Induction of ferroptotic and amyloidogenic signatures linked to Alzheimer's disease by chemically distinct air pollutants
11 affiliations
- 1Keck School of Medicine of the University of Southern California, 1975 Zonal Ave, Los Angeles, CA, 90033, USA
- 2Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA; Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
- 3Leonard Davis School of Gerontology, University of Southern California, 3715 McClintock Ave, Los Angeles, CA, 90089, USA
- 4Viterbi School of Engineering, University of Southern California, Los Angeles, CA, 90089, USA
- 5Department of Family Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA
- 6Department of Biological Sciences, Mississippi State University, Starkville, MS, 39762, USA
- 7Population and Public Health Sciences, Keck School of Medicine of the University of Southern California, 1975 Zonal Ave, Los Angeles, CA, 90033, USA
- 8Department of Medicine, New York University Grossman School of Medicine, New York, NY, 10016, USA
- 9College of Pharmacy, University of New Mexico, Albuquerque, NM, 87106, USA
- 10Leonard Davis School of Gerontology, University of Southern California, 3715 McClintock Ave, Los Angeles, CA, 90089, USA; Dornsife College, University of Southern California, 3551 Trousdale Pkwy, Los Angeles, CA, 90089, USA
- 11Leonard Davis School of Gerontology, University of Southern California, 3715 McClintock Ave, Los Angeles, CA, 90089, USA; Corresponding author. Leonard Davis School of Gerontology University of Southern California, 3715 McClintock Ave 313D, Los Angeles, CA, 90089, USA.
Abstract
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.
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BibTeX
@article{shkirkova2026induction,
title = {{Induction of ferroptotic and amyloidogenic signatures linked to Alzheimer's disease by chemically distinct air pollutants}},
author = {Kristina Shkirkova and Naomi S. Sta Maria and Herbert Anson and Yashar Aghaei and Mohammad Mahdi Badami and Ararat Chakhoyan and Jose A. Godoy-Lugo and Claire Chung and Salma Durra and Angela Tang-Tan and Lifu Zhao and Alexandra Demetriou and Manuel Morales and Sindhu Daggupati and Isabella Bent and Hyoungjin Park and Caleb Franklin and Selena Chen and Giovanni Chahine and Skyye Dodds-Lewis and Masako Morishita and Russell E. Jacobs and Jean-François Gout and Wendy J. Mack and Henry Jay Forman and Bérénice A. Benayoun and Marc Vermulst and Mitchell D. Cohen and Matthew Campen and Constantinos Sioutas and William J. Mack and Caleb E. Finch and Max A. Thorwald},
journal = {Redox Biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104390},
url = {https://doi.org/10.1016/j.redox.2026.104390},
note = {CC BY},
}
RIS
TY - JOUR
TI - Induction of ferroptotic and amyloidogenic signatures linked to Alzheimer's disease by chemically distinct air pollutants
AU - Kristina Shkirkova
AU - Naomi S. Sta Maria
AU - Herbert Anson
AU - Yashar Aghaei
AU - Mohammad Mahdi Badami
AU - Ararat Chakhoyan
AU - Jose A. Godoy-Lugo
AU - Claire Chung
AU - Salma Durra
AU - Angela Tang-Tan
AU - Lifu Zhao
AU - Alexandra Demetriou
AU - Manuel Morales
AU - Sindhu Daggupati
AU - Isabella Bent
AU - Hyoungjin Park
AU - Caleb Franklin
AU - Selena Chen
AU - Giovanni Chahine
AU - Skyye Dodds-Lewis
AU - Masako Morishita
AU - Russell E. Jacobs
AU - Jean-François Gout
AU - Wendy J. Mack
AU - Henry Jay Forman
AU - Bérénice A. Benayoun
AU - Marc Vermulst
AU - Mitchell D. Cohen
AU - Matthew Campen
AU - Constantinos Sioutas
AU - William J. Mack
AU - Caleb E. Finch
AU - Max A. Thorwald
PY - 2026
DA - 2026/10/30
JO - Redox Biology
DO - 10.1016/j.redox.2026.104390
UR - https://doi.org/10.1016/j.redox.2026.104390
AB - 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.
SN - 2213-2317
ER -