Exploring the origins of myelin abnormalities in normal ageing and in vascular dementia

根据世界卫生组织的数据，全球约有5000万人患有认知障碍。 紊乱痴呆症的发病率随着年龄的增长而增加，特别是对于65岁以上的人。CNS白色病变 也已知随着年龄的增长而增加，并增加患痴呆症的风险。血管性痴呆（VD） 是老年人认知异常的第二大常见原因，仅次于阿尔茨海默病（AD）。VD 与各种心血管疾病有关，这些疾病被认为是导致弥漫性白色物质 导致痴呆的疾病。这一提议的基本假设是，细胞毒性的影响， 与衰老和多种心血管疾病相关的CNS血管系统破坏所造成的环境 疾病对少突胶质细胞的活力和功能特别有害。我们认为， 少突胶质细胞由于其独特的代谢需求而表现出的对细胞应激的敏感性使得它们 特别容易受到随着年龄的增长而变化的细胞外环境的影响， 大脑循环的改变。作为以下原因的后果发生的白色异常 少突胶质细胞的扰动可能对神经退行性疾病、认知和行为的发展至关重要。 变化目前提案的目标是从机械上了解老龄化的影响， 脑血管异常对少突胶质细胞的影响，在人和小鼠模型中。我们的重点将放在 研究内在的细胞保护途径在少突胶质细胞对不良反应的反应中所起的作用， 由这些条件产生的细胞毒性环境。我们将重点关注三种细胞保护途径： 综合应激反应（ISR）途径是由多种应激启动的，包括氧化应激、缺氧 和炎症;核因子红细胞2相关因子2（NRF 2）途径被激活， 缺氧诱导因子1（HIF-1）途径是氧化应激的主要转录调节因子。 细胞缺氧反应我们将检查人类死后的样本， 在少突胶质细胞系细胞中激活这些通路，我们将类似地评估它们的 在衰老的小鼠中激活，这是已知的显示少突胶质细胞和髓鞘缺陷。我们还将 检查射血分数保留（HFpEF）心力衰竭小鼠模型的少突胶质细胞和髓鞘 与ISR、NRF 2和HIF激活相关的异常。HFpEF是一种常见的心血管异常 与痴呆症有关。我们还将使用遗传学方法进一步研究这些 衰老和脑血管异常造成的不利CNS环境的细胞保护途径。 总之，这些努力将大大增加我们对少突胶质细胞对药物反应的了解。 衰老和脑血管功能障碍造成的细胞毒性CNS环境。更好地欣赏 髓鞘生成胶质细胞功能障碍对痴呆发病机制的贡献对于我们理解 这一日益增长的健康问题，并可能作为设计的神经保护治疗策略的基础。

According to the World Health Organization approximately 50 million people worldwide suffer from cognitive disorders. The incidence of dementia increases with age, especially for those over 65. CNS white matter lesions are also known to increase with age and to increase the risk of developing dementia. Vascular dementia (VD) is the second most common cause of cognitive abnormalities in the elderly behind Alzheimer’s disease (AD). VD has been associated with various cardiovascular maladies, which are thought to contribute to diffuse white matter disease leading to dementia. The underlying hypothesis of this proposal is that the impact of the cytotoxic environment created by disruptions to the CNS vasculature associated with aging and diverse cardiovascular disorders are particularly detrimental to oligodendrocyte viability and function. We posit that the heightened sensitivity to cellular stress that oligodendrocytes display due to their unique metabolic demands makes them particularly vulnerable to the changing extracellular environment that develops with advancing age and in response an altered cerebral circulation. The white matter abnormalities that occur as a consequence of oligodendrocyte perturbation are likely critical to the development of neurodegenerative, cognitive and behavioral changes. The goal of the current proposal is to a gain a mechanistic understanding of the impact of ageing and cerebrovascular abnormalities on oligodendrocytes, both in humans and in mouse models. Our focus will be on examining the role that intrinsic cytoprotective pathways play in the response of oligodendrocytes to the adverse cytotoxic environment created by these conditions. We will focus on three cytoprotective pathways: the integrated stress response (ISR) pathway is initiated by a variety of stresses including oxidative stress, hypoxia and inflammation; the nuclear factor erythroid 2-related factor 2 (NRF2) pathway is activated in response to oxidative stress; and the hypoxia-inducible factor 1 (HIF-1) pathway is the master transcriptional regulator of the cellular response to hypoxia. We will examine human postmortem samples from individuals with vascular dementia for activation of these pathways in oligodendrocyte lineage cells, and we will similarly assess their activation in ageing mice, which are known to display oligodendrocyte and myelin deficiencies. We will also examine a mouse model of heart failure with preserved ejection fraction (HFpEF) for oligodendrocyte and myelin abnormalities linked to ISR, NRF2 and HIF activation. HFpEF is a common cardiovascular abnormality associated with dementia. We will also use a genetic approach to further examine the response of these cytoprotective pathways to the adverse CNS environment created by ageing and cerebrovascular abnormalities. Together, these efforts will substantially increase our understanding of the response of oligodendrocytes to the cytotoxic CNS environment created by ageing and cerebrovascular dysfunction. A better appreciation of the contribution of myelinating glia dysfunction to the pathogenesis of dementia is essential to our understanding of this growing health concern and may serve as the basis for the design of neuroprotective therapeutic strategies.