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 通过受污染的空气接触汽车尾气和工业燃烧产生的废物 公众中最常见的环境暴露之一，以及长期暴露在这种环境中 污染的空气及其主要成分--细颗粒物和超细颗粒物(PM)长期以来一直被认为是 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，最近以人口为基础的流行病学 研究确认PM对人类认知功能的显著影响，并表明它是一种增加的风险 发展为阿尔茨海默氏症(AD)。这些发现表明，接触PM会产生终生影响 对中枢神经系统和实质性神经毒性的影响，导致认知功能减退和 可能是阿尔茨海默病的神经病理发展。然而，研究尚未完全阐明生物学上的 PM诱导的神经毒性的分子和细胞水平的机制，或阐明功能， 形态、解剖和/或病理改变导致认知能力下降和AD风险增加。 根据我们的专业知识和最近在该领域出现的证据，我们假设接触PM 通过加重的小胶质细胞扰乱树突棘并促进毒性淀粉样β蛋白(Aβ)的积聚 激活和神经炎症。这项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、β积聚、小胶质细胞激活和炎症特征 并通过消融小胶质细胞，确定小胶质细胞在PM诱导的神经毒性中的主要作用。这个 提出的项目具有重要意义，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 神经毒性和揭示吸入PM对认知能力下降和AD风险的生物学影响。破译 暴露在环境PM中引发的细胞级联将显示出高度内在的优点 了解环境对大脑健康的影响，将有助于提高公众对 暴露在环境污染物中的风险。这个项目具有重大的翻译价值，作为一个 提高对暴露于PM影响认知能力下降的生物学机制的理解 将为采取更有效的预防和治疗措施铺平道路。