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.

项目摘要/摘要 暴露于通过污染空气产生的工业组合产生的汽车排气和废物是 公众中最常见的环境暴露之一，并长期接触此类环境 污染的空气及其主要成分，细和超细颗粒物（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 研究确定了PM对人类认知功能的重大影响，并表明这是增加的风险 用于发展阿尔茨海默氏病（AD）。这些发现表明，暴露于PM会引起终生影响 在中枢神经系统和实质性神经毒性上，导致认知能力下降和 可能是AD神经病理学的发展。但是，研究尚未完全阐明生物学 PM诱导的神经毒性的机制，分子和细胞水平，或阐明功能 形态学，解剖学和/或病理变化导致认知能力下降并增加AD的风险。 鉴于我们的专业知识和最近在该领域的新兴证据，我们假设暴露于PM 通过聚集的小胶质细胞促进树突状刺并促进有毒淀粉样蛋白β（Aβ）物种的积聚 激活和神经炎症。拟议的研究将严格评估树突状脊柱的变化 暴露于环境的小鼠中的形态，Aβ积累，小胶质细胞激活和炎症特征 相关的PM并通过磨料来确定小胶质细胞在PM诱导的神经毒性中的主要作用。 拟议的项目很重要，因为我们旨在将小胶质细胞确定为继承PM引起的关键调解人 神经毒性并揭示了遗传性PM对认知下降和AD风险的生物学影响。解密 通过暴露于环境PM触发的蜂窝级联反应将使高度内在的优点暴露于 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。该项目具有显着的转化价值，作为 对暴露于PM的生物学机制的理解有所改善 将为更有效的预防和治疗措施铺平道路。