Abstract
Exposure to air pollutants, including particulate matter, results in activation of the brain inflammatory response and Alzheimer disease (AD)-like pathology in dogs and humans. However, the length of time required for inhalation of ambient particulate matter to influence brain inflammation and AD pathology is less clear. Here, we studied the effect of 3 and 9 months of air particulate matter (<2.5 μm diameter, PM2.5) exposure on brain inflammatory phenotype and pathological hallmarks of AD in C57BL/6 mice. Using western blot, ELISA, and cytokine array analysis we quantified brain APP, beta-site APP cleaving enzyme (BACE), oligomeric protein, total Aβ 1–40 and Aβ 1–42 levels, inducible nitric oxide synthase (iNOS), nitrotyrosine-modified proteins, HNE-Michael adducts, vascular cell adhesion molecule 1 (VCAM-1), glial markers (GFAP, Iba-1), pre- and post- synaptic markers (synaptophysin and PSD-95), cyclooxygenase (COX-1, COX-2) levels, and the cytokine profile in PM2.5 exposed and filtered air control mice. Only 9 month PM2.5 exposure increased BACE protein levels, APP processing, and Aβ 1–40 levels. This correlated with a concomitant increase in COX-1 and COX-2 protein levels and a modest alteration in the cytokine profile. These data support the hypothesis that prolonged exposure to airborne particulate matter has the potential to alter brain inflammatory phenotype and promote development of early AD-like pathology.
Highlights
Alzheimer’s disease (AD) is a progressive dementia characterized by altered processing of amyloid precursor protein (APP), formation of beta-amyloid plaques (Aβ), hyper-phosphorylated tau containing neurofibrillary tangles, and synaptic loss in the brain
These changes correlated with increases in COX-1, COX-2, and PSD-95 protein levels and a modest increase in the chemotactic cytokine profile
These data demonstrated that a modest increase in the chemotactic cytokine profile and Aβ levels in 9 month PM2.5 exposure brains correlated with increased levels of the prostaglandin producing enzymes, COX-1 and COX-2. In this pilot study we demonstrated that long-term exposure to ambient airborne particulate matter modestly increased cytokine, Aβ, and COX-1/2 levels associated with early AD-like doi:10.1371/journal.pone.0127102.g009
Summary
Alzheimer’s disease (AD) is a progressive dementia characterized by altered processing of amyloid precursor protein (APP), formation of beta-amyloid plaques (Aβ), hyper-phosphorylated tau containing neurofibrillary tangles, and synaptic loss in the brain. 5.3 million Americans with AD [1] and this number is expected to rise to 13.8 million by 2050 [2]. During 1979–2010, while the total mortality in the U.S decreased, the total number of deaths resulting from AD increased by 68% during 2000–2010 [3]. From all the known risk factors, advancing age is the greatest risk factor for AD. This inconsistent rise in AD-related deaths cannot be explained by an overall increase in the aging population. There is a need to seek putative risk factors that can provide measurable association with disease pathology but can be modulated at the population level
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