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）是最普遍的神经退行性疾病，也是痴呆症的主要原因