Glutathione, Brain Metabolism and Inflammation in Alzheimer's Disease

阿尔茨海默病（AD）与显著的、进行性的认知能力下降有关，不受FDA批准的药物的阻碍。 线粒体燃料代谢的关键缺陷可能导致AD的认知能力下降。主要的线粒体燃料 在禁食（和进食）状态下大脑的选择是葡萄糖。相反，禁食的线粒体燃料的选择，其余的 身体是脂肪酸。因此，燃料氧化被分配在大脑的葡萄糖和其余部分的脂肪酸之间。 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， 在AD患者中摄取减少，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的标志）相关，胰岛素抵抗限制脑葡萄糖摄取。AD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 在AD患者中存在机械联系，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（OxS）可能是统一的联系。OxS与AD密切相关。 谷胱甘肽（GSH，最丰富的细胞内抗氧化蛋白）对抗OxS。GSH缺乏易患OxS， 并与AD相关联。我们报道了老年人OxS升高是由于GSH缺乏引起的， 由于其前体氨基酸甘氨酸和半胱氨酸的可利用性降低，补充甘氨酸， 半胱氨酸（作为N-乙酰半胱氨酸，一种半胱氨酸供体）作为GlyNAC口服2周，纠正甘氨酸、半胱氨酸和 GSH，并将老年人的OxS降低到年轻人的水平，逆转受损的MFO，并降低胰岛素 阻力40%。由于衰老是AD的主要危险因素，我们研究了8名老年人在治疗前后的认知能力。 接受GlyNAC 24周和停止GlyNAC 12周后，与8名未补充GlyNAC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)、较高的胰岛素抵抗和炎症。GlyNAC补充24周显著改善认知功能 和全身线粒体燃料氧化，并降低OxS，胰岛素抵抗和炎症。停止后 GlyNAC，所有的好处开始消退。我们研究了98周龄的C57 BL/6 J小鼠，发现与20周龄的年轻小鼠相比， 老年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 底物丙酮酸盐、谷氨酸盐和琥珀酸盐，以及升高的炎症（TSPO表达） 8-周纠正了这些缺陷，提高了认知能力。总的来说，这些数据表明大脑MGO的异常， 炎症、OxS和胰岛素抵抗联合收割机会导致认知能力下降，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的反应尚未在患有糖尿病的患者中进行研究。 AD.这项提案的目的是研究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、脑葡萄糖摄取不足和脑炎症改善AD患者的认知能力。

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.