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 精神错乱。痴呆症的发病率随着年龄的增长而增加，特别是对65岁以上的人。中枢神经系统白质损害 众所周知，随着年龄的增长，痴呆症的发病率也会增加，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脑白质弥散的原因 导致痴呆症的疾病。这一提议的基本假设是，细胞毒性的影响 与衰老和心血管疾病相关的中枢神经系统血管中断所造成的环境 疾病对少突胶质细胞的活力和功能尤其有害。我们假设被强化的 少突胶质细胞由于其独特的代谢需求而表现出对细胞应激的敏感性，使它们 特别容易受到细胞外环境变化的影响，这种环境随着年龄的增长而发展 对大脑循环的改变作出反应.脑白质异常作为脑白质异常的结果 少突胶质细胞的扰动可能对神经退行性变、认知和行为的发展至关重要 改变。目前提案的目标是对老龄化的影响和 人类和小鼠模型中少突胶质细胞的脑血管异常。我们的重点将放在 检测内源性细胞保护通路在少突胶质细胞对不良反应中的作用 由这些条件造成的细胞毒性环境。我们将重点介绍三条细胞保护途径： 整合应激反应(ISR)通路是由氧化应激、缺氧等多种应激反应启动的 核因子红系2相关因子2(NRF2)途径被激活，以响应 而缺氧诱导因子1(HIF-1)途径是HIF-1的主要转录调节因子。 细胞对低氧的反应。我们将检查患有血管疾病的人的尸检样本 痴呆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 在衰老小鼠中的激活，已知表现为少突胶质细胞和髓鞘缺乏。我们还将 检测少突胶质细胞和髓鞘保存射血分数(HFpEF)的心力衰竭小鼠模型 与ISR、NRF2和HIF激活有关的异常。HFpEF是一种常见的心血管异常 与痴呆症有关。我们还将使用遗传方法来进一步检查这些 衰老和脑血管异常所造成的不良中枢神经系统环境的细胞保护途径。 综上所述，这些努力将大大增加我们对少突胶质细胞对 衰老和脑血管功能障碍造成的细胞毒性中枢神经系统环境。更好地认识到 髓鞘胶质细胞功能障碍在痴呆发病机制中的作用对我们理解 这一日益增长的健康问题，可能成为设计神经保护性治疗策略的基础。

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.