Pathogenesis of Early- Versus Late-Stage Alcohol-Mediated White Matter Degeneration

长期大量饮酒或酗酒会损害大脑结构和功能的完整性。 乙醇的神经毒性和退行性作用针对整个寿命的白质(WM)，导致 髓鞘，髓鞘维持受损，轴突变性。由于WM完整性对许多CNS至关重要 为了更好地了解乙醇如何对WM产生不利影响，需要更好地了解乙醇对WM的影响，以防止或 纠正相关的神经行为和认知缺陷。少突胶质细胞功能障碍是 WM变性，因为少突胶质细胞负责合成和维持髓鞘。髓磷脂是 需要支持和保护轴突，并确保有效的神经元传导性。我们假设酒精- 相关性脑变性(ARBD)可分为：1)早期、可逆性阶段，即 主要与髓鞘丢失有关，并由氧化应激、炎症和神经毒性神经酰胺介导。 通过髓鞘破坏和脂类代谢紊乱而积聚；2)后期，以 通过PI3K-Akt-mTor-mTORC抑制胰岛素/IGF-1信号转导。后者的后果包括损失 成熟的少突胶质细胞和致密的髓鞘，少突胶质细胞成熟受损，轴突损伤，以及 随着神经酰胺的堆积和硫脂的耗竭，进一步的神经鞘脂脂代谢失调。 我们预计，禁欲将足以补救WM ARBD的早期阶段，而积极的 需要进行干预，如胰岛素增敏剂治疗，以扭转Long所遭受的WM损害 一段时间的重度酒精暴露。然而，ARBD的早期和晚期都可能对神经酰胺有反应。 像麦角菌素这样的抑制剂。目标1将描述细胞的结构、生化和分子病理学 慢性酒精暴露大鼠模型的早期WM ARBD。AIM 2将利用一种大鼠模型 和人死后大脑通过PI3K-Akt-mTOR评估受损的胰岛素/IGF-1信号的作用 MTORC1和mTORC2是少突胶质细胞功能障碍和鞘磷脂代谢改变的驱动因素 在WM ARBD的后期。目标3将评估戒断、神经酰胺抑制剂和 胰岛素增敏剂治疗少突胶质细胞功能障碍及相关髓鞘改变 WM ARBD早期与晚期的鞘磷脂组成。此外，一个新的子目标将确定 乙醇诱导中枢神经系统WM髓鞘脂异常的程度及其对 治疗可以在外周血单核细胞(PBMC)中检测到。我们的基本假设是 通过使用定量免疫组织化学，电子显微镜，多重ELISA， 信使核糖核酸研究和基质辅助激光解吸/电离-成像质谱仪。研究计划 是新奇的、机械性的、健壮的、透明的、包容两性的、人类验证研究、前景 根据ARBD分期进行分层治疗，以及潜在监测ARBD相关的方法 WM生化病理学和非侵入性PBMC检测的治疗反应。

Chronic heavy or binge alcohol consumption damages the structural and functional integrity of the brain. Ethanol’s neurotoxic and degenerative effects target white matter (WM) across the lifespan, resulting in loss of myelin, impaired myelin maintenance, and degeneration of axons. Since WM integrity is critical to many CNS functions, better understanding of how ethanol exerts its adverse effects on WM is needed to prevent or remediate the associated neurobehavioral and cognitive deficits. Oligodendrocyte dysfunction is at the core of WM degeneration since oligodendroglia are responsible for synthesizing and maintaining myelin. Myelin is needed to support and protect axons and ensure efficient neuronal conductivity. We hypothesize that alcohol- related brain degeneration (ARBD) involving WM could be divided into: 1) an early, reversible stage that is mainly associated with myelin loss and mediated by oxidative stress, inflammation, and neurotoxic ceramide accumulation via myelin breakdown and dysregulation of lipid metabolism; and 2) a later stage marked by impaired insulin/IGF-1 signaling through PI3K-Akt-mTOR-mTORC. Consequences of the latter include loss of mature oligodendrocytes and compact myelin, impaired maturation of oligodendroglia, axonal damage, and further progressive dysregulated sphingolipid metabolism with ceramide accumulation and sulfatide depletion. We anticipate that abstinence will be sufficient to remediate early stages of WM ARBD, whereas active interventions, such as insulin sensitizer treatments, will be required to reverse WM damage sustained by long periods of heavy alcohol exposure. However, both early and late stages of ARBD will likely respond to ceramide inhibitors such as myriocin. Aim 1 will characterize the structural, biochemical and molecular pathologies of early-stage WM ARBD in an established rat model of chronic ethanol exposure. Aim 2 will utilize a rat model and human postmortem brains to assess the roles of impaired insulin/IGF-1 signaling through PI3K-Akt-mTOR and mTORC1 versus mTORC2 as drivers of oligodendrocyte dysfunction and altered sphingolipid metabolism in the later stages of WM ARBD. Aim 3 will evaluate the effectiveness of abstinence, ceramide inhibitor, and insulin sensitizer treatments in remediating oligodendrocyte dysfunction and associated alterations in myelin sphingolipid composition in early versus late stages of WM ARBD. In addition, a novel sub-aim will determine the degree to which ethanol-induced CNS WM myelin sphingolipid abnormalities and their responses to treatment can be detected in peripheral blood mononuclear cells (PBMCs). Our underlying hypotheses are addressed through the use of quantitative immunohistochemistry, electron microscopy, multiplex ELISAs, mRNA studies, and Matrix-assisted laser desorption/ionization-imaging mass spectrometry. The research plan is novel, mechanistic, robust, transparent, and inclusive of both sexes, human validation studies, prospects for stratifying treatment according to ARBD stage, and approaches for potentially monitoring ARBD-associated WM biochemical pathology and responses to treatment with non-invasive PBMC assays.