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

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。年迈的退伍军人面临患AD的额外风险，目前的治疗无法停止 疾病的发展。炎症、氧化应激和小胶质细胞激活是关键因素。 推动AD患者进行性神经元损伤，但病理神经免疫过程如何发生仍是一个 争论的焦点。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的风险，但潜在的 机制尚不清楚。许多美国退伍军人暴露在高水平的空气污染中，包括臭氧， 无论是在服役期间还是在返回后的城市环境中。关于空气如何存在机械论的争议 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不依赖于启动神经免疫反应的传统细胞因子。 增强中枢神经系统疾病，尤其是阿尔茨海默病。实验动物研究记录了小胶质细胞的激活， 正常大鼠和小鼠早期类AD神经病理的证据及类AD的增强 阿尔茨海默病小鼠模型对臭氧反应的神经病理学。重要的是，由于化学反应，臭氧不能 通过肺之外，直接与脑实质相互作用。我们最近的报告表明，臭氧 暴露会导致未知的外周来源的循环信号，启动持续性小胶质细胞 体内激活，增强体外小胶质细胞的促炎反应，并增强Aβ42诱导的 体外神经毒性，不依赖于传统的循环细胞因子。我们的初步数据显示HMGB1为 肺-脑轴中的一个关键循环因子，对臭氧的反应是增强小胶质细胞的激活和 阿尔茨海默病样神经病理的初步研究。在这里，我们假设接触臭氧会导致循环 HMGB1，然后引起神经炎症，影响AD样神经病理。因此，我们的具体情况 目的是：1)评估HMGB1在臭氧诱导的神经炎症和AD样神经病理中的作用；2) 明确髓系细胞在臭氧诱导的神经炎症和AD样神经病理中的作用；3)表征 臭氧诱导的神经炎症的血管调节。这些发现将揭示关键的机制， 肺-脑轴负责臭氧和肺损伤如何有害地影响AD的中枢神经系统健康， 为干预和减轻退伍军人阿尔茨海默病的病理改变创造关键的机会。

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.