Leonard Davis School of Gerontology, University of Southern California, Los Angeles, United States
Mafalda Cacciottolo
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, United States
Kevin R Doty
Zilkha Neurogenetic Institute, Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, United States
Carla D'Agostino
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, United States
Max Thorwald
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, United States
Nikoo Safi
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, United States
Department of Pathology, Yale School of Medicine, New Haven, United States
Constantinos Sioutas
Department of Civil and Environmental Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, United States
Terrence C Town
Zilkha Neurogenetic Institute, Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, United States
Henry Jay Forman
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, United States
Hongqiao Zhang
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, United States
Todd E Morgan
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, United States
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, United States; Dornsife College, University of Southern California, Los Angeles, United States
The neurotoxicity of air pollution is undefined for sex and APOE alleles. These major risk factors of Alzheimer’s disease (AD) were examined in mice given chronic exposure to nPM, a nano-sized subfraction of urban air pollution. In the cerebral cortex, female mice had two-fold more genes responding to nPM than males. Transcriptomic responses to nPM had sex-APOE interactions in AD-relevant pathways. Only APOE3 mice responded to nPM in genes related to Abeta deposition and clearance (Vav2, Vav3, S1009a). Other responding genes included axonal guidance, inflammation (AMPK, NFKB, APK/JNK signaling), and antioxidant signaling (NRF2, HIF1A). Genes downstream of NFKB and NRF2 responded in opposite directions to nPM. Nrf2 knockdown in microglia augmented NFKB responses to nPM, suggesting a critical role of NRF2 in air pollution neurotoxicity. These findings give a rationale for epidemiologic studies of air pollution to consider sex interactions with APOE alleles and other AD-risk genes.
