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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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效应：年龄和性别影响新证据表明，交通相关空气污染 (TRAP) 与认知能力之间存在密切关联临床和实验研究表明白质毒性和海马神经元萎缩。然而，对于颗粒物 (PM) 暴露的背后原因却知之甚少。病理生理学和选择性脆弱性的证据支持脑血管功能障碍的关键作用。阿尔茨海默病 (AD) 的发病和进展，其中皮质灌注不足与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 过表达中的损伤、海马神经元损失和 Aβ 代谢改变暴露于慢性脑灌注不足（CCH）的小鼠可能患有 AD 或认知障碍。证明通过血管机制对 TRAP 暴露的有害影响的敏感性增加。该计划利用专门关注脑血管对 AD/的贡献的实验模型我们认为纳米颗粒物 (nPM) 暴露和 CCH 表现出协同作用。对内嗅皮层和海马（包括穿支）神经退行性通路的影响 AD 患病率存在明显的年龄和性别差异，其中年龄较大。女性受影响最大。这些因素也会影响脑血管储备、缺血性损伤反应和血脑屏障。拟议项目旨在确定年龄和性别对 nPM 和 CCH 暴露的影响。单独或结合起来，通过以下具体目标： 1) 检查个人/的年龄依赖性 nPM 暴露和 CCH 对白质毒性、海马/内嗅皮层神经元的联合影响损伤和神经认知，2）检查 nPM 和 CCH 对神经认知的独立/联合影响中的性别差异上述结果，3) 检查 nPM 促进神经退行性病变的机制途径我们小组之前的研究中已经使用了 CCH 设置中的过程。路边城市 nPM 通过南加州大学气溶胶开发的创新颗粒采样器收集组（Sioutas）进行了全身暴露。检查炎症介质和 BBB 的因子设计将评估独立和综合效应。 nPM 和 CCH 对白质毒性、海马/内嗅皮层损伤和神经认知的影响。一起管理时，我们预计这些暴露会表现出与 AD 病理学一致的协同作用。预计年长的雌性小鼠会表现出最大的脆弱性。与野生型小鼠中炎症上调和血脑屏障通透性的基线相互作用。项目 3 的数据将用于研究 EFAD 转基因和诱导型巨噬细胞的机制/ 小胶质细胞特异性 TLR4 敲除小鼠的知识将增进我们对年龄和性别的理解。对空气污染继发的神经毒性的影响和 AD 中认知能力下降的血管机制很明显。