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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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&apos 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

项目摘要

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.

我们的首要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，TRAP 是一种我们最近发表的流行病学报告在大多数美国老年人居住的城市地区普遍存在。数据显示 PM2.5 升高（颗粒物 <2.5 µm）与痴呆症增加之间存在密切关联 65 岁以上女性的风险，ApoE4 纯合子存在偏差（JC Chen in Cacciottolo et al 2017，PMID 28140404）在同一份报告中，Finch-Sioutas 实验室的雌性小鼠实验研究表明暴露于 nPM（TRAP 的纳米级亚组分）会促进淀粉样蛋白生成，并具有 ApoE4 偏好。变化包括海马 CA1 神经突和髓磷脂的消耗，这模拟了 AD 和 AD 的选择性损伤在小鼠中风模型中，nPM 暴露加剧了脑缺血损伤（William Mack：Liu et al 2016，PMID 27071057）性别和 ApoE 等位基因的差异表明异质性的来源。人类对 TRAP 的反应。我们提出四个项目：对两个全国妇女群体的流行病学研究（项目 1，JC Chen：女性健康倡议记忆研究；和男性（项目 2，C Franz 和 W Kremen：越南时代双胞胎老龄化研究 (VETSA) 和两项空气污染暴露实验研究（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）。解决一组常见问题：(1) TRAP 施加的 AD 风险是什么？相关风险因性别、生命阶段和 APOE/其他等位基因而异？ (2) TRAP 会引起哪些神经退行性变化？ AD 早期认知能力下降的风险是什么？ (3) 哪些大脑通路最容易受到影响？ (4) 是否有共同的机制（例如，淀粉样蛋白生成、脑血管损伤和灌注不足和神经炎症）会导致过早认知能力下降和 AD 风险增加吗？两个支持核心提供群体神经信息学、血脑屏障 (BBB) 的神经影像学和有髓束、大规模空气污染模型和流行病学、吸入暴露评估和神经毒理学。神经影像核心 B1 提供跨地点和协调的人脑成像。中介分析（项目 1-2）提供小鼠 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 协调一致。 WHIMS 和 VETSA 的群体暴露估计（项目 1-2）提供了小鼠的吸入暴露；用于性别和 ApoE 等位基因反应（项目 3）和慢性脑灌注不足（项目 C3）的研究；对于 P01 整合，行政核心构建了大脑炎症蛋白对 TRAP 的反应。 AirPollBrain（由 Finch 和 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。该计划的结果将加深对 TRAP 对 AD 风险和加速认知的贡献的理解下降，并为 AD 环境神经毒理学的预防性干预提供依据。