Comparing effects of gaseous vs. particulate components of traffic-related air pollution on Alzheimer’s disease biomarkers in a genetically susceptible rat model

Abstract

Epidemiological data link traffic-related air pollution (TRAP) to increased risk of Alzheimer’s disease (AD) and AD-related dementia (ADRD), and while experimental animal studies corroborate this association, most utilized exposure paradigms that failed to recapitulate the complexity of current, real-world TRAP exposure. Furthermore, the specific components of TRAP that promote AD pathogenesis remain unknown. This study assesses AD-relevant pathology in a transgenic rat model of AD (TgF344-AD) following chronic exposure to the gas phase vs. particulate matter (PM) components of TRAP in emissions from light-duty only (LDV) vs. combined light- and heavy-duty (LDV+HDV) vehicles. Male and female TgF344-AD rats were transported to the Caldecott Tunnel Exposure Facility (CTEF) at 1 month of age after being randomly assigned to one of six exposure groups: (1) filtered air (FA), (2) LDV+HDV gases only; (3) LDV PM only; (4) LDV+HDV PM only; (5) LDV PM and gases; and (6) LDV+HDV PM and gases. AD-relevant endpoints were quantified in 4-, 9-, 12-, and 15- month-old animals. Cortical Aβ levels at the 4, 9, and 15-month timepoints were significantly influenced by sex-by-exposure interactions. Amyloid plaque accumulation in the entorhinal cortex and hippocampus exhibited significant sex-dependent effects at 9 and 12 months so males and females were analyzed separately across all timepoints. At 9 months, females exposed to LDV+HDV PM had increased amyloid plaques in the hippocampus, and at 15 months, both females and males exposed to LDV PM and females exposed to LDV PM and gases exhibited significantly increased plaque levels in the entorhinal cortex. The rate of plaque accumulation over all four time points was accelerated in the entorhinal cortices of both sexes exposed to LDV and LDV+HDV PM alone or in combination with gases. There were no exposure effects on phosphorylated tau or Thioflavin S staining; however, the rate of neuronal cell loss with increasing age was significantly increased by exposure to LDV emissions in both females and males. Collectively, these findings demonstrate that chronic exposure to ambient TRAP in real-time promoted AD-relevant outcomes in the TgF344-AD rat with effects that varied according to age, sex, and brain region. TRAP effects occurred more prominently in groups exposed to LDV PM. Further research is needed to determine the mechanism(s) by which sex-dependent TRAP effects exacerbate AD pathogenesis so that effective interventions can be developed to improve the health of the aging brain.