Constituents of air pollution, the ultrafine particles (UFP) with a diameter of ≤0.1 μm, are considerably related to traffic emissions. Several studies link air pollution to Alzheimer's disease (AD), yet the exact relationship between the two remains poorly understood. Mitochondria are known targets of environmental toxicants, and their dysfunction is associated with neurodegenerative diseases. The olfactory mucosa (OM), located at the rooftop of the nasal cavity, is directly exposed to the environment and in contact with the brain. Mounting evidence suggests that the UFPs can impact the brain directly through the olfactory tract. By using primary human OM cultures established from nasal biopsies of cognitively healthy controls and individuals diagnosed with AD, we aimed to decipher the effects of traffic-related UFPs on mitochondria. The UFP samples were collected from the exhausts of a modern heavy-duty diesel engine (HDE) without aftertreatment systems, run with renewable diesel (A0) and petroleum diesel (A20), and from an engine of a 2019 model diesel passenger car (DI-E6d) equipped with state-of-the-art aftertreatment devices and run with renewable diesel (Euro6). OM cells were exposed to three different UFPs for 24-h and 72-h, after which cellular processes were assessed on the functional and transcriptomic levels. Our results show that UFPs impair mitochondrial functions in primary human OM cells by hampering oxidative phosphorylation (OXPHOS) and redox balance, and the responses of AD cells differ from cognitively healthy controls. RNA-Seq and IPA® revealed inhibition of OXPHOS and mitochondrial dysfunction in response to UFPs A0 and A20. Functional validation confirmed that A0 and A20 impair cellular respiration, decrease ATP levels, and disturb redox balance by altering NAD and glutathione metabolism, leading to increased ROS and oxidative stress. RNA-Seq and functional assessment revealed the presence of AD-related alterations in human OM cells and that different fuels and engine technologies elicit differential effects.

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

Department of Computer Science University of Verona 37134 Verona Italy

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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