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

项目总结 阿尔茨海默病(AD)是最常见的神经退行性疾病，也是痴呆的主要原因 在老年人身上。目前的治疗方法无法阻止疾病的进展，强调了 了解阿尔茨海默病的病因和病理生物学。严重的城市空气污染一直是 与人类AD风险增加和淀粉样斑块负荷增加有关，但潜在的 人们对这一机制知之甚少。臭氧(臭氧)是城市空气污染中的一种活性气体成分，与 增加AD的风险，但吸入后仅限于呼吸道，这意味着外周的作用 AD神经病理学中对空气污染的免疫反应。小胶质细胞，驻留在脑内的实质髓系细胞 据报道，大脑是AD神经病理的关键媒介，但最近的证据也支持 外周免疫细胞的潜在作用，如中性粒细胞。然而，这些髓系细胞是如何变成 阿尔茨海默病的病理异常在很大程度上是未知的。我们之前已经证明，吸入臭氧会触发 与持续性神经免疫反应相关的促炎性肺免疫反应 老鼠和老鼠。臭氧吸入如何影响正常生理状态下的神经免疫反应 人们对正在进行的AD过程知之甚少。肺-脑轴假说认为，肺 吸入环境暴露的后果部分地通过以下途径失调神经免疫反应 外周免疫细胞改变以增强中枢神经系统疾病的病理，我们提出的关键概念 直接在这里测试。我们假设，接触臭氧会引起神经免疫变化并加剧Aβ 外周免疫细胞转运的神经病理以及CXCR2和VEGF是脑出血的主要机制 这一过程。因此，我们的目标是：1)明确CXCR2在臭氧诱导的神经免疫中的作用 2)检测CXCR2在臭氧诱导的小胶质细胞斑块联合损伤中的作用 淀粉样蛋白神经病理增强；3)证实血管内皮细胞生长因子在臭氧诱导的β细胞增强中的作用 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和血管内皮生长因子)在肺-脑轴中如何负责外周 免疫隔膜影响大脑并增强AD过程，识别关键机会以缓解 AD神经病理学。

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.