Center for Innovation in Brain Science and Department of Pharmacology, University of Arizona, Tucson, AZ, USA.
School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
Sci Rep. 2020 May 22;10(1):8528. doi: 10.1038/s41598-020-65402-5.
Decline in brain glucose metabolism is a hallmark of late-onset Alzheimer's disease (LOAD). Comprehensive understanding of the dynamic metabolic aging process in brain can provide insights into windows of opportunities to promote healthy brain aging. Chronological and endocrinological aging are associated with brain glucose hypometabolism and mitochondrial adaptations in female brain. Using a rat model recapitulating fundamental features of the human menopausal transition, results of transcriptomic analysis revealed stage-specific shifts in bioenergetic systems of biology that were paralleled by bioenergetic dysregulation in midlife aging female brain. Transcriptomic profiles were predictive of outcomes from unbiased, discovery-based metabolomic and lipidomic analyses, which revealed a dynamic adaptation of the aging female brain from glucose centric to utilization of auxiliary fuel sources that included amino acids, fatty acids, lipids, and ketone bodies. Coupling between brain and peripheral metabolic systems was dynamic and shifted from uncoupled to coupled under metabolic stress. Collectively, these data provide a detailed profile across transcriptomic and metabolomic systems underlying bioenergetic function in brain and its relationship to peripheral metabolic responses. Mechanistically, these data provide insights into the complex dynamics of chronological and endocrinological bioenergetic aging in female brain. Translationally, these findings are predictive of initiation of the prodromal / preclinical phase of LOAD for women in midlife and highlight therapeutic windows of opportunity to reduce the risk of late-onset Alzheimer's disease.
大脑葡萄糖代谢下降是迟发性阿尔茨海默病 (LOAD) 的标志。全面了解大脑代谢的动态老化过程，可以深入了解促进健康大脑老化的机会窗口。 与大脑葡萄糖代谢低下和线粒体适应相关的是，生理年龄和内分泌年龄的老化。使用模拟人类更年期过渡的基本特征的大鼠模型，转录组分析的结果揭示了生物学中生物能系统的特定阶段变化，而中年女性大脑的生物能失调也与之平行。转录组谱可预测基于无偏、发现为基础的代谢组学和脂质组学分析的结果，这些结果揭示了衰老女性大脑从以葡萄糖为中心的动态适应到辅助燃料来源的利用，包括氨基酸、脂肪酸、脂质和酮体。大脑和外周代谢系统之间的耦合是动态的，在代谢应激下从解偶联转变为偶联。 总的来说，这些数据提供了大脑生物能功能及其与外周代谢反应关系的转录组和代谢组系统的详细概况。从机制上讲，这些数据为女性大脑的生理年龄和内分泌生物能老化的复杂动态提供了深入了解。从翻译的角度来看，这些发现可以预测中年女性 LOAD 前驱期/临床前期的开始，并强调了减少迟发性阿尔茨海默病风险的治疗机会窗口。
