Glymphatic impairment as a crucial factor in particulate matter exposure related development of Alzheimer's disease pathology
类淋巴系统损伤是与颗粒物暴露相关的阿尔茨海默病病理学发展的关键因素
基本信息
- 批准号:10718104
- 负责人:
- 金额:$ 73.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:APP-PS1AccelerationAddressAdrenergic AgentsAdverse effectsAffectAge MonthsAgingAirAir PollutionAlzheimer like pathologyAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease related dementiaAmyloid beta-ProteinAnimal ModelAstrocytesBehavioralBlood VesselsBrainCellsCerebrospinal FluidCervicalChemistryCognitive deficitsCranial NervesDedicationsDepositionDevelopmentDiameterDiseaseDisease ProgressionExhibitsExposure toFunctional disorderGeneticHumanHuman Amyloid Precursor ProteinImpaired cognitionInflammationInflammatoryInhalationInhalation ExposureIntercellular FluidLinkLiquid substanceMapsMeningealModelingMolecularMusNeurobiologyOrganismOxidative StressParticulate MatterPathologicPathologyPathway interactionsPatternPlayProcessProteinsResolutionRiskRodentRodent ModelRoleScanningSignal TransductionSleepSleep disturbancesSpinal nerve structureSubarachnoid SpaceSystemTestingTimeTissuesToxic Environmental SubstancesToxicologyTransgenic OrganismsTransmission Electron MicroscopyVenousWaste ProductsWild Type Mouseabeta depositionagedbioprocessbrain healthbrain parenchymabrain tissuecognitive performancecomorbiditydementia riskexperimental studyfluid flowglymphatic clearanceglymphatic dysfunctionglymphatic functionglymphatic systemhuman modelimprovedinnovationinterdisciplinary approachlymphatic vesselmouse modelmutantnervous system disorderneuroinflammationoverexpressionpharmacologicpresenilin-1regenerativeresponsesleep qualitysystemic inflammatory responseultrafine particlewastingwater channelwhite matter
项目摘要
Environmental toxicants and, more specifically, exposure to ambient particulate matter (PM) air pollution
increases the risk of developing Alzheimer's Disease (AD) and AD-Related Dementias (ADRD). Yet, our current
understanding of the mechanisms by which PM exposure augments the progression of ADRD-related pathology
and cognitive impairment is very limited. We posit that airborne ultrafine particles (UFP, <100 nm diameter) are
causally related to the development or progression of AD/ADRD. The glymphatic pathway is emerging as a key
to maintaining brain health and its dysfunction is implicated in several neurological disorders. This glial-
dependent clearance pathway is dedicated to draining soluble waste proteins and its existence has been
documented in the brain of multiple species, including humans. The proposal is based on preliminary studies
showing that exposure to model UFP significantly suppresses glymphatic fluid transport and increases the β
amyloid load in a murine model of AD pathology. We hypothesize that airborne UFP are transported to the
brain upon inhalation exposure and cause both systemic and neuroinflammation, thus either indirectly
or directly impairing glymphatic fluid flow and accelerating AD/ADRD-like pathology and behavioral
deficits in a mouse model of AD. The proposed aims will test our hypothesis by addressing the following
questions: Aim 1: How does short (3 days) or repeated (3 months intermittent) exposure to UFP affect glymphatic
fluid transport and cognitive performance in young (3 months) and aged (15 months) wildtype mice? Aim 2: Can
glymphatic impairment resulting from UFP exposure change the progression of Aβ deposition in a murine
AD/ADRD model? Aim 3: Will UFP accumulate and interact with cells along the major glymphatic fluid transport
segments? We will here use high-resolution analytical scanning transmission electron microscopy to analyze
precisely where in the brain parenchyma the UFP accumulate and interact. Aim 4: We will explore the molecular
mechanisms of UFP exposure-related glymphatic impairment and pathological progression in a murine
AD/ADRD model via pharmacological inhibition of adrenergic signaling. Moreover, a detailed study of AQP4
vascular polarization response to air particulate matter exposure, sleep disruption and how do adrenergic
inhibition reverse these signatures of pathology, would also be explored? The innovative aspects of the proposal
build upon a unique multidisciplinary approach where expertise in particulate matter toxicology (Elder), basic
and applied chemistry with particular focus on the study of UFP in living systems (Graham), neurobiology of
diseases and regenerative mechanisms (Hussain), and fundamentals of waste products and metabolites
clearance (Nedergaard), will be combined to address the question if and how do UFP enter, distribute,
accumulate, and ultimately undergo bioprocessing and efflux from the brain.
The proposed experiments represent the first fundamental analysis and mechanistic underpinning of the
interconnection between PM exposure, glymphatics, inflammation, and ADRD initiation and progression.
环境毒物,更具体地说,暴露于环境颗粒物(PM)空气污染
增加患阿尔茨海默病(AD)和AD相关痴呆(ADRD)的风险。然而,我们目前
了解PM暴露增强ADRD相关病理进展的机制
认知障碍是非常有限的。我们认为,空气中的超细颗粒(UFP,直径<100 nm)是
与AD/ADRD的发生或进展有因果关系。胶质淋巴通路正在成为
维持大脑健康和它的功能障碍与几种神经系统疾病有关。这个神经胶质-
依赖性清除途径致力于排出可溶性废物蛋白质,并且其存在已被
在包括人类在内的多个物种的大脑中都有记录。这项建议是根据初步研究提出的
显示暴露于模型UFP显著抑制胶质淋巴液转运,并增加β
在AD病理学的鼠模型中的淀粉样蛋白负荷。我们假设空气中的UFP被运送到
吸入暴露后会引起全身和神经炎症,因此,
或直接损害胶质淋巴液流动并加速AD/ADRD样病理和行为
在AD小鼠模型中的缺陷。提出的目标将通过解决以下问题来检验我们的假设
问题:目标1:短期(3天)或重复(3个月间歇)暴露于UFP如何影响胶质淋巴细胞
年轻(3个月)和老年(15个月)野生型小鼠的液体转运和认知能力?目标2:可以
UFP暴露导致的胶质淋巴损伤改变了小鼠Aβ沉积的进展
AD/ADRD模型?目的3:UFP是否会在主要胶质淋巴液转运过程中积聚并与细胞相互作用
片段?我们将在这里使用高分辨率分析扫描透射电子显微镜来分析
在脑实质中UFP的聚集和相互作用的精确位置。目的4:我们将探索分子
UFP清除相关的胶质淋巴损伤和小鼠病理进展的机制
通过药理学抑制肾上腺素能信号传导的AD/ADRD模型。此外,对AQP 4的详细研究
血管极化反应的空气颗粒物暴露,睡眠中断和如何做肾上腺素能
抑制逆转这些签名的病理,也将探讨?提案的创新方面
建立在一个独特的多学科的方法,在颗粒物毒理学的专业知识(长老),基本
和应用化学,特别关注生命系统中的UFP研究(Graham),
疾病和再生机制(侯赛因),以及废物和代谢物的基本原理
清除(Nedergaard),将结合起来解决问题,如果和如何UFP进入,分发,
积累,并最终经历生物处理和从大脑流出。
提出的实验代表了第一个基本分析和机械基础的
PM暴露、glymphatics、炎症和ADRD发生和进展之间的相互关系。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Alison Elder其他文献
Alison Elder的其他文献
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{{ truncateString('Alison Elder', 18)}}的其他基金
International Nanotoxicology Congress: Nanotox 2016
国际纳米毒理学大会:Nanotox 2016
- 批准号:
9195226 - 财政年份:2016
- 资助金额:
$ 73.39万 - 项目类别:
Impact of Ambient Ultrafine Particle Exposures on Alzheimer's Disease Progression
环境超细颗粒暴露对阿尔茨海默病进展的影响
- 批准号:
8502926 - 财政年份:2013
- 资助金额:
$ 73.39万 - 项目类别:
Impact of Ambient Ultrafine Particle Exposures on Alzheimer's Disease Progression
环境超细颗粒暴露对阿尔茨海默病进展的影响
- 批准号:
9065942 - 财政年份:2013
- 资助金额:
$ 73.39万 - 项目类别:
Impact of Ambient Ultrafine Particle Exposures on Alzheimer's Disease Progression
环境超细颗粒暴露对阿尔茨海默病进展的影响
- 批准号:
8852615 - 财政年份:2013
- 资助金额:
$ 73.39万 - 项目类别:
Impact of Ambient Ultrafine Particle Exposures on Alzheimer's Disease Progression
环境超细颗粒暴露对阿尔茨海默病进展的影响
- 批准号:
8731894 - 财政年份:2013
- 资助金额:
$ 73.39万 - 项目类别:
Impact of Ambient Ultrafine Particle Exposures on Alzheimer's Disease Progression
环境超细颗粒暴露对阿尔茨海默病进展的影响
- 批准号:
9278171 - 财政年份:2013
- 资助金额:
$ 73.39万 - 项目类别:
Hazard Assessment and Risk Estimation of Inhaled Nanomaterials Exposure
吸入纳米材料暴露的危害评估和风险评估
- 批准号:
7852941 - 财政年份:2009
- 资助金额:
$ 73.39万 - 项目类别:
Hazard Assessment and Risk Estimation of Inhaled Nanomaterials Exposure
吸入纳米材料暴露的危害评估和风险评估
- 批准号:
7939792 - 财政年份:2009
- 资助金额:
$ 73.39万 - 项目类别:
Hazard Assessment and Risk Estimation of Inhaled Nanomaterials Exposure
吸入纳米材料暴露的危害评估和风险评估
- 批准号:
8071680 - 财政年份:2009
- 资助金额:
$ 73.39万 - 项目类别:
Fate and Effects of Nanoparticles: Relationship to Physicochemical Properties
纳米颗粒的命运和影响:与理化性质的关系
- 批准号:
7341306 - 财政年份:2007
- 资助金额:
$ 73.39万 - 项目类别:
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