Glymphatic impairment as a crucial factor in particulate matter exposure related development of Alzheimer's disease pathology

类淋巴系统损伤是与颗粒物暴露相关的阿尔茨海默病病理学发展的关键因素

• 批准号: 10718104
• 负责人: Alison Elder
• 金额: $ 73.39万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718104
• 关键词: APP-PS1; Acceleration; Address; Adrenergic Agents; Adverse effects; Affect; Age Months; Aging; Air; Air Pollution; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Model; Astrocytes; Behavioral; Blood Vessels; Brain; Cells; Cerebrospinal Fluid; Cervical; Chemistry; Cognitive deficits; Cranial Nerves; Dedications; Deposition; Development; Diameter; Disease; Disease Progression; Exhibits; Exposure to; Functional disorder; Genetic; Human; Human Amyloid Precursor Protein; Impaired cognition; Inflammation; Inflammatory; Inhalation; Inhalation Exposure; Intercellular Fluid; Link; Liquid substance; Maps; Meningeal; Modeling; Molecular; Mus; Neurobiology; Organism; Oxidative Stress; Particulate Matter; Pathologic; Pathology; Pathway interactions; Pattern; Play; Process; Proteins; Resolution; Risk; Rodent; Rodent Model; Role; Scanning; Signal Transduction; Sleep; Sleep disturbances; Spinal nerve structure; Subarachnoid Space; System; Testing; Time; Tissues; Toxic Environmental Substances; Toxicology; Transgenic Organisms; Transmission Electron Microscopy; Venous; Waste Products; Wild Type Mouse; abeta deposition; aged; bioprocess; brain health; brain parenchyma; brain tissue; cognitive performance; comorbidity; dementia risk; experimental study; fluid flow; glymphatic clearance; glymphatic dysfunction; glymphatic function; glymphatic system; human model; improved; innovation; interdisciplinary approach; lymphatic vessel; mouse model; mutant; nervous system disorder; neuroinflammation; overexpression; pharmacologic; presenilin-1; regenerative; response; sleep quality; systemic inflammatory response; ultrafine particle; wasting; water channel; white matter

Environmental toxicants and, more specifically, exposure to ambient particulate matter (PM) air pollution increases the risk of developing Alzheimer's Disease (AD) and AD-Related Dementias (ADRD). Yet, our current understanding of the mechanisms by which PM exposure augments the progression of ADRD-related pathology and cognitive impairment is very limited. We posit that airborne ultrafine particles (UFP, <100 nm diameter) are causally related to the development or progression of AD/ADRD. The glymphatic pathway is emerging as a key to maintaining brain health and its dysfunction is implicated in several neurological disorders. This glial- dependent clearance pathway is dedicated to draining soluble waste proteins and its existence has been documented in the brain of multiple species, including humans. The proposal is based on preliminary studies showing that exposure to model UFP significantly suppresses glymphatic fluid transport and increases the β amyloid load in a murine model of AD pathology. We hypothesize that airborne UFP are transported to the brain upon inhalation exposure and cause both systemic and neuroinflammation, thus either indirectly or directly impairing glymphatic fluid flow and accelerating AD/ADRD-like pathology and behavioral deficits in a mouse model of AD. The proposed aims will test our hypothesis by addressing the following questions: Aim 1: How does short (3 days) or repeated (3 months intermittent) exposure to UFP affect glymphatic fluid transport and cognitive performance in young (3 months) and aged (15 months) wildtype mice? Aim 2: Can glymphatic impairment resulting from UFP exposure change the progression of Aβ deposition in a murine AD/ADRD model? Aim 3: Will UFP accumulate and interact with cells along the major glymphatic fluid transport segments? We will here use high-resolution analytical scanning transmission electron microscopy to analyze precisely where in the brain parenchyma the UFP accumulate and interact. Aim 4: We will explore the molecular mechanisms of UFP exposure-related glymphatic impairment and pathological progression in a murine AD/ADRD model via pharmacological inhibition of adrenergic signaling. Moreover, a detailed study of AQP4 vascular polarization response to air particulate matter exposure, sleep disruption and how do adrenergic inhibition reverse these signatures of pathology, would also be explored? The innovative aspects of the proposal build upon a unique multidisciplinary approach where expertise in particulate matter toxicology (Elder), basic and applied chemistry with particular focus on the study of UFP in living systems (Graham), neurobiology of diseases and regenerative mechanisms (Hussain), and fundamentals of waste products and metabolites clearance (Nedergaard), will be combined to address the question if and how do UFP enter, distribute, accumulate, and ultimately undergo bioprocessing and efflux from the brain. The proposed experiments represent the first fundamental analysis and mechanistic underpinning of the interconnection between PM exposure, glymphatics, inflammation, and ADRD initiation and progression.

环境毒物，更具体地说，暴露于环境颗粒物 (PM) 空气污染 增加阿尔茨海默病 (AD) 和 AD 相关痴呆症 (ADRD) 的风险，但我们目前正在发展中。 了解 PM 暴露促进 ADRD 相关病理进展的机制 我们认为空气中的超细颗粒（UFP，直径<100 nm）是非常有限的。 与 AD/ADRD 的发生或进展有因果关系的类淋巴通路正在成为关键。 维持大脑健康及其功能障碍与多种神经系统疾病有关。 依赖性清除途径致力于排出可溶性废蛋白，其存在已被证实 该提议基于初步研究，记录在包括人类在内的多个物种的大脑中。 显示接触模型 UFP 显着抑制类淋巴液转运并增加 β AD 病理学小鼠模型中的淀粉样蛋白负荷我们认为空气中的 UFP 正在运输到大脑。 吸入暴露后会进入大脑并引起全身和神经炎症，因此间接 或直接损害类淋巴液流动并加速 AD/ADRD 样病理和行为 AD 小鼠模型中的缺陷 所提出的目标将通过解决以下问题来检验我们的假设。 问题： 目标 1：短期（3 天）或重复（间歇性 3 个月）接触 UFP 如何影响类淋巴系统 年轻（3 个月）和老年（15 个月）野生型小鼠的液体运输和认知表现 目标 2：可以吗？ UFP 暴露导致的类淋巴系统损伤改变了小鼠体内 Aβ 沉积的进展 AD/ADRD 模型？目标 3：UFP 会沿着主要的类淋巴液运输积累并与细胞相互作用吗？ 我们在这里将使用高分辨率分析扫描透射电子显微镜来分析 UFP 在脑实质中的精确积累和相互作用目标 4：我们将探索分子机制。 小鼠 UFP 暴露相关的类淋巴损伤和病理进展的机制 通过药物抑制肾上腺素信号传导的 AD/ADRD 模型此外，还对 AQP4 进行了详细研究。 血管极化对空气颗粒物暴露、睡眠中断的反应以及肾上腺素能如何 抑制逆转这些病理特征，是否也将探讨该提案的创新方面？ 建立在独特的多学科方法的基础上，其中包括颗粒物毒理学（Elder）、基础 和应用化学，特别关注生命系统中 UFP 的研究（格雷厄姆），神经生物学 疾病和再生机制（Hussain），以及废物和代谢物的基础知识 许可（Nedergaard），将被合并以解决 UFP 是否以及如何进入、分发、 积累，并最终经过生物处理并从大脑中流出。 所提出的实验代表了第一个基本分析和机械基础 PM 暴露、类淋巴系统、炎症和 ADRD 发生和进展之间的相互关系。