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

颗粒物引起小鼠神经毒性和认知能力下降的机制

• 批准号: 9789887
• 负责人: Masashi Kitazawa
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789887
• 关键词: Affect; Air; Air Pollution; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Anatomy; Automobile Exhaust; Automobiles; Awareness; Biological; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Diseases; Bypass; Carbon Monoxide; Cardiovascular system; Cell Lineage; Chronic; Cities; Cognitive; Coupled; Cross-Sectional Studies; Data; Dementia; Dendritic Spines; Deposition; Developing Countries; Development; Disease; Disease model; Environmental Exposure; Environmental Impact; Environmental Pollution; Environmental Risk Factor; Exhibits; Exposure to; General Population; Genetic; Goals; Health; Heavy Metals; Human; Impaired cognition; Individual; Industrialization; Inflammation; Inflammatory; Inflammatory Response; Ingestion; Inhalation; Inhalation Exposure; Institutes; Knock-in; Laboratories; Lead; Liver; Longitudinal Studies; Measures; Mediating; Mediator of activation protein; Memory impairment; Methodology; Microglia; Molecular; Morbidity - disease rate; Morphology; Mus; Nervous System Trauma; Neuraxis; Neurologic Symptoms; Nitrogen Oxides; Olfactory Nerve; Particulate Matter; Pathologic; Pharmacology; Play; Population; Predisposition; Preventive; Reporting; Research; Risk; Rodent Model; Role; Statistical Data Interpretation; Synapses; Therapeutic; Toxic effect; Vertebral column; base; brain health; brain parenchyma; cardiovascular risk factor; cognitive development; cognitive function; environmental particulate; epidemiology study; improved; interest; mortality; mouse model; nervous system disorder; neuroinflammation; neuropathology; neurotoxic; neurotoxicity; novel; oxidative damage; population based; response; traffic-related air pollution; ultrafine particle; wasting

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.

项目概要/摘要 通过受污染的空气接触汽车尾气和工业燃烧产生的废物是 公众最常见的环境暴露之一，并且长期暴露于这种环境 污染空气及其主要成分细颗粒物和超细颗粒物 (PM) 长期以来被认为是 心血管发病率和死亡率的主要危险因素值得注意的是，最近基于人群的流行病学。 研究确定 PM 对人类认知功能的重大影响，并表明其风险增加 这些研究结果表明，接触 PM 会造成终生影响。 对中枢神经系统和显着的神经毒性，导致加速认知能力下降和 可能是 AD 神经病理学的发展 然而，研究尚未完全阐明其生物学意义。 PM 诱导神经毒性的机制，在分子和细胞水平上，或阐明功能， 形态学、解剖学和/或病理学变化导致认知能力下降和 AD 风险增加。 鉴于我们的专业知识和该领域最近出现的证据，我们认为接触 PM 扰乱树突棘并通过加剧的小胶质细胞促进有毒的淀粉样蛋白-β (Aβ) 物质的积累 拟议的研究将严格评估树突棘的变化。 暴露于环境中的小鼠的形态、Aβ 积累、小胶质细胞激活和炎症特征 相关的 PM 并通过消融小胶质细胞来确定小胶质细胞在 PM 诱导的神经毒性中的主要作用。 拟议的项目意义重大，因为我们的目标是确定小胶质细胞是吸入 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。 暴露于环境颗粒物引发的细胞级联将表现出内在的高度价值 了解环境对大脑健康的影响，将有助于提高公众的意识 作为一个项目，该项目具有重大的转化价值。 更好地了解 PM 暴露影响认知能力下降的生物机制 将为采取更有效的预防和治疗措施铺平道路。