Mechanism of white matter pathology in Alzheimer's disease

项目总结 少突胶质细胞(OL)死亡引起的髓鞘变性和白质丢失是 阿尔茨海默病(AD)会导致认知障碍，并与疾病状态相关。失掉了老兵， 伴随着髓鞘密度降低、轴突丢失和星形胶质细胞增生症的是白质的主要变化。 在阿尔茨海默病患者和阿尔茨海默病动物模型中都会发生这种情况。OL是最丰富的神经胶质细胞类型 在大脑中，但在神经退行性变背景下研究最少的细胞群，尽管它们在 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患者脑细胞转录学强调了OL在AD发生发展中的关键作用。这个 OL功能障碍的潜在机制及其在AD的发生和发展中的作用仍然存在 未知。我们最近的工作首次报告了AD患者和AD小鼠中成熟的OL NLRP3炎性小体相关性炎性损伤，伴有脱髓鞘和轴突 退化。无偏的蛋白质组学分析进一步表明己糖激酶1(HK1)依赖的糖酵解 阿尔茨海默病小鼠脑白质中抑制最多的是通路。成熟的骨质疏松症严重依赖糖酵解获得能量 生产，即使在氧气存在的情况下也是如此。HK是启动第一步的限速酶 通过葡萄糖的磷酸化进行糖酵解。OL特异性地表达脑HK亚型HK1。HK1本地化 线粒体外膜，HK1从线粒体解离，使其酶活性降低 活性，足以抑制糖酵解和诱导NLRP3炎症小体激活。我们发现香港一号 AD患者和AD小鼠的OL免疫密度和酶活性均显著降低。在成熟的运营组织中 在阿尔茨海默病中，线粒体分裂蛋白的过度激活破坏了HK1线粒体联系 动力蛋白相关蛋白1(Drp1)、Drp1和HK1协同诱导NLRP3炎症小体激活和 白介素1β的释放，引发炎症。成熟的OL特异性基因Drp1杂合性敲除 AD小鼠恢复HK1依赖的糖酵解，取消NLRP3炎症小体激活，纠正髓鞘 减少损失，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，即糖酵解缺陷是由 DRp1-HK1分子开关，诱导OL代谢紊乱和炎症，并导致脑白质 变性、阿尔茨海默病病理和认知障碍。成功完成拟议的研究将 支持OL代谢缺陷是导致炎症的关键病理过程的假设， 脱髓鞘、白质丢失、AD相关的神经病理和认知缺陷。这些研究是 进一步揭示新的Drp1-HK1 OL通路在AD中的作用并确定这一点至关重要 病理途径是治疗AD的可能靶点。

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.