The Effects of Chronic Exposure to Ambient Traffic-Related Air Pollution on Alzheimer’s Disease Phenotypes in Wildtype and Genetically Predisposed Male and Female Rats

Abstract

Background: Epidemiological data link traffic-related air pollution (TRAP) to increased risk of Alzheimer’s disease (AD). Preclinical data corroborating this association are largely from studies of male animals exposed acutely or subchronically to high levels of isolated fractions of TRAP. What remains unclear is whether chronic exposure to ambient TRAP modifies AD risk and the influence of sex on this interaction. Objectives: This study sought to assess effects of chronic exposure to ambient TRAP on the time to onset and severity of AD phenotypes in a preclinical model and to determine whether sex or genetic susceptibility influences outcomes. Methods: Male and female TgF344-AD rats that express human AD risk genes and wildtype littermates were housed in a vivarium adjacent to a heavily trafficked tunnel in Northern California and exposed for up to 14 months to filtered air (FA) or TRAP drawn from the tunnel and delivered to animals unchanged in real time. Refractive particles in the brain and AD phenotypes were quantified in 3-, 6-, 10-, and 15-month-old animals using hyperspectral imaging, behavioral testing, and neuropathologic measures. Results: Particulate matter (PM) concentrations in TRAP exposure chambers fluctuated with traffic flow but remained below 24-h PM with aerodynamic diameter less than or equal to 2.5 micrometers ( ) U.S. National Ambient Air Quality Standards limits. Ultrafine PM was a predominant component of TRAP. Nano-sized refractive particles were detected in the hippocampus of TRAP animals. TRAP-exposed animals had more amyloid plaque deposition, higher hyperphosphorylated tau levels, more neuronal cell loss, and greater cognitive deficits in an age-, genotype-, and sex-dependent manner. TRAP-exposed animals also had more microglial cell activation, but not astrogliosis. Discussion: These data demonstrate that chronic exposure to ambient TRAP promoted AD phenotypes in wildtype and genetically susceptible rats. TRAP effects varied according to age, sex, and genotype, suggesting that AD progression depends on complex interactions between environment and genetics. These findings suggest current regulations are insufficient to protect the aging brain. https://doi.org/10.1289/EHP8905

Aryl Hydrocarbon Receptor Signaling Synergizes with TLR/NF-κB-Signaling for Induction of IL-22 Through Canonical and Non-Canonical AhR Pathways

“…The Caldecott Tunnel Exposure Facility (CTEF) is located immediately adjacent to a major freeway tunnel system in the San Francisco Bay Area and facilitates chronic exposure studies on TRAP ( Patten et al, 2020 ; Patten et al, 2021 ; Edwards et al, 2020 ). Emissions are drawn directly from the tunnel and delivered unaltered in real-time to onsite exposure chambers.…”

Chronic exposure to ambient traffic-related air pollution (TRAP) alters gut microbial abundance and bile acid metabolism in a transgenic rat model of Alzheimer’s disease

“…Male and female Tg344-AD (TG) rats that overexpress the human mutant amyloid precursor protein (APPSW) and presenilin 1 (PS1ΔE9)) transgenes, and age-matched WT rats were housed in TRAP or FA exposure chambers beginning at postnatal day 28 and continuing for up to 14 months as described previously [91] .…”

“…A transgenic model of AD, the TgF344-TG rat, expresses both mutant human amyloid precursor protein (APP) and presenilin 1 (PS1ΔE9) genes and manifests signs with face validity to early onset of familial AD [29] . We recently characterized the effect of traffic-related air pollution (TRAP) on AD-relevant neuropathology in this TG rat model and wildtype rats [91] . We observed that TRAP increased amyloid plaque deposition, hyperphosphorylated tau levels, neuronal cell loss, microglial cell activation, and cognitive deficits in an age-, sex-, and host genotype-specific manner.…”

Air Pollution Particulate Matter Amplifies White Matter Vascular Pathology and Demyelination Caused by Hypoperfusion

“…Environmental and lifestyle factors modify the risk of neurodegenerative diseases. Population-based studies strongly associate elevated levels of air pollution particulate matter with reduced brain white matter regional volumes (4)(5)(6)(7)(8). Additionally, experimental studies with mice show harmful effects of particulate matter (PM) on both corpus callosum white matter and hippocampus (7)(8)(9)(10).…”

“…Population-based studies strongly associate elevated levels of air pollution particulate matter with reduced brain white matter regional volumes (4)(5)(6)(7)(8). Additionally, experimental studies with mice show harmful effects of particulate matter (PM) on both corpus callosum white matter and hippocampus (7)(8)(9)(10). The joint effects of underlying health conditions and environmental exposures are understudied.…”