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

探索正常衰老和血管性痴呆中髓磷脂异常的起源

• 批准号: 10186055
• 负责人: Margaret E Flanagan
• 金额: $ 221.12万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186055
• 关键词: Adult; Age; Aging; Alleles; Alzheimer' s Disease; Animals; Autopsy; Behavioral; Behavioral Assay; Biological Assay; Blood flow; Brain; Cardiovascular Abnormalities; Cardiovascular Diseases; Cardiovascular system; Cell Lineage; Cells; Cellular Stress; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cognition; Cognition Disorders; Cognitive; Dementia; Development; Diffuse; EFRAC; Elderly; Environment; Eukaryotic Cell; Failure; Functional disorder; Genes; Genetic Transcription; Gliosis; Goals; Health; Heart failure; High Fat Diet; Human; Hypertension; Hypoxia; Impaired cognition; Impairment; Incidence; Individual; Inflammation; Lead; Lesion; Link; Maintenance; Memory; Metabolic; Metabolic syndrome; Molecular; Mus; Mutant Strains Mice; Mutation; Myelin; Nerve Degeneration; Neuroglia; Neurologic; Neurology; Neurons; Nitric Oxide Synthase; Nutrient; Obesity; Oligodendroglia; Oxidative Stress; Oxygen; Pathogenesis; Pathologic; Pathway interactions; Pharmacology; Play; Positioning Attribute; Process; Reporting; Risk; Role; Sampling; Series; Stimulus; Stress; Tamoxifen; Therapeutic; Time; Universities; Vascular Dementia; Vascular blood supply; White Matter Disease; World Health Organization; biological adaptation to stress; brain health; cell type; cerebrovascular; clinically relevant; comorbidity; cytotoxic; dementia risk; design; extracellular; genetic approach; hypoxia inducible factor 1; juvenile animal; mouse model; neuropathology; normal aging; nuclear factor-erythroid 2; nutrient deprivation; oligodendrocyte lineage; preservation; response; sex; therapeutically effective; white matter; young adult

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.

据世界卫生组织称，全球约有 5000 万人患有认知障碍 失调。痴呆症的发病率随着年龄的增长而增加，尤其是 65 岁以上的老年人。 中枢神经系统白质病变 众所周知，它们会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 继阿尔茨海默病（AD）之后，老年人认知异常的第二个最常见原因。血管病 与各种心血管疾病有关，这些疾病被认为与弥漫性白质有关 导致痴呆的疾病。该提案的基本假设是细胞毒性的影响 与衰老和多样化心血管相关的中枢神经系统脉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。我们假设提高 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，这使得它们 特别容易受到随着年龄增长而变化的细胞外环境的影响 反应改变脑循环。由于以下原因发生的白质异常 少突胶质细胞扰动可能对神经退行性、认知和行为的发展至关重要 变化。当前提案的目标是从机制上理解衰老和衰老的影响 人类和小鼠模型中少突胶质细胞的脑血管异常。我们的重点将是 检查内在细胞保护途径在少突胶质细胞对不利因素的反应中所起的作用 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）途径由多种应激启动，包括氧化应激、缺氧 和炎症；核因子红细胞 2 相关因子 2 (NRF2) 途径被激活 氧化应激；缺氧诱导因子 1 (HIF-1) 通路是缺氧诱导因子 1 (HIF-1) 的主要转录调节因子 细胞对缺氧的反应。我们将检查患有血管疾病的个体的尸检样本 痴呆症中少突胶质细胞谱系细胞中这些途径的激活，我们将类似地评估它们 衰老小鼠中的激活，已知这些小鼠表现出少突胶质细胞和髓鞘质缺陷。我们还将 检查射血分数保留 (HFpEF) 的小鼠心力衰竭模型中的少突胶质细胞和髓磷脂 与 ISR、NRF2 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。我们还将使用遗传方法来进一步检查这些反应 衰老和脑血管异常造成的不良中枢神经系统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 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。更好的欣赏 髓鞘神经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点至关重要 这种日益增长的健康问题可以作为设计神经保护治疗策略的基础。