Mechanisms of particulate matter-induced neurotoxicity and cognitive decline in mice

项目总结/摘要 暴露于汽车尾气和工业燃烧产生的废物， 这是公众最常见的环境暴露之一，长期暴露于这种环境中， 污染的空气及其主要成分，细和超细颗粒物（PM），长期以来一直被认为是一种 心血管疾病发病率和死亡率的主要危险因素。值得注意的是，最近基于人口的流行病学 研究发现PM对人类认知功能有显著影响，并表明PM会增加人类的风险。 阿尔茨海默病（AD）的发病机制这些发现表明，暴露于PM会造成终身影响 对中枢神经系统的影响和严重的神经毒性，导致认知能力加速下降， 可能是AD神经病理学的发展。然而，研究尚未完全阐明生物学 PM诱导的神经毒性的机制，在分子和细胞水平，或阐明功能， 在一些实施方案中，AD可导致形态学、解剖学和/或病理学变化，导致认知下降和AD风险增加。 根据我们的专业知识和该领域最近出现的证据，我们假设暴露于PM 扰乱树突棘，并通过加重小胶质细胞，促进毒性淀粉样β（Aβ）物质的积累， 激活和神经炎症。这项拟议中的研究将严格评估树突棘的变化 形态学、Aβ积聚、小胶质细胞活化和炎症特征。 相关的PM，并确定小胶质细胞的主要作用PM诱导的神经毒性通过消融它们。的 建议的项目是重要的，因为我们的目标是确定小胶质细胞作为吸入PM诱导的关键介质， 神经毒性，并揭示吸入PM对认知能力下降和AD风险的生物学影响。解密 暴露于环境PM引发的细胞级联将表现出高度内在的优点， 了解环境对大脑健康的影响，并将有助于提高公众对 暴露于环境污染物的风险。该项目具有重要的转化价值， 更好地理解暴露于PM影响认知能力下降的生物学机制 将为更有效的预防和治疗措施铺平道路。

PROJECT SUMMARY/ABSTRACT Exposure to automobile exhaust and wastes generated by industrial combustion through contaminated air is one of the most common environmental exposures among the general public, and long-term exposure to such polluted air and its main constituent, fine and ultrafine particulate matter (PM), has long been recognized as a major risk factor for cardiovascular morbidity and mortality. Notably, recent population-based epidemiological studies identify PM's significant influence on cognitive function in humans, and indicate it as an increased risk for developing Alzheimer's disease (AD). These findings suggest that exposure to PM causes lifelong impact on the central nervous system and substantial neurotoxicity, giving rise to accelerated cognitive decline and possibly the development of AD neuropathology. However, research has yet to fully elucidate the biological mechanisms of PM-induced neurotoxicity, at the molecular and cellular levels, or to elucidate functional, morphological, anatomical, and/or pathological changes leading to cognitive decline and increased risk for AD. Given our expertise and recently emerging evidence in the field, we hypothesize that the exposure to PM perturbs dendritic spines and promotes the buildup of toxic amyloid-beta (Aβ) species by aggravated microglial activation and neuroinflammation. The proposed research will rigorously assess the changes in dendritic spine morphology, Aβ buildup, microglial activation, and inflammatory profiles in mice exposed to environmentally- relevant PM and determine the microglia's prime role in PM-induced neurotoxicity by ablating them. The proposed project is significant as we aim to identify microglia as a key mediator of inhaled PM-induced neurotoxicity and reveal inhaled PM's biological impact on cognitive decline and the risk for AD. Deciphering cellular cascades triggered by exposure to environmental PM will exhibit highly intrinsic merit toward understanding the environmental impact on brain health and will contribute to improving public awareness of the risk of exposure to environmental contaminants. This project has significant translational value, as an improved understanding of the biological mechanisms by which exposure to PM influences cognitive decline will pave the way for more effective preventive and therapeutic measures.