Urban Air Pollution and Alzheimer's Disease: Risk, Heterogeneity, and Mechanisms

城市空气污染与阿尔茨海默病：风险、异质性和机制

• 批准号: 10216922
• 负责人: Jiu-Chiuan Chen
• 金额: $ 224.03万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216922
• 关键词: AD transgenic mice; Accounting; Address; Adverse effects; Affect; Aging; Air; Air Pollutants; Air Pollution; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; American; Apolipoprotein E; Area; Automobile Exhaust; Biological; Blood - brain barrier anatomy; Brain; Brain imaging; Brain region; Caliber; California; Cardiovascular system; Cerebral Ischemia; Chronic; Clinical; Cohort Studies; Communities; Data; Development; Disease; Elderly; Environmental Epidemiology; Environmental Exposure; Environmental Health; Epidemiology; Etiology; Experimental Models; Exposure to; Female; Finches; Funding; Geography; Goals; Health; Heterogeneity; Hippocampus (Brain); Homozygote; Human; Immune system; Impaired cognition; Individual; Inflammatory; Infrastructure; Inhalation Exposure; Interdisciplinary Study; Knock-out; Knowledge; Life; Life Cycle Stages; Link; Literature; Mediation; Memory; Modeling; Mus; Myelin; Nerve Degeneration; Neurites; Neurobiology; Neuropsychology; Neurosciences; Neurotoxins; Outcome; Particulate Matter; Pathway interactions; Population; Population Study; Predisposition; Process; Proteins; Public Health; Publishing; Recommendation; Reporting; Research; Research Personnel; Resources; Respiratory System; Risk; Role; Science; Sex Differences; Site; Source; Structure; TLR4 gene; Translating; Twin Studies; Universities; Vietnam; Woman; Women' s Health; age difference; aging brain; ambient air pollution; amyloidogenesis; apolipoprotein E-4; base; brain pathway; cerebral hypoperfusion; cerebral ischemic injury; cerebrovascular; cognitive neuroscience; cohesion; cohort; cost; dementia risk; design; empowered; epidemiologic data; epidemiology study; experimental study; fine particles; frontier; gender difference; high resolution imaging; human population study; hypoperfusion; imaging study; improved; innovation; men; metropolitan; mild cognitive impairment; mouse model; multidisciplinary; nanosized; neglect; neuroimaging; neuroinflammation; neuroinformatics; neuropathology; neurotoxic; neurotoxicity; neurotoxicology; neurovascular; novel; older women; pollutant; pre-clinical; predictive marker; premature; preventive intervention; programs; response; risk variant; sex; spatiotemporal; stroke model; symposium; tool; tractography; traffic-related air pollution; urban area; white matter

Our overarching goal is to further resolve the neurodegenerative role of traffic-related air pollutants (TRAP), a ubiquitous exposure in urban areas where most older Americans reside. Our recently published epidemiologic data showed strong association between elevated PM2.5 (particulate matter <2.5µm) and increased dementia risk in women >65 years, with a bias for ApoE4 homozygotes (JC Chen in Cacciottolo et al 2017, PMID 28140404). In this same report, experimental studies of female mice from the Finch-Sioutas Labs showed that exposure to nPM (a nano-sized subfraction of TRAP) was pro-amyloidogenic with an ApoE4 bias. Other changes include attrition of hippocampal CA1 neurites and myelin, which model selective damage in AD and cerebral ischemia. In a mouse stroke model, nPM exposure exacerbated cerebral ischemic damage (William Mack: Liu et al 2016, PMID 27071057). Differences by sex and ApoE alleles suggest sources of heterogeneity in human responses to TRAP. We propose four projects: epidemiological studies of two nationwide cohorts of women (Project 1, JC Chen: Women's Health Initiative Memory Studies; WHIMS) and men (Project 2, C Franz and W Kremen: Vietnam Era Twin Study of Aging, VETSA) and two experimental studies of air pollution exposure (Project 3, Finch: mouse models of aging and AD; Project 4 Wm Mack, chronic ceebral hypoperfusion). These projects address a common set of questions: (1) What is the AD risk imposed by TRAP and does the associated risk vary by sex, life stage, and APOE/other alleles? (2) What neurodegenerative changes are induced by TRAP and what is the resulting risk for early cognitive decline of AD? (3) Which brain pathways are most susceptible to TRAP neurotoxicity? (4) Do shared mechanisms (e.g., amyloidogenesis, cerebrovascular damage and hypoperfusion, and neuroinflammation) predispose to premature cognitive decline and an increased AD risk? Two supporting Cores provide population neuroinformatics, neuroimaging of blood-brain-barrier (BBB) and myelinated tracts, large-scale air pollution modeling and epidemiology, inhalation exposure assessment and neurotoxicology. Neuroimaging Core B1 provides human brain imaging harmonized across sites and mediation analyses (Projects1-2). B2 provides high-resolution imaging of BBB and tractography for mouse models (Projects 3-4). Core C Environmental Exposure and Neurotoxicology subcore C1 harmonizes population exposure estimates for WHIMS and VETSA (Projects1-2); C2 provides inhalation exposure of mice for studies of sex and ApoE allele responses (Project 3) and of chronic cerebral hypoperfusion (Project 4); C3 analyzes brain inflammatory protein responses to TRAP. For P01 integration, the Administrative Core builds on the infrastructure of AirPollBrain (led by Finch& Chen), a USC-funded collaborative network since 2010. Results of this program will advance understanding of TRAP contributions to AD risk and accelerated cognitive decline, and provide a rationale for preventive intervention in the environmental neurotoxicology of AD.

我们的总体目标是进一步解决交通相关空气污染物（TRAP）的神经退行性作用， 在大多数美国老年人居住的城市地区，我们最近发表的流行病学 数据显示，PM2.5（颗粒物<2.5µm）升高与痴呆症增加之间存在强烈关联 >65岁女性的风险，对ApoE 4纯合子存在偏倚（JC Chen in Cacciottolo et al 2017，PMID 28140404）。在同一份报告中，Finch-Sioutas实验室对雌性小鼠的实验研究表明， 暴露于nPM（TRAP的纳米级亚组分）是促淀粉样蛋白生成的，具有ApoE 4偏倚。其他 这些变化包括海马CA 1区神经突起和髓鞘的磨损，它们模拟了AD中的选择性损伤， 脑缺血在小鼠中风模型中，nPM暴露加剧了脑缺血性损伤（William Mack：Liu等人2016，PMID 27071057）。性别和ApoE等位基因的差异提示异质性的来源 人类对陷阱的反应。 我们提出了四个项目：对两个全国性妇女群体进行流行病学研究（项目1，JC Chen：女性健康倡议记忆研究; WHIMS）和男性（项目2，C Franz和W Kremen： Vietnam Era Twin Study of Aging，VETSA）和两项空气污染暴露的实验研究（项目3， Finch：衰老和AD的小鼠模型;项目4 Wm Mack，慢性脑灌注不足）。这些项目 解决一组常见的问题：（1）什么是反倾销风险强加的陷阱和相关的风险是否 不同性别、生命阶段和APOE/其他等位基因？(2)TRAP会引起哪些神经退行性变化 AD早期认知功能下降的风险是什么？(3)哪些大脑通路最容易受到 TRAP神经毒性(4)共享机制（例如，淀粉样蛋白生成、脑血管损伤和 灌注不足和神经炎症）易导致认知功能过早下降和AD风险增加？ 两个支持核心提供人口神经信息学，血脑屏障（BBB）的神经成像和 有髓神经束、大规模空气污染建模和流行病学、吸入暴露评估和 神经毒理学Neuroimaging Core B1提供了跨站点协调的人脑成像， 调解分析（项目1 -2）。B2为小鼠提供BBB和纤维束成像的高分辨率成像 模型（项目3-4）。核心C环境暴露和神经毒理学子核心C1协调 WHIMS和VETSA的人群暴露估计值（项目1 -2）; C2提供小鼠的吸入暴露 用于研究性别和ApoE等位基因反应（项目3）和慢性脑灌注不足（项目4）; C3 分析大脑炎症蛋白对TRAP的反应。对于P01集成，管理核心构建 AirPollBrain（由Finch& Chen领导）的基础设施，这是一个自2010年以来由南加州大学资助的协作网络。 该计划的结果将促进对TRAP对AD风险和加速认知功能的贡献的理解。 下降，并提供了预防性干预AD的环境神经毒理学的理由。