Urban air pollution and cerebral hypoperfusion: aging and sex influences

空气污染与脑低灌注的联合作用：年龄和性别的影响 新出现的证据表明，与交通相关的空气污染(TRAP)与认知能力之间存在很强的关联 衰老。临床和实验研究表明白质毒性和海马神经元萎缩 在颗粒物(PM)暴露的环境中。然而，人们对其背后的原因知之甚少 病理生理学和选择性弱点。证据支持脑血管功能障碍的关键作用 在阿尔茨海默病(AD)的发生和发展中，皮质低血流灌注与 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过表达的损伤、海马神经元丢失和Aβ代谢改变 慢性脑低灌流(CCH)小鼠。阿尔茨海默病或认知障碍患者可能 通过血管机制表现出对诱捕器暴露的有害影响的敏感性增加。 该计划利用了专门关注脑血管对AD/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 内嗅皮层和海马区包括穿支在内对神经退行性变通路的影响 通路和弥漫性白质束。AD的患病率在年龄和性别上有明显的差异，年龄较大 受影响最大的是女性。这些因素也影响脑血管储备、缺血损伤反应和血脑屏障。 渗透性。拟议的项目旨在确定年龄和性别对NPM和CCH暴露的影响 单独和结合，通过以下具体目标：1)检查个人的年龄依赖性/ NPM暴露与CCH联合作用对白质毒性、海马/内嗅皮质神经元的影响 2)在NPM和CCH的单独/联合作用下，检验性别差异。 上述结果和，3)检查NPM促进神经退行性变的机制途径 CCH设置中的进程。NPM暴露模型已经在我们小组先前的研究中使用。附近 路旁城市NPM是通过南加州大学气溶胶公司开发的创新颗粒采样器收集的 集团(苏塔斯)。全身暴露是要进行的。CCH模型已经过改进和利用，以 检查炎症介质和血脑屏障。析因设计将评估以下各项的独立效应和组合效应 NPM和CCH对白质毒性、海马/内嗅觉皮质损伤和神经认知的影响。什么时候 如果一起管理，我们预计这些风险敞口将显示出协同效应。与AD病理一致，我们 预计年龄较大的雌性老鼠会表现出最大的脆弱性。我们假设影响是相关联的 炎性上调和血脑屏障通透性。在野生型小鼠和 来自项目3的数据将被用于研究EFAD转基因和可诱导巨噬细胞的机制。 小胶质细胞特异性TLR4基因敲除小鼠。预期的知识将促进我们对年龄和性别的理解 阿尔茨海默病对空气污染继发的神经毒性和认知功能下降的血管机制的影响明显。

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.