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: 10033165
• 负责人: JOSEPH C MASDEU
• 金额: $ 80.82万
• 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/10033165
• 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; Placebos; Play; Positron-Emission Tomography; Proteins; Pyruvate; Randomized; Reporting; Research Design; Rest; Role; SLC2A1 gene; Succinates; Supplementation; Testing; Theft; Work; brain metabolism; cognitive function; combat; 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.

阿尔茨海默病 (AD) 与显着的、进行性的认知能力下降有关，FDA 批准的药物无法阻止这种情况。 线粒体燃料代谢的关键缺陷可能导致 AD 认知能力下降。主要线粒体燃料 大脑在禁食（和进食）状态下的选择是葡萄糖。相反，禁食线粒体燃料是其余时间的首选 身体是脂肪酸。因此，燃料氧化分为大脑的葡萄糖和其余部分的脂肪酸。 身体。衰老是 AD 的主要危险因素。线粒体脂肪酸氧化（MFO）在衰老过程中受损，脑葡萄糖 AD 患者的摄取量减少，但其潜在机制尚不清楚。衰老与线粒体 功能障碍还与胰岛素抵抗（AD 的一个标志）有关，胰岛素抵抗限制了大脑对葡萄糖的摄取。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与 与 AD 患者存在机制上的联系，更重要的是，是否可以逆转它们以改善认知？进行中 我实验室的工作发现氧化应激（OxS）可能是统一的纽带。 OxS 与 AD 密切相关。 谷胱甘肽（GSH，最丰富的细胞内抗氧化蛋白）可对抗 OxS。 GSH 缺乏易患 OxS， 并与 AD 相连。我们报道了老年人中 OxS 升高是由于 GSH 缺乏导致的 由于其前体氨基酸甘氨酸和半胱氨酸的可用性降低而导致合成困难。补充甘氨酸和 半胱氨酸（N-乙酰半胱氨酸，半胱氨酸供体）口服 GlyNAC 2 周，纠正甘氨酸、半胱氨酸和 GSH，并将老年人的 OxS 降低至年轻人的水平，逆转受损的 MFO，并降低胰岛素 电阻降低40%。由于衰老是 AD 的主要危险因素，我们研究了 8 名老年人在老年痴呆症前后的认知情况 接受 GlyNAC 24 周和停止 GlyNAC 12 周后，与 8 名未补充补充剂的年轻人相比， 健康对照：老年人认知受损、OxS 升高、MFO 降低、线粒体葡萄糖氧化升高 (MGO)、更高的胰岛素抵抗和炎症。补充 GlyNAC 24 周显着改善认知能力 全身线粒体促进氧化，并降低 OxS、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 98 周龄的 C57BL/6J 小鼠，发现与年轻的 20 周龄小鼠相比 年老小鼠的认知能力下降，线粒体复合物 I 和 II 氧化葡萄糖的能力严重受损 底物丙酮酸、谷氨酸和琥珀酸，以及炎症升高（TSPO 表达） 补充 GlyNAC 8周的时间纠正了这些缺陷并提高了认知能力。总的来说，这些数据表明大脑 MGO 异常， 炎症、OxS 和胰岛素抵抗共同导致认知能力下降，而 GlyNAC（通过 GSH）可以纠正这些问题 改善认知缺陷。然而，这些缺陷及其对 GlyNAC 的反应尚未在患有以下疾病的患者中进行研究： 广告。该提案的目标是研究 AD 患者的这些缺陷，并测试补充 GlyNAC 是否可以 通过纠正 GSH 缺乏、大脑葡萄糖摄取不良和大脑炎症来改善 AD 认知能力。