The Role of Peripheral Immune Cell Trafficking in Ozone-Induced Alzheimer's Disease Neuropathology

点击翻译按钮获取中文摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease and the leading cause of dementia in the elderly. Current treatment is unable to halt disease progression, emphasizing the importance of understanding the etiology and pathobiology underlying AD. High levels of urban air pollution have been associated with increased AD risk and elevated amyloid plaque load in humans, but the underlying mechanisms are poorly understood. Ozone (O3), a reactive gas component of urban air pollution, is linked to increased AD risk, but confined to the respiratory tract after inhalation, implicating a role for the peripheral immune response to air pollution in AD neuropathology. Microglia, the resident parenchymal myeloid cells in the brain, are reported to be key mediators of AD neuropathology, but recent evidence also supports a potential role for peripheral immune cells, such as neutrophils. Yet, how these myeloid cells become pathologically dysregulated in AD is largely unknown. We have previously shown that O3 inhalation triggers a pro-inflammatory pulmonary immune response that is associated with a persistent neuroimmune response in mice and rats. How O3 inhalation affects the neuroimmune response during normal physiology and during ongoing AD processes is poorly understood. The Lung-Brain Axis hypothesis holds that the pulmonary consequences of inhaled environmental exposures dysregulates the neuroimmune response in part, through peripheral immune cell changes to augment CNS disease pathology, critical concepts that we propose to directly test here. We hypothesize that O3 exposure causes neuroimmune changes and exacerbates Aβ neuropathology via peripheral immune cell trafficking and that CXCR2 and VEGF are primary mechanisms in this process. As such, our aims are to: 1) Define the role of CXCR2 in the O3-induced neuroimmune response; 2) Examine the role of CXCR2 in the O3-induced impairment of microglial plaque association and augmentation of amyloid neuropathology; 3) Confirm the role of VEGF in O3-induced augmentation of beta amyloid neuropathology and neurotoxicity. These findings will reveal key mechanisms (peripheral immune cell/neutrophil trafficking, CXCR1, and VEGF) in the Lung-Brain Axis responsible for how the peripheral immune compartment affects the brain and augments AD processes, identifying key opportunities to mitigate AD neuropathology.