O3 and the Lung-Brain Axis: Regulating Alzheimer's-like Neuropathology

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。老年退伍军人面临发展AD的额外风险，目前的治疗无法停止 疾病进展。炎症、氧化应激和小胶质细胞活化被认为是关键因素 在AD中驱动进行性神经元损伤，但病理性神经免疫过程如何发生仍然是一个问题。 辩论点。越来越多的研究也指出了环境在AD中的作用。新的研究表明， 城市空气污染暴露，包括地面臭氧（O3），可能会增加AD风险，但潜在的 机制不明。许多美国退伍军人暴露在高水平的空气污染中，包括O3， 无论是在服役期间还是在返回后的城市环境中。关于空气是如何 污染会影响大脑。肺-脑轴假说认为吸入性肺损伤 污染物引起的循环信号独立于传统的细胞因子，引发神经免疫反应 增加CNS疾病，特别是AD。实验动物研究记录了小胶质细胞活化， 在正常大鼠和小鼠中早期AD样神经病理学的证据，以及AD样神经病理学的增强。 AD小鼠模型中的神经病理学对O3的响应。重要的是，由于反应化学，O3无法 穿过肺部直接与脑实质接触。我们最近的报告表明，O3 暴露导致未知的和外周来源的循环信号，启动持续性小胶质细胞 激活，增强离体小胶质细胞促炎反应，并增强Aβ42诱导的 神经毒性离体，独立于传统的循环细胞因子。我们的初步数据表明HMGB 1是 肺-脑轴中的一种关键循环因子，对O3的反应是增强小胶质细胞活化， AD样神经病理学的初步测量。在这里，我们假设O3暴露导致循环 HMGB 1，然后引起神经炎症并影响AD样神经病理学。因此，我们的具体 目的是：1）评估HMGB 1在O3诱导的神经炎症和AD样神经病理中的作用; 2） 明确髓系细胞在O3诱导的神经炎症和AD样神经病理学中的作用; 3）表征 O3诱导的神经炎症的血管调节。这些发现将揭示定义 肺-脑轴负责O3和肺损伤如何有害地影响AD中的CNS健康， 创造关键的机会，干预和减轻病理退伍军人与AD。

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and the leading cause of dementia in the elderly. Aging veterans face additional risk for developing AD and current treatment is unable to halt disease progression. Inflammation, oxidative stress, and microglial activation are implicated as key factors driving progressive neuron damage in AD, but how the pathological neuroimmune process occurs remains a point of debate. Increasing studies also point to a role for the environment in AD. New research reveals that urban air pollution exposure, including ground level ozone (O3), may elevate AD risk, but the underlying mechanisms are unknown. Many US veterans are exposed to elevated levels of air pollution, including O3, both during service and in urban environments upon return. Mechanistic controversy exists regarding how air pollution can affect the brain. The Lung-Brain Axis hypothesis holds that pulmonary damage from inhaled pollutants causes circulating signals independent of traditional cytokines that prime the neuroimmune response to augment CNS disease, particularly AD. Experimental animal studies document microglial activation, evidence of early AD-like neuropathology in normal rats and mice, and augmentation of AD-like neuropathology in an AD mouse model in response to O3. Importantly, due to reactive chemistry, O3 is unable to pass beyond the lung to directly interact with the brain parenchyma. Our recent reports indicate that O3 exposure causes an unknown and peripherally-derived circulating signal that initiates persistent microglial activation in vivo, augments the microglial pro-inflammatory response ex vivo, and enhances Aβ42-induced neurotoxicity ex vivo, independent of traditional circulating cytokines. Our preliminary data implicate HMGB1 as a key circulating factor in the Lung-Brain Axis and in response to O3 that augments microglial activation and preliminary measures of AD-like neuropathology. Here, we hypothesize that O3 exposure results in circulating HMGB1, which then causes neuroinflammation and impacts AD-like neuropathology. As such, our specific aims are to: 1) Assess the role of HMGB1 on O3-induced neuroinflammation and AD-like neuropathology; 2) Define the role of myeloid cells in O3-induced neuroinflammation & AD-like neuropathology; 3) Characterize the vascular regulation of O3-induced neuroinflammation. These findings will reveal key mechanisms defining a Lung-Brain Axis responsible for how O3 and pulmonary damage deleteriously impacts CNS health in AD, creating critical opportunities to intervene and mitigate pathology in veterans with AD.