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.

阿尔茨海默病 (AD) 是最常见的神经退行性疾病，也是痴呆症的主要原因 老年退伍军人面临着罹患AD的额外风险，而目前的治疗无法停止。 炎症、氧化应激和小胶质细胞激活是疾病进展的关键因素。 导致 AD 中进行性神经元损伤，但病理性神经免疫过程如何发生仍然是一个谜 越来越多的研究也指出了环境在 AD 中的作用。 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 许多美国退伍军人都暴露在高浓度的空气污染中，其中包括 O3、 无论是在服役期间还是在返回后的城市环境中，都存在关于空气如何运行的机械争议。 肺脑轴假说认为，污染会影响大脑。 污染物引起独立于传统细胞因子的循环信号，从而引发神经免疫反应 增强中枢神经系统疾病，特别是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 AD 样神经病理学的证据，以及 AD 样增强 AD 小鼠模型对 O3 的神经病理学研究 重要的是，由于化学反应，O3 无法发挥作用。 我们最近的报告表明，O3 可以穿过肺部直接与脑实质相互作用。 暴露会导致未知的外周衍生循环信号，从而启动持续性小胶质细胞 体内激活，增强离体小胶质细胞促炎症反应，并增强 Aβ42 诱导的 我们的初步数据表明 HMGB1 具有离体神经毒性，与传统的循环细胞因子无关。 肺脑轴中的一个关键循环因子，对 O3 做出反应，增强小胶质细胞的激活和 AD 样神经病理学的初步测量在这里，我们追求 O3 暴露导致循环。 HMGB1，然后引起神经炎症并影响类似 AD 的神经病理学。 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) 定义骨髓细胞在 O3 诱导的神经炎症和 AD 样神经病理学中的作用 3) 表征； 这些发现将揭示 O3 诱导的神经炎症的关键机制。 肺脑轴负责 O3 和肺部损伤如何对 AD 中的中枢神经系统健康产生有害影响， 为干预和减轻患有 AD 的退伍军人的病理状况创造重要机会。