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.

项目概要 阿尔茨海默病 (AD) 是最常见的神经退行性疾病，也是痴呆症的主要原因 在老年人中，目前的治疗无法阻止疾病进展，强调了这一点的重要性。 了解 AD 的病因学和病理学。 与人类 AD 风险增加和淀粉样斑块负荷升高相关，但潜在的 臭氧 (O3) 是城市空气污染的一种活性气体成分，其机制尚不清楚。 AD 风险增加，但吸入后仅限于呼吸道，暗示外周血管的作用 AD 神经病理学中对空气污染的免疫反应。 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（例如中性粒细胞）的潜在作用然而，这些骨髓细胞如何变成。 AD 中的病理失调在很大程度上是未知的。我们之前已经表明，吸入 O3 会引发疾病。 促炎性肺部免疫反应与持续的神经免疫反应相关 小鼠和大鼠吸入 O3 如何影响正常生理过程中的神经免疫反应 人们对正在进行的 AD 过程知之甚少。 吸入环境暴露的后果部分是通过调节神经免疫反应 外周免疫细胞的变化可增强中枢神经系统疾病病理学，这是我们提出的关键概念 我们在这里直接测试，O3 暴露会导致神经免疫变化和 Aβ 恶化。 CXCR2 和 VEGF 是通过外周免疫细胞运输进行神经病理学的主要机制 因此，我们的目标是：1) 定义 CXCR2 在 O3 诱导的神经免疫中的作用。 2) 检查 CXCR2 在 O3 诱导的小胶质细胞斑块关联损伤中的作用； 淀粉样蛋白神经病理学的增强；3) 确认 VEGF 在 O3 诱导的 β 增强中的作用 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、CXCR1 和 VEGF）在肺脑轴中负责外周 免疫区室影响大脑并增强 AD 过程，识别缓解的关键机会 AD 神经病理学。