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

基本信息

  • 批准号:
    10263215
  • 负责人:
  • 金额:
    $ 80.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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)与显著的、进行性的认知能力下降有关,FDA批准的药物不会阻止这种疾病。 线粒体燃料代谢的关键缺陷可能导致AD患者的认知能力下降。线粒体的主要燃料 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他动物的首选 人体是由脂肪酸组成的。因此,燃料氧化被分配给大脑的葡萄糖和大脑其余部分的脂肪酸 尸体。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患者摄取减少,但其潜在机制尚不清楚。衰老与线粒体 功能障碍也与胰岛素抵抗(AD的一个标志)有关,它限制了大脑对葡萄糖的摄取。广告也是 与神经炎有很强的联系。线粒体功能障碍、胰岛素抵抗和神经炎症 阿尔茨海默病患者的机制联系,更重要的是,它们能否逆转以改善认知?正在进行中 我实验室的研究发现,氧化应激(OXS)可能是统一的纽带。OXS与AD有很强的联系。 谷胱甘肽(GSH,细胞内含量最丰富的抗氧化蛋白)可对抗OXS。GSH缺乏易患OXS, 并与AD有关。我们报告了老年人体内OXS的升高是由于GSH缺乏引起的 由于其前体氨基酸甘氨酸和半胱氨酸的可获得性降低而合成。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)口服作为GlyNAC,治疗2周,纠正甘氨酸,半胱氨酸和 GSH,并将老年人体内的OXS降低到年轻人的水平,逆转受损的MFO,降低胰岛素 抵抗力下降40%。由于衰老是阿尔茨海默病的主要危险因素,我们研究了8名老年人在衰老前后的认知 接受GlyNAC治疗24周和停用GlyNAC 12周后,结果与8名未补充GlyNAC的年轻人相比, 健康对照:老年人认知受损,氧合酶升高,MFO降低,线粒体葡萄糖氧化增加 (MGO),更高的胰岛素抵抗和炎症。补充24周GlyNAC可显著改善认知功能 和全身线粒体的氧化,并降低氧化应激,胰岛素抵抗和炎症。停下来后 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20周龄的年轻小鼠相比 老年小鼠认知功能下降,线粒体复合体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,以及增加炎症(TSPO表达)GlyNAC补充治疗 8周矫正了这些缺陷,提高了认知能力。总而言之,这些数据表明大脑MGO的异常, 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 缺陷,以提高认知。然而,这些缺陷及其对GlyNAC的反应尚未被研究过 广告。这项建议的目标是研究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脑部炎症来改善AD患者的认知。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

JOSEPH C MASDEU其他文献

JOSEPH C MASDEU的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('JOSEPH C MASDEU', 18)}}的其他基金

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
  • 财政年份:
    2020
  • 资助金额:
    $ 80.16万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 80.16万
  • 项目类别:
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:
    10653817
  • 财政年份:
    2020
  • 资助金额:
    $ 80.16万
  • 项目类别:

相似海外基金

How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 80.16万
  • 项目类别:
    Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 80.16万
  • 项目类别:
    Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 80.16万
  • 项目类别:
    Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 80.16万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 80.16万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 80.16万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 80.16万
  • 项目类别:
    Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 80.16万
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    $ 80.16万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    $ 80.16万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了