Traffic-Related Emissions Induce Angiotensin II-Dependent Oxidative Stress in the Hippocampus of ApoE-Null Male Mice

Traffic-related air pollution (TRAP) is known to contribute to oxidative stress in the central nervous system (CNS) and has been linked to increased risk of Alzheimer's disease (AD). Alterations in the renin-angiotensin system (RAS), specifically increased angiotensin II (Ang II) signaling via the angiotensin II type 1 (AT₁) receptor, are implicated in increased oxidative stress in the CNS via activation of NADPH oxidase (NOX). As exposure to TRAP may further elevate AD risk, we investigated whether exposure to inhaled mixed gasoline and diesel vehicle emissions (MVE) promotes RAS-dependent expression of factors that contribute to AD pathophysiology in an apolipoprotein E-deficient (ApoE^-/-) mouse model. Male ApoE^-/- mice (6-8 weeks old) on a high-fat diet were treated with either an ACE inhibitor (captopril, 4 mg/kg/day) or water and exposed to filtered air (FA) or MVE (200 µg PM/m³) for 30 days. MVE exposure elevated plasma Ang II, inflammation, and oxidative stress in the hippocampus, associated with increased levels of Aph-1 homolog B (APH1B), a gamma-secretase subunit, and beta-secretase 1 (BACE1), involved in Aβ production. Each of these endpoints was normalized with ACEi treatment. These findings indicate that TRAP exposure in ApoE^-/- mice drives a RAS- and NOX-dependent oxidative and inflammatory response and shifts Aβ processing towards an amyloidogenic profile before overt Aβ deposition, suggesting a potential therapeutic approach for air pollution-induced AD risk.