The Role of Peripheral Immune Cell Trafficking in Ozone-Induced Alzheimer's Disease Neuropathology

外周免疫细胞贩运在臭氧诱发的阿尔茨海默病神经病理学中的作用

• 批准号: 10467207
• 负责人: Michelle L Block
• 金额: $ 173.55万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10467207
• 关键词: Affect; Air Pollution; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Blood Circulation; Brain; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cells; Central Nervous System Diseases; Cervical lymph node group; Data; Dementia; Disease Marker; Disease Progression; Elderly; Environmental Exposure; Etiology; Excision; Exposure to; Gases; Gene Expression; Genetic Transcription; Human; IL8RA gene; IL8RB gene; Immune; Immune response; Impairment; Inflammatory; Inhalation; Link; Lung; Lung immune response; Mediator of activation protein; Microglia; Mouse Strains; Mus; Myeloid Cells; Neurites; Neurodegenerative Disorders; Neuroimmune; Neurons; Neutrophil Infiltration; Ozone; Pathologic; Pathology; Peripheral; Physiology; Process; Rattus; Reporting; Respiratory System; Role; Senile Plaques; Signal Transduction; Splenectomy; TREM2 gene; Testing; Vascular Endothelial Growth Factor Receptor-3; Vascular Endothelial Growth Factors; amyloid pathology; antagonist; chemokine receptor; cytokine; indexing; macrophage; neuroinflammation; neuropathology; neurotoxicity; neutrophil; ozone exposure; receptor; response; trafficking; transcriptome

PROJECT SUMMARY Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease and the leading cause of dementia in the elderly. Current treatment is unable to halt disease progression, emphasizing the importance of understanding the etiology and pathobiology underlying AD. High levels of urban air pollution have been associated with increased AD risk and elevated amyloid plaque load in humans, but the underlying mechanisms are poorly understood. Ozone (O3), a reactive gas component of urban air pollution, is linked to increased AD risk, but confined to the respiratory tract after inhalation, implicating a role for the peripheral immune response to air pollution in AD neuropathology. Microglia, the resident parenchymal myeloid cells in the brain, are reported to be key mediators of AD neuropathology, but recent evidence also supports a potential role for peripheral immune cells, such as neutrophils. Yet, how these myeloid cells become pathologically dysregulated in AD is largely unknown. We have previously shown that O3 inhalation triggers a pro-inflammatory pulmonary immune response that is associated with a persistent neuroimmune response in mice and rats. How O3 inhalation affects the neuroimmune response during normal physiology and during ongoing AD processes is poorly understood. The Lung-Brain Axis hypothesis holds that the pulmonary consequences of inhaled environmental exposures dysregulates the neuroimmune response in part, through peripheral immune cell changes to augment CNS disease pathology, critical concepts that we propose to directly test here. We hypothesize that O3 exposure causes neuroimmune changes and exacerbates Aβ neuropathology via peripheral immune cell trafficking and that CXCR2 and VEGF are primary mechanisms in this process. As such, our aims are to: 1) Define the role of CXCR2 in the O3-induced neuroimmune response; 2) Examine the role of CXCR2 in the O3-induced impairment of microglial plaque association and augmentation of amyloid neuropathology; 3) Confirm the role of VEGF in O3-induced augmentation of beta amyloid neuropathology and neurotoxicity. These findings will reveal key mechanisms (peripheral immune cell/neutrophil trafficking, CXCR1, and VEGF) in the Lung-Brain Axis responsible for how the peripheral immune compartment affects the brain and augments AD processes, identifying key opportunities to mitigate AD neuropathology.

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是最常见的神经退行性疾病，也是导致痴呆的主要原因 在老年人中。目前的治疗无法阻止疾病进展，强调了以下方面的重要性： 了解AD的病因学和病理生物学。城市空气污染严重， 与人类AD风险增加和淀粉样斑块负荷升高相关，但潜在的 机制知之甚少。臭氧（O3）是城市空气污染的一种活性气体成分， 增加AD风险，但吸入后仅限于呼吸道，暗示外周 AD神经病理学中对空气污染免疫反应小胶质细胞，在骨髓中的常驻实质髓样细胞， 据报道，大脑是AD神经病理学的关键介质，但最近的证据也支持 外周免疫细胞，如中性粒细胞的潜在作用。然而，这些骨髓细胞如何成为 AD中的病理失调在很大程度上未知。我们之前已经证明，吸入O3会触发 促炎性肺免疫应答与持续性神经免疫应答相关， 小鼠和大鼠。O3吸入如何影响正常生理过程中和 对正在进行的AD过程知之甚少。肺-脑轴假说认为， 吸入性环境暴露的后果部分地使神经免疫反应失调， 外周免疫细胞的变化，以增加中枢神经系统疾病的病理，关键的概念，我们提出， 直接在这里测试。我们假设O3暴露引起神经免疫改变并加重Aβ 通过外周免疫细胞运输的神经病理学和CXCR 2和VEGF是主要的机制， 这个过程因此，我们的目标是：1）确定CXCR 2在O3诱导的神经免疫中的作用。 2）检查CXCR 2在O3诱导的小胶质斑块缔合损伤中的作用， 增强淀粉样蛋白神经病理学; 3）证实VEGF在O3诱导的β-淀粉样蛋白增加中的作用。 淀粉样蛋白神经病理学和神经毒性。这些发现将揭示关键机制（外周免疫 细胞/中性粒细胞运输，CXCR 1和VEGF）在肺-脑轴负责如何外周 免疫区室影响大脑并增强AD过程，确定减轻AD的关键机会 AD神经病理学