Glutathione, Brain Metabolism and Inflammation in Alzheimer's Disease

谷胱甘肽、脑代谢和阿尔茨海默氏病的炎症

• 批准号: 10391568
• 负责人: JOSEPH C MASDEU
• 金额: $ 80.16万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391568
• 关键词: Acetylcysteine; Affect; Age-associated memory impairment; Aging; Alanine; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease risk; Amino Acids; Antioxidants; Brain; Calorimetry; Clinical Trials; Cognition; Complex; Cysteine; Data; Defect; Dementia; Diet; Double-Blind Method; Elderly; Encephalitis; F2-Isoprostanes; FDA approved; Fasting; Fatty Acids; GLUT-3 protein; Glucose; Glutamates; Glutathione; Glycine; Goals; Human; Impaired cognition; Impairment; Inflammation; Insulin; Insulin Resistance; Link; Liver; Manuscripts; Measures; Metabolic; Metabolism; Mitochondria; Mus; Myocardium; Neurons; Oral; Organ; Outcome; Oxidative Stress; Oxides; Patients; Pharmaceutical Preparations; Placebo Control; Placebos; Play; Positron-Emission Tomography; Proteins; Pyruvate; Randomized; Reporting; Research Design; Rest; Role; SLC2A1 gene; Succinates; Supplementation; Testing; Theft; Work; brain dysfunction; brain metabolism; cognitive function; fatty acid oxidation; fluorodeoxyglucose positron emission tomography; glucose metabolism; glucose production; glucose uptake; improved; irritation; mitochondrial dysfunction; neuroinflammation; oxidation; response; tau Proteins; uptake

Alzheimer's disease (AD) is associated with significant, progressive cognitive decline, unimpeded by FDA-approved drugs. Key defects in mitochondrial fuel metabolism could contribute to cognitive decline in AD. The primary mitochondrial fuel of choice for the brain in the fasted (and fed) state is glucose. Conversely, fasted mitochondrial fuel of choice for the rest of the body is fatty-acids. Hence fuel oxidation is partitioned between glucose for the brain, and fatty-acids for the rest of the body. Aging is a major risk factor for AD. Mitochondrial fatty-acid oxidation (MFO) is impaired in aging, and brain glucose uptake is decreased in patients with AD, but underlying mechanisms are not well understood. Aging and mitochondrial dysfunction are also associated with insulin resistance (a hallmark of AD), which limits brain glucose-uptake. AD is also strongly linked to neuroinflammation. Could mitochondrial dysfunction, insulin resistance and neuroinflammation be mechanistically linked in patients with AD, and more importantly, could they be reversed to improve cognition? Ongoing work from my lab has uncovered that Oxidative Stress (OxS) could be the unifying link. OxS is strongly linked to AD. Glutathione (GSH, the most abundant intracellular antioxidant protein) combats OxS. GSH deficiency predisposes to OxS, and is linked to AD. We reported that elevated OxS in older humans is caused by GSH deficiency due to diminished synthesis because of decreased availability of its precursor amino-acids glycine and cysteine. Supplementing glycine and cysteine (as N-acetylcysteine, a cysteine donor) orally as GlyNAC for 2w corrected deficiencies of glycine, cysteine and GSH, and lowered OxS in older humans to levels in younger humans, reversed impaired MFO, and lowered insulin resistance by 40%. Since aging is a major risk factor for AD, we studied cognition in 8 older humans before and after receiving GlyNAC for 24w and after stopping GlyNAC for 12w, and outcomes compared to 8 unsupplemented young, healthy controls: older humans had impaired cognition, elevated OxS, lower MFO, higher mitochondrial glucose oxidation (MGO), higher insulin resistance and inflammation. GlyNAC supplementation for 24w significantly improved cognition and whole-body mitochondrial fuel oxidation, and lowered OxS, insulin resistance, and inflammation. After stopping GlyNAC, all benefits began to recede. We studied 98-week old C57BL/6J mice and found that compared to young 20-week old mice, they had cognitive decline, and severely impaired ability of mitochondrial complexes I and II to oxidize glucose substrates pyruvate, glutamate and succinate, and elevated inflammation (TSPO expression) GlyNAC supplementation for 8-weeks corrected these defects and improved cognition. Collectively, these data suggest that abnormalities in brain MGO, inflammation, OxS, and insulin resistance combine to cause cognitive decline, and GlyNAC (via GSH) can correct these defects to improve cognition. However, these defects and their response to GlyNAC have not been studied in patients with AD. The goal of this proposal is to study these defects in patients with AD, and test whether supplementing GlyNAC can improve cognition in AD by correcting GSH deficiency, poor brain glucose uptake and brain inflammation.

阿尔茨海默氏病（AD）与FDA批准的药物不受阻碍，与大量进行性认知下降有关。 线粒体燃料代谢的主要缺陷可能导致AD认知能力下降。主要线粒体燃料 在禁食（和喂养）状态下的大脑选择是葡萄糖。相反，其余部分禁食的线粒体燃料 身体是脂肪酸。因此，将燃料氧化分配在大脑的葡萄糖和其余的脂肪酸之间 身体。衰老是AD的主要危险因素。线粒体脂肪酸氧化（MFO）在衰老中受损，脑葡萄糖 AD患者的摄取减少，但尚不清楚潜在的机制。衰老和线粒体 功能障碍还与胰岛素抵抗（AD的标志）有关，该胰岛素限制了脑葡萄糖摄取。广告也是 与神经炎症密切相关。线粒体功能障碍，胰岛素抵抗和神经炎症是否可能 在AD患者中有机械上的联系，更重要的是，它们是否可以逆转以改善认知？正在进行 我实验室的工作发现氧化应激（OX）可能是统一的联系。牛与AD密切相关。 谷胱甘肽（GSH，最丰富的细胞内抗氧化剂蛋白）打击牛。 GSH缺乏易于牛， 并链接到广告。我们报道说，老年人的牛升高是由于GSH缺乏症引起的 合成由于其前体氨基酸甘氨酸和半胱氨酸的可用性降低。补充甘氨酸和 半胱氨酸（作为N-乙酰半胱氨酸，半胱氨酸供体）口服甘氨酸，用于2W的甘氨酸，半胱氨酸和半胱氨酸的缺乏症 GSH，并将年龄较大的人的牛降低到年轻人类的水平，逆转MFO并降低了胰岛素 阻力增加40％。由于衰老是AD的主要危险因素，因此我们在8个大人之前和之后研究了认知 接收24周的甘糖果，在停止甘纳克12周后，结果与8个未补充的Young相比 健康对照：老年人的认知受损，牛升高，较低的MFO，较高的线粒体葡萄糖氧化 （MGO），较高的胰岛素抵抗和炎症。补充24W的Glynac可显着改善认知 以及全身线粒体燃料氧化，以及降低的OX，胰岛素抵抗和炎症。停止后 Glynac，所有的好处都开始消退。我们研究了为期98周的C57BL/6J小鼠，发现与20周的年轻相比 老鼠，它们的认知能力下降，线粒体复合物I和II的能力严重受损 丙酮酸，谷氨酸和琥珀酸酯以及升高的炎症（TSPO表达）glynac补充 8周纠正了这些缺陷并改善了认知。总的来说，这些数据表明大脑MGO异常， 炎症，牛和胰岛素耐药性结合起来引起认知能力下降，而glynac（通过GSH）可以纠正这些 缺陷以改善认知。但是，这些缺陷及其对Glynac的反应尚未在患有 广告。该建议的目的是研究AD患者中的这些缺陷，并测试补充Glynac是否可以 通过纠正GSH缺乏，脑葡萄糖摄取和脑部炎症来改善AD的认知。