Mechanism of white matter pathology in Alzheimer's disease

阿尔茨海默病的白质病理机制

• 批准号: 10381841
• 负责人: XIN QI
• 金额: $ 60.75万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10381841
• 关键词: Adult; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Animal Model; Animals; Astrocytes; Axon; Behavioral; Bioenergetics; Biological Assay; Brain; Cell Aging; Cells; Cessation of life; Cognitive; Cognitive deficits; Data; Demyelinations; Development; Disease; Disease Progression; Dissociation; Dynamin; Enzymes; Event; Exhibits; Exposure to; Financial compensation; Functional disorder; Genetic Suppression; Glucose; Glycolysis; Glycolysis Inhibition; Glycolysis Pathway; Human; Impaired cognition; Impairment; Inflammasome; Inflammation; Inflammatory; Injury; Interleukin-1 beta; Knock-in; Knock-in Mouse; Knock-out; Lead; Maintenance; Measures; Mediating; Metabolic; Metabolism; Mitochondria; Molecular; Mus; Myelin; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Oligodendroglia; Outer Mitochondrial Membrane; Oxygen; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Production; Protein Dephosphorylation; Protein Isoforms; Proteins; Proteomics; Regulation; Reporting; Role; Signal Transduction; Symptoms; Therapeutic; Time; Work; age related; astrogliosis; axonal degeneration; beta-Galactosidase; cell population study; cell type; cognitive function; density; driving force; effective therapy; enzyme activity; genome wide association study; hexokinase; improved; in vivo; myelin degeneration; myelination; neuroinflammation; neuropathology; novel; oligodendrocyte precursor; precursor cell; remyelination; senescence; stressor; transcriptomics; upstream kinase; white matter

PROJECT SUMMARY Myelin degeneration and white matter loss that result from oligodendrocyte (OL) death are early events in Alzheimer’s disease (AD) that lead to cognitive deficits and correlate with disease status. The loss of OLs, accompanied by a reduction of myelin density, axonal loss, and astrogliosis, are major changes in white matter that occur in the brains in both AD patients and animal models of AD. OLs are the most abundant glial cell type in the brain but the least studied cell population in the context of neurodegeneration, despite their vital role in myelin maintenance and neuronal support. Recent genome-wide association studies and large-scale single- cell transcriptomics of AD patient brains emphasized the crucial role of OLs in the development of AD. The underlying mechanisms of OL dysfunction and its contribution to the initiation and progression of AD remain unknown. Our recent work reports, for the first time, that mature OLs in AD patients and AD mice exhibit NLRP3 inflammasome-associated inflammatory injury, concomitant with demyelination and axonal degeneration. Unbiased proteomic analysis further suggests that the hexokinase 1 (HK1)-dependent glycolysis pathway is most suppressed in AD mouse white matter. Mature OLs rely heavily on glycolysis for energy production, even in the presence of oxygen. HK is the rate-limiting enzyme that initiates the first step of glycolysis by the phosphorylation of glucose. OLs specifically express a brain HK isoform, HK1. HK1 localizes to the mitochondrial outer membrane, and the dissociation of HK1 from mitochondria decreases its enzymatic activity, which is sufficient to inhibit glycolysis and induce NLRP3 inflammasome activation. We found that HK1 immunodensity and enzyme activity significantly decreased in OLs in AD patients and AD mice. In mature OLs in AD, the HK1 mitochondrial association is disrupted by overactivation of the mitochondrial fission protein dynamin-related protein 1 (Drp1), and Drp1 and HK1 synergistically elicit NLRP3 inflammasome activation and the release of interleukin-1β, triggering inflammation. The mature OL-specific heterozygous knockout of Drp1 in AD mice restores HK1-dependent glycolysis, abolishes NLRP3 inflammasome activation, corrects myelin loss, reduces neuroinflammation and axonal degeneration, and improves cognitive function in animals. These findings support the scientific premise of the proposed project that glycolytic deficiency in OLs, driven by the Drp1-HK1 molecular switch, induces OL metabolic dysregulation and inflammation and causes white matter degeneration, AD pathology, and cognitive impairment. Successful completion of the proposed studies will support the hypothesis that OL metabolic deficiency is a key pathological process that induces inflammation, demyelination, white matter loss, and AD-associated neuropathology and cognitive deficits. These studies are crucial to further reveal the role of the novel Drp1-HK1 OL pathway in AD and determine whether this pathological pathway is a plausible treatment target for AD.

项目摘要 由少突胶质细胞（OL）死亡引起的髓鞘变性和白色物质丢失是脑缺血的早期事件， 阿尔茨海默病（AD）是导致认知缺陷并与疾病状态相关的疾病。OL的损失， 伴随髓鞘密度减少、轴突缺失和星形胶质细胞增生的是白色物质的主要变化 在AD患者和AD动物模型的大脑中发生。OL是最丰富的神经胶质细胞类型 但在神经变性的背景下研究最少的细胞群，尽管它们在神经变性中起着重要作用。 髓鞘维持和神经元支持。最近的全基因组关联研究和大规模的单- AD患者脑的细胞转录组学强调了OL在AD发展中的关键作用。的 OL功能障碍的潜在机制及其对AD发生和发展的作用仍然存在 未知我们最近的工作首次报道，AD患者和AD小鼠中的成熟OL表现出 NLRP 3炎性小体相关炎性损伤，伴随脱髓鞘和轴突损伤 退化无偏蛋白质组学分析进一步表明，己糖激酶1（HK 1）依赖的糖酵解 在AD小鼠白色物质中，成熟的OL严重依赖糖酵解提供能量 即使在氧气存在的情况下，HK是启动第一步的限速酶， 通过葡萄糖磷酸化的糖酵解。OL特异性表达脑HK同种型HK 1。HK 1本地化 线粒体外膜，HK 1从线粒体的解离降低了其酶活性。 活性，其足以抑制糖酵解并诱导NLRP 3炎性体活化。我们发现HK 1 AD患者和AD小鼠OLs的免疫密度和酶活性均显著降低。在成熟OL中 在AD中，HK 1线粒体结合被线粒体分裂蛋白的过度活化破坏 动力蛋白相关蛋白1（Drp 1），Drp 1和HK 1协同诱导NLRP 3炎性小体活化， 释放白细胞介素-1 β，引发炎症。Drp 1成熟OL特异性杂合敲除 在AD小鼠中，恢复HK 1依赖性糖酵解，消除NLRP 3炎性小体激活，纠正髓鞘 损失，减少神经炎症和轴突变性，并改善动物的认知功能。这些 研究结果支持了拟议项目的科学前提，即由糖酵解驱动的OLs糖酵解缺陷， Drp 1-HK 1分子开关，诱导OL代谢失调和炎症并导致白色物质 变性、AD病理学和认知损害。成功完成拟议的研究将 支持OL代谢缺陷是诱导炎症的关键病理过程的假设， 脱髓鞘、白色物质损失和AD相关的神经病理学和认知缺陷。这些研究 关键是进一步揭示新的Drp 1-HK 1 OL通路在AD中的作用，并确定这是否 病理途径是AD的合理治疗靶点。