Urban air pollution and cerebral hypoperfusion: aging and sex influences

城市空气污染和脑灌注不足：衰老和性别的影响

• 批准号: 10456755
• 负责人: William J Mack
• 金额: $ 30.94万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456755
• 关键词: Aerosols; Affect; Age; Aging; Air Pollution; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Atrophic; Biological Markers; Blood Vessels; Blood capillaries; C57BL/6 Mouse; Cerebrovascular Disorders; Chronic; Clinical Research; Cognitive aging; Cognitive deficits; Complement component C5; Corpus Callosum; Data; Dependence; Deposition; Diffuse; Elderly; Estradiol; Exhibits; Experimental Models; Exposure to; Failure; Feedback; Female; Functional disorder; Gene set enrichment analysis; Genetic; Heterogeneity; Hippocampus (Brain); Impaired cognition; Individual; Inflammation; Inflammation Mediators; Inflammatory; Injury; Intervention; Ischemia; Joints; Knockout Mice; Knowledge; Lectin; Magnetic Resonance Imaging; Memory impairment; Metabolism; Microglia; Modeling; Molecular; Mus; Mutation; Nerve Degeneration; Neurocognition; Neurocognitive Deficit; Neuronal Dysfunction; Neuronal Injury; Neurons; Outcome; Outcome Assessment; Particulate Matter; Pathogenesis; Pathology; Pathway interactions; Perforant Pathway; Pericytes; Persons; Predisposition; Prevalence; Process; Reperfusion Therapy; Risk; Risk Assessment; Role; Sampling; Secondary to; Severities; Sex Differences; Stains; System; TLR4 gene; Testing; Tissues; Toxic effect; Transgenic Organisms; Up-Regulation; Vascular Dementia; Vulnerable Populations; Wild Type Mouse; blood-brain barrier permeabilization; cerebral hypoperfusion; cerebrovascular; density; design; entorhinal cortex; experimental study; fine particles; hemodynamics; hypoperfusion; inflammatory marker; innovation; ischemic injury; macrophage; male; middle age; mouse model; multiphoton microscopy; nanoparticulate; nanosized; nervous system disorder; neuroinflammation; neuron loss; neurotoxic; neurotoxicity; older women; overexpression; particle; programs; response to injury; sex; synergism; tractography; traffic-related air pollution; transcriptome sequencing; vascular factor; white matter; white matter damage; white matter injury

Joint Effects of Air Pollution and Cerebral Hypoperfusion: Age and Sex Influence Emerging evidence suggests a strong association between traffic-related air pollution (TRAP) and cognitive aging. Clinical and experimental studies demonstrate white matter toxicity and hippocampal neuronal atrophy in the setting of particulate matter (PM) exposure. Little is known, however, about the underlying pathophysiology and selective vulnerabilities. Evidence supports a critical role for cerebral vascular dysfunction in the onset and progression of Alzheimer's disease (AD), with cortical hypoperfusion implicated in the pathogenesis of neuronal dysfunction and cognitive deficits. Studies have demonstrated increased memory impairment, hippocampal neuronal loss, and altered Aβ metabolism in APPSwInd and APP overexpressing mice exposed to chronic cerebral hypoperfusion (CCH). Individuals with AD or cognitive impairment may demonstrate increased susceptibility to deleterious effects of TRAP exposure through vascular mechanisms. This program leverages experimental models focused exclusively on the cerebrovascular contributions to AD/ cognitive decline. We hypothesize that nanoparticulate matter (nPM) exposure and CCH exhibit synergistic effects on neurodegenerative pathways from the entorhinal cortex and hippocampus including the perforant pathway and diffuse white matter tracts. Age and sex variances are evident in AD prevalence, with older women most affected. These factors also impact cerebrovascular reserve, ischemic injury response, and BBB permeability. The proposed project seeks to determine age and sex influences on nPM and CCH exposure alone, and in combination, through the following specific aims: 1) Examine age dependence for the individual/ joint effects of nPM exposure and CCH on white matter toxicity, hippocampal / entorhinal cortex neuronal injury, and neurocognition, 2) Examine sex differences in the independent/ joint effects of nPM and CCH on the above outcomes and, 3) Examine mechanistic pathways by which nPM promotes neurodegenerative processes in the setting of CCH. The nPM exposure model has been used in our group's prior studies. Near roadside urban nPM is collected by means of innovative particle samplers developed by the USC Aerosol group (Sioutas). Whole body exposures are administered. The CCH model has been refined and leveraged to examine inflammatory mediators and BBB. A factorial design will assess independent and combined effects of nPM and CCH on white matter toxicity, hippocampal/ entorhinal cortex injury, and neurocognition. When administered together, we expect these exposures to exhibit synergy. Consistent with AD pathologies, we expect older female mice to demonstrate greatest vulnerability. We hypothesize that effects are associated with inflammatory upregulation and BBB permeability. Baseline interactions established in wild type mice and data from Project 3 will be leveraged to study mechanism in EFAD-Transgenic and inducible macrophage/ microglial specific TLR4 knockout mice. Expected knowledge will advance our understanding of age and sex impact on neurotoxicity secondary to air pollution and vascular mechanisms of cognitive decline evident in AD.

空气污染和脑灌注不足的联合作用：年龄和性别的影响 新出现的证据表明，交通相关的空气污染（TRAP）与认知能力之间存在密切联系。 衰老临床和实验研究表明，白色物质毒性和海马神经元萎缩 在颗粒物（PM）暴露的设置中。然而，人们对潜在的 病理生理学和选择性脆弱性。证据支持脑血管功能障碍的关键作用 在阿尔茨海默病（AD）的发病和进展中，皮质灌注不足与阿尔茨海默病（AD）的发病和进展有关。 神经元功能障碍和认知缺陷的发病机制。研究表明记忆力增强 APPSwInd和APP过度表达的损伤、海马神经元丢失和Aβ代谢改变 暴露于慢性脑灌注不足（CCH）的小鼠。AD或认知障碍患者可能 表明通过血管机制对TRAP暴露的有害作用的易感性增加。 该计划利用专门关注脑血管对AD的贡献的实验模型， 认知能力下降我们假设纳米颗粒物（nPM）暴露和CCH表现出协同作用， 对内嗅皮层和海马神经退行性通路的影响，包括 通道和弥漫性白色物质束。年龄和性别差异在AD患病率中是明显的， 女性受影响最大。这些因素还影响脑血管储备、缺血性损伤反应和BBB。 磁导率拟议的项目旨在确定年龄和性别对nPM和CCH暴露的影响 通过以下具体目标，单独或结合使用：1）检查个人的年龄依赖性; nPM暴露和CCH对白色物质毒性、海马/内嗅皮层神经元 2）检查nPM和CCH对神经功能的独立/联合影响的性别差异， 3）检查nPM促进神经退行性变的机制途径 在CCH的设置过程中。nPM暴露模型已被用于我们小组的先前研究。附近 城市路边的纳米颗粒物是通过南加州大学气溶胶研究所开发的新型粒子采样器收集的 组（Sioutas）。给予全身暴露。CCH模型已经过完善和利用， 检查炎症介质和血脑屏障。析因设计将评估以下因素的独立和联合效应： nPM和CCH对白色物质毒性、海马/内嗅皮质损伤和神经认知的影响。当 我们希望这些接触能产生协同作用。与AD病理学一致，我们 年长的雌性小鼠表现出最大的脆弱性。我们假设这些影响与 炎症上调和血脑屏障通透性。在野生型小鼠中建立的基线相互作用， 将利用项目3的数据研究EFAD-转基因和诱导型巨噬细胞/ 小胶质细胞特异性TLR 4敲除小鼠。预期的知识将促进我们对年龄和性别的理解 对继发于空气污染的神经毒性和AD中明显的认知下降的血管机制的影响。