Air Pollution Exposure and the Lung-Brain Axis: Implications for Alzheimer's Disease

Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disease that is expected to affect approximately 6.2 million Americans. Despite its high prevalence, the mechanisms underlying AD remain poorly understood. In recent years, increasing reports indicate that exposure to urban air pollution is a risk factor for the development of AD. However, the mechanistic underpinnings of this association are not well studied. Rats exposed to diesel exhaust (DE) showed neuroinflammation and impaired expression of TREM2 and disease-associated microglia (DAM), a cell subtype hypothesized to play beneficial roles during neurodegeneration, markers. Microglia in the cortex of rats exposed to DE, also showed decreased association with the vasculature, providing a novel link between the microglia and the brain vasculature. Examining the functional role of TREM2 during DE exposures, Trem2-/- mice showed an altered pro-inflammatory profile in both the brain and lungs in response to DE particles as well as altered phagocytic oxidase related gene expression. Examining another prominent component of air pollution, ozone (O3), in a mouse model of AD, it was discovered that subchronic O3 exposure exacerbates amyloid pathology through impaired microglial-plaque association in 5xFAD mice. 5xFAD mice exposed to O3 also showed increased expression of pro-inflammatory cytokines, increased markers of dystrophic neurites, and decreased expression of key acetylcholinergic pathway components. Examining the peri-plaque microenvironment, it was discovered that O3 dysregulates key DAM proteins and amyloid processing proteins. In the lung, it was found that O3 exacerbated immune cell infiltration in 5xFAD mice compared to WT controls, suggesting that ongoing amyloid pathology regulates pulmonary immune response to air pollution. To examine how O3-induced pulmonary immune responses may be signaling to the CNS, we examined the serum of 5xFAD mice, where HMGB1, VEGF, and IL-9 were upregulated. Injection of rHMGB1 into mice showed similar gene changes to 5xFAD mice exposed to O3, along with impaired Trem2 expression. Using a peripheral myeloid specific knock-out model of HMGB1, we also show that HMGB1 regulates O3-induced Trem2 expression impairment. Taken together, these data support that air pollution exposure impairs TREM2, DAM cells, and the microglial plaque response through a bidirectional lung-brain axis to exacerbate AD-like pathology.