Inhalation of Distinct Emission Components Comprising Traffic-Related Air Pollution Elicits Sex-Specific Effects on Pulmonary and Systemic Inflammation in the TgF344-AD Transgenic Rat Model of Alzheimer’s Disease

Abstract Air pollution is associated with not only respiratory but also neurodegenerative diseases, such as Alzheimer’s disease (AD). While underlying mechanisms remain unclear, the lung–brain axis has been proposed as a potential pathway in which pulmonary inflammation triggered by air pollution promotes systemic inflammation, which in turn triggers neuroinflammation to promote AD pathogenesis. This study defines chronic effects of ambient traffic-related air pollution (TRAP) and the contribution of TRAP-derived particulate matter (PM) vs gases, on peripheral inflammation in a transgenic rat model of AD. Female and male TgF344-AD rats that overexpress human AD risk genes were exposed for 3 months to TRAP drawn directly from a major freeway tunnel in Northern California, USA and delivered in real-time to animals housed in an exposure facility adjacent to the tunnel. Animals were exposed to filtered air, unfractionated TRAP (PM + Gas), or TRAP fractionated into PM-only or gas-only in the emissions of either a combination of light- and heavy-duty vehicles (LDV + HDV) or LDV-only. Our assessment of inflammatory mediators in the plasma and lung revealed sex- and component-specific TRAP effects. Overall, TgF344-AD females developed type 1 systemic inflammation in response to PM(LDV + HDV), while TgF344-AD males developed pulmonary type 1 inflammation and exhibited stronger type 2 adaptations, largely driven by exposure to Gas(LDV + HDV). Transgenic males had substantial increases in circulating HMGB1, but unchanged pulmonary HMGB1, across all TRAP exposures, whereas transgenic females had no changes in circulating HMGB1 but elevated pulmonary HMGB1 in the PM + Gas(LDV + HDV) group. While we expected synergistic or additive effects of PM and gas components on biological outcomes, we observed distinct inflammatory profiles for each component. Exposure to PM or gas fractions of TRAP induced more robust biological responses than the combined exposure to PM + Gas. These findings highlight the importance of studying the interactions of emission source-, pollutant type-effects of TRAP by sex on inflammation to understand multi-organ responses.