Induction of ferroptotic and amyloidogenic signatures linked to Alzheimer's disease by chemically distinct air pollutants.

Air pollution (AirP) exposure is associated with increased risk of Alzheimer's disease (AD), yet AirP is chemically heterogeneous, complicating identification of shared pathogenic drivers. We compared acute cortical responses to two chemically distinct but metal-rich AirP sources, diesel exhaust particles (DEP) and World Trade Center (WTC) dust, and contrasted them with woodsmoke (WS), a particulate exposure containing substantially lower metal content. Despite major differences in particle composition and size, DEP and WTC elicited highly convergent transcriptomic responses, sharing more than 1200 differentially expressed genes associated with oxidative stress, interferon signaling, ferroptosis, neuronal remodeling, and amyloid processing. These transcriptional changes were accompanied by disrupted glutathione synthesis, altered ferritin-mediated iron storage and heme metabolism, and selective impairment of lipid raft antioxidant defenses, resulting in a 40% increase in lipid raft 4-hydroxynonenal (HNE) with WTC dust with DEP trending similarly, and at least a 65% reduction in phospholipid hydroperoxide detoxification capacity, and 36% increase in the aggregation-prone Aβ42 peptide for both pollution sources. Notably, both exposures produced acute white-matter abnormalities within the corpus callosum despite the absence of bulk brain iron accumulation, indicating that redistribution of bioactive iron rather than total iron burden may be sufficient to promote oxidative injury. In contrast, WS produced a distinct transcriptional profile, lacked coordinated ferroptotic priming, failed to induce lipid peroxidation or Aβ42 accumulation, and showed minimal effects on iron metabolism. Together, these findings identify metal-associated oxidative mechanisms as a convergent pathway linking chemically distinct forms of AirP to ferroptotic vulnerability, amyloidogenic processing, and AD-relevant pathology.