Traffic-related ultrafine particles (UFPs) are an emerging health concern affecting the brain and increasing the risk of Alzheimer's disease (AD). PI3K/AKT signaling is known to contribute to neuronal survival and to be altered in AD. The nasal olfactory mucosa (OM) is a sensory tissue exposed directly to ambient air, and a starting point for olfactory neural circuits towards the brain. Evidence of air pollution-induced transcriptional regulation via microRNAs (miRNA) and DNA methylation (DNAmet) is accumulating and air pollutant-mediated disturbances in PI3K/AKT signaling have been reported. By utilizing a highly translational human-based in vitro model of OM, we aimed to investigate possible gene regulatory mechanisms in PI3K/AKT signaling induced by UFPs, and to compare the responses between cognitively healthy and individuals with AD. miRNA expression was analyzed using next-generation sequencing (NGS) and chip-based methylation analysis was performed to detect differentially methylated loci (DML). These data were combined with previously published transcriptomics analysis (mRNA) to construct an mRNA-miRNA-DNAmet-integrative network. Protein level changes were studied by immunoassays. We observed UFP-induced reductions in viability and increases in oxidative stress and DNA damage without eminent cell death. Integrative network analysis revealed multiple connections of miRNAs to differentially expressed genes in the PI3K/AKT pathway, and effects were most prominent in AD cells. Similarly, in AD cells DML were identified in transcription factor and apoptosis genes, downstream of PI3K/AKT signaling. Conclusively, traffic-related UFPs influence gene regulation of PI3K/AKT signaling to modulate OM cell survival, with existing AD pathology resulting in heightened vulnerability to UFP effects.

A 1 Virtanen Institute for Molecular Sciences University of Eastern Finland 70210 Kuopio Finland

Department of Neurology Neuro Centre Kuopio University Hospital 70210 Kuopio Finland

Department of Neurology Neuro Centre Kuopio University Hospital 70210 Kuopio Finland; Brain Research Unit Department of Neurology School of Medicine University of Eastern Finland 70210 Kuopio Finland; Department of Neurology and Geriatrics Helsinki University Hospital and Neurosciences Faculty of Medicine University of Helsinki 00014 Helsinki Finland

Department of Otorhinolaryngology University of Eastern Finland and Kuopio University Hospital 70210 Kuopio Finland

Department of Toxicology and Molecular Epidemiology Institute of Experimental Medicine of the Czech Academy of Sciences Videnska 1083 142 20 Prague Czech Republic

Inhalation Toxicology Laboratory Department of Environmental and Biological Sciences University of Eastern Finland 70211 Kuopio Finland

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