Exposure to vehicle emissions results in altered blood brain barrier permeability and expression of matrix metalloproteinases and tight junction proteins in mice

Abstract

BackgroundTraffic-generated air pollution-exposure is associated with adverse effects in the central nervous system (CNS) in both human exposures and animal models, including neuroinflammation and neurodegeneration. While alterations in the blood brain barrier (BBB) have been implicated as a potential mechanism of air pollution-induced CNS pathologies, pathways involved have not been elucidated.ObjectivesTo determine whether inhalation exposure to mixed vehicle exhaust (MVE) mediates alterations in BBB permeability, activation of matrix metalloproteinases (MMP) -2 and −9, and altered tight junction (TJ) protein expression.MethodsApolipoprotein (Apo) E−/− and C57Bl6 mice were exposed to either MVE (100 μg/m3 PM) or filtered air (FA) for 6 hr/day for 30 days and resulting BBB permeability, expression of ROS, TJ proteins, markers of neuroinflammation, and MMP activity were assessed. Serum from study mice was applied to an in vitro BBB co-culture model and resulting alterations in transport and permeability were quantified.ResultsMVE-exposed Apo E−/− mice showed increased BBB permeability, elevated ROS and increased MMP-2 and −9 activity, compared to FA controls. Additionally, cerebral vessels from MVE-exposed mice expressed decreased levels of TJ proteins, occludin and claudin-5, and increased levels of inducible nitric oxide synthase (iNOS) and interleukin (IL)-1β in the parenchyma. Serum from MVE-exposed animals also resulted in increased in vitro BBB permeability and altered P-glycoprotein transport activity.ConclusionsThese data indicate that inhalation exposure to traffic-generated air pollutants promotes increased MMP activity and degradation of TJ proteins in the cerebral vasculature, resulting in altered BBB permeability and expression of neuroinflammatory markers.

Serum-borne bioactivity caused by pulmonary multiwalled carbon nanotubes induces neuroinflammation via blood–brain barrier impairment

“…Rats exposed to diesel emissions for 6 mo demonstrated significant increases in cortical TNFα, α-synuclein, and amyloid-β42 peptide expression (36). Oppenheim et al (37) identified significant increases in brain fluorescein uptake resulting from long-term exposure (50 d) to a mixture of gasoline and diesel emissions in ApoE −/− mice. These findings were associated with increased cerebrovascular gelatinase levels and reduced occludin and claudin-5 expression and, in parallel, increased inducible nitric oxide synthase expression in the brain parenchyma.…”

Microglial priming through the lung—brain axis: the role of air pollution‐induced circulating factors

“…Although the specific serum components that enter the brain parenchyma are undetermined, blood—brain barrier permeability is notably impaired in aging (65), by neurodegenerative diseases (66), and by air pollution exposure (67), which facilitates entry of aberrant circulating factors into the brain and optimizes the opportunity of serum factors to interact with microglia. In fact, peripheral circulating cytokines are the first candidates implicated in how peripheral damage regulates the brain (52), particularly microglial priming (68).…”

Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease

“…In mouse experimental studies, aerosolized nickel nanoparticles caused a rapid and drastic increase in Aβ40 and Aβ42 [154]. Also, APOE null mice exposed to mixed vehicle exhaust have accelerated BBB breakdown, decreased expression of tight junction proteins (e.g., occludin, claudin-5) and increased generation of reactive oxygen species activity [155]. …”