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

O3 和肺脑轴：调节阿尔茨海默病样神经病理学

• 批准号: 9898298
• 负责人: Michelle L Block
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898298
• 关键词: 3xTg-AD mouse; Affect; Aging; Air Pollution; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-42; Amyloid beta-Protein; Animals; Antibodies; Automobile Driving; Blood Circulation; Blood Vessels; Blood capillaries; Brain; Cells; Central Nervous System Diseases; Chemicals; Chemistry; Data; Dementia; Disease Progression; Elderly; Environment; Exposure to; Face; Glycyrrhizic Acid; HMGB1 gene; Health; Health system; Homeostasis; ITGAM gene; Impaired cognition; Impairment; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Injury; Link; Lung; Measures; Memory impairment; Microglia; Mus; Myeloid Cells; Neuraxis; Neurodegenerative Disorders; Neuroimmune; Neuroimmunomodulation; Neurons; Oxidative Stress; Pathologic; Pathology; Peripheral; Production; Rattus; Regulation; Reporting; Research; Risk; Role; Services; Signal Transduction; Source; Testing; Vascular Endothelium; Veterans; blood-brain barrier function; brain endothelial cell; brain parenchyma; cerebral capillary; cerebrovascular; cognitive function; cytokine; improved; in vivo; inhibitor/antagonist; lung injury; mouse model; neuroinflammation; neuropathology; neurotoxicity; ozone exposure; pollutant; receptor; response; tropospheric ozone

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.

阿尔茨海默氏病（AD）是最普遍的神经退行性疾病，是痴呆症的主要原因 在过去。老年退伍军人面临开发AD和当前治疗的额外风险 疾病进展。炎症，氧化应激和小胶质细胞激活作为关键因素 在AD中驱动渐进性神经元损害，但是病理神经免疫性过程仍在 辩论点。越来越多的研究还表明了环境在AD中的作用。新研究表明 城市空气污染的暴露，包括地面臭氧（O3），可能会提高AD风险，但基础 机制是未知的。许多美国退伍军人受到升高的空气污染水平，包括O3， 在返回时，在服务期间和城市环境中。关于空气的方式存在机理争议 污染会影响大脑。肺脑轴假说认为遗传造成肺部损伤 污染物引起循环信号，独立于传统细胞因子，这是神经免疫反应的基础 增加CNS病，特别是AD。实验动物研究记录小胶质激活， 正常大鼠和小鼠的早期广告样神经病理学的证据，以及类似广告的增强 AD小鼠模型中的神经病理学响应O3。重要的是，由于反应性化学，O3无法 超越肺部以直接与脑实质相互作用。我们最近的报告表明O3 暴露会导致未知和周围衍生的循环信号，启动持续的小胶质细胞 在体内激活，增强了小胶质细胞促炎反应，并增强了Aβ42诱导的 神经毒性离体，与传统循环细胞因子无关。我们的初步数据将HMGB1视为 肺脑轴的关键循环因素，并响应O3，增强了小胶质激活和 广告样神经病理学的初步测量。在这里，我们假设O3暴露会导致循环 HMGB1，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HMGB1对O3诱导的神经炎症和AD样神经病理学的作用； 2） 定义髓样细胞在O3诱导的神经炎症和AD样神经病理学中的作用； 3）特征 O3诱导的神经炎症的血管调节。这些发现将揭示定义的关键机制 肺脑轴负责O3和肺损伤如何影响AD中的CNS健康， 创造关键的机会来干预和减轻AD退伍军人的病理学。