持有氧糖酵解和柠檬酸循环驱动的氧化磷酸化和ATP生成。来自研究健康系统中雌激素干预和神经退行性损伤之前的实验和临床范例的数据表明，通过维持钙稳态，增强与柠檬酸循环偶联的糖酵解（有氧糖酵解），持续和增强线粒体功能，保护免受自由基损伤，有效的胆固醇运输和β淀粉样蛋白清除，增强神经防御和存活。E2作用机制在线粒体上的会聚也是在退化神经系统中激活时的潜在脆弱点，并且可能通过增加钙稳态失调的负荷而加剧退化过程。数据表明，随着神经系统健康的连续性从健康发展到不健康，雌激素或激素治疗的益处也是如此。如果神经元在雌激素暴露时是健康的，它们对雌激素的反应对神经元存活和神经功能都是有益的。相反，如果神经系统健康受到损害，雌激素暴露随着时间的推移加剧神经死亡。雌激素作用假说的健康细胞偏好提供了一个透镜，通过它来评估科学调查的基础到临床领域的结果差异，并预测雌激素和激素治疗干预的未来应用，以维持神经系统健康，并预防与年龄相关的神经退行性疾病，如阿尔茨海默氏症。总的来说，E2通过最大化有氧糖酵解（氧化磷酸化与丙酮酸代谢偶联）促进脑线粒体的能量能力。在老化的大脑中增强的有氧糖酵解将被预测为防止大脑转换为使用替代燃料来源，例如阿尔茨海默氏症的特征性酮体途径。
Estrogen-induced signaling pathways in hippocampal and cortical neurons converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis and citric acid cycle-driven oxidative phosphorylation and ATP generation. Data derived from experimental and clinical paradigms investigating estrogen intervention in healthy systems and prior to neurodegenerative insult indicate enhanced neural defense and survival through maintenance of calcium homeostasis, enhanced glycolysis coupled to the citric acid cycle (aerobic glycolysis), sustained and enhanced mitochondrial function, protection against free radical damage, efficient cholesterol trafficking and beta amyloid clearance. The convergence of E2 mechanisms of action onto mitochondrial is also a potential point of vulnerability when activated in a degenerating neural system and could exacerbate the degenerative processes through increased load on dysregulated calcium homeostasis. The data indicate that as the continuum of neurological health progresses from healthy to unhealthy so too do the benefits of estrogen or hormone therapy. If neurons are healthy at the time of estrogen exposure, their response to estrogen is beneficial for both neuronal survival and neurological function. In contrast, if neurological health is compromised, estrogen exposure over time exacerbates neurological demise. The healthy cell bias of estrogen action hypothesis provides a lens through which to assess the disparities in outcomes across the basic to clinical domains of scientific inquiry and on which to predict future applications of estrogen and hormone therapeutic interventions sustain neurological health and to prevent age-associated neurodegenerative diseases such as Alzheimer’s. Overall, E2 promotes the energetic capacity of brain mitochondria by maximizing aerobic glycolysis (oxidative phosphorylation coupled to pyruvate metabolism). The enhanced aerobic glycolysis in the aging brain would be predicted to prevent conversion of the brain to using alternative sources of fuel such as the ketone body pathway characteristic of Alzheimer’s.
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影响因子：
17.7
作者：
Alexander, GE;Chen, K;Reiman, EM
通讯作者：
Reiman, EM
影响因子：
4.8
作者：
Dubal, Dena B.;Rau, Shane W.;Wise, Phyllis M.
通讯作者：
Wise, Phyllis M.
影响因子：
4.8
作者：
Cheng, CM;Cohen, M;Bondy, CA
通讯作者：
Bondy, CA
DOI：
10.1016/s0960-0760(02)00261-3
发表时间：
2002-12-01
影响因子：
4.1
作者：
Cardona-Gómez, GP;Mendez, P;Garcia-Segura, LM
通讯作者：
Garcia-Segura, LM
DOI：
10.1111/j.1749-6632.2000.tb06370.x
发表时间：
2000-01-01
期刊：
VASCULAR FACTORS IN ALZHEIMER'S DISEASE
影响因子：
--
作者：
Blass, JP;Sheu, RKF;Gibson, GE
通讯作者：
Gibson, GE