White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease.
White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease.
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白质脂质是衰老女性大脑的生酮燃料供应：对阿尔茨海默氏病的影响。
DOI：
10.1016/j.ebiom.2015.11.002
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发表时间：
2015-12
期刊：
影响因子：
11.1
通讯作者：
Brinton RD
中科院分区：
文献类型：
--
作者：
Klosinski LP;Yao J;Yin F;Fonteh AN;Harrington MG;Christensen TA;Trushina E;Brinton RD
白质变性是包括阿尔茨海默氏症在内的神经退行性疾病的病理特征。年龄仍然是阿尔茨海默氏症的最大风险因素，与年龄相关的迟发性阿尔茨海默氏症的患病率在女性中最高。我们在一个与阿尔茨海默病风险最大的性别一致的动物模型中研究了白质退化的潜在机制。这些分析结果表明，在女性脑老化过程中，线粒体呼吸下降，线粒体过氧化氢产生增加，胞浆磷脂酶-A2鞘磷脂酶途径激活。电子显微镜和脂肪组学分析证实髓鞘变性。脂肪酸和线粒体脂肪酸代谢机制的增加与脑酮体的增加和血浆酮体的下降是一致的。这种机制途径及其时间阶段性激活，将衰老早期的线粒体功能障碍与白质变性的后期发展联系在一起。髓磷脂的分解代谢产生酮体可以被视为一种系统水平的适应性反应，以满足大脑的燃料和能量需求。阐明导致老年女性大脑白质分解代谢的启动因素和机制途径，为防治阿尔茨海默病和多发性硬化症等脱髓鞘疾病提供潜在的治疗靶点。针对疾病阶段和相关机制将是至关重要的。线粒体功能障碍激活髓鞘脂类分解代谢的机制，以产生用于产生ATP的酮体。导致脑部酮体驱动能量产生的机制与女性生殖衰老的阶段相吻合。在衰老过程中髓鞘分解代谢途径的顺序激活提供了多个治疗靶点和疗效窗口。白质变性是包括阿尔茨海默氏症在内的多种神经退行性疾病的标志，其背后的机制尚不清楚。在这里，我们提供了一种跨越多个衰老转变的机械性途径，将衰老早期的线粒体功能障碍与晚年白质变性联系起来。髓磷脂的分解代谢产生酮体可以被视为一种适应性的生存反应，以满足大脑的燃料和能量需求。女性患晚发性AD的风险最大，因此，我们在女性大脑中的分析解决了AD的病理机制和治疗目标，以预防、延迟和治疗受影响最严重的性别的AD，与男性潜在的相关性。
White matter degeneration is a pathological hallmark of neurodegenerative diseases including Alzheimer's. Age remains the greatest risk factor for Alzheimer's and the prevalence of age-related late onset Alzheimer's is greatest in females. We investigated mechanisms underlying white matter degeneration in an animal model consistent with the sex at greatest Alzheimer's risk. Results of these analyses demonstrated decline in mitochondrial respiration, increased mitochondrial hydrogen peroxide production and cytosolic-phospholipase-A2 sphingomyelinase pathway activation during female brain aging. Electron microscopic and lipidomic analyses confirmed myelin degeneration. An increase in fatty acids and mitochondrial fatty acid metabolism machinery was coincident with a rise in brain ketone bodies and decline in plasma ketone bodies. This mechanistic pathway and its chronologically phased activation, links mitochondrial dysfunction early in aging with later age development of white matter degeneration. The catabolism of myelin lipids to generate ketone bodies can be viewed as a systems level adaptive response to address brain fuel and energy demand. Elucidation of the initiating factors and the mechanistic pathway leading to white matter catabolism in the aging female brain provides potential therapeutic targets to prevent and treat demyelinating diseases such as Alzheimer's and multiple sclerosis. Targeting stages of disease and associated mechanisms will be critical. Mitochondrial dysfunction activates mechanisms for catabolism of myelin lipids to generate ketone bodies for ATP production. Mechanisms leading to ketone body driven energy production in brain coincide with stages of reproductive aging in females. Sequential activation of myelin catabolism pathway during aging provides multiple therapeutic targets and windows of efficacy. The mechanisms underlying white matter degeneration, a hallmark of multiple neurodegenerative diseases including Alzheimer's, remain unclear. Herein we provide a mechanistic pathway, spanning multiple transitions of aging, that links mitochondrial dysfunction early in aging with later age white matter degeneration. Catabolism of myelin lipids to generate ketone bodies can be viewed as an adaptive survival response to address brain fuel and energy demand. Women are at greatest risk of late-onset-AD, thus, our analyses in female brain address mechanisms of AD pathology and therapeutic targets to prevent, delay and treat AD in the sex most affected with potential relevance to men.