Air pollution-related neurodegeneration: effects of magnetite nanoparticles on cultured human astrocytes and neurons

Air pollution is a critical global public health problem deeply entangled with social, economic and legislative factors worldwide and it is exacerbated by the rapid rate of urbanisation and industrialisation (Olloquequi J et al., 2024). A major contributor to global air pollution are the traffic-related air pollutants (TRAPs), including magnetite nanoparticles (MNPs). Air pollution is estimated to have caused 4.2 million premature deaths worldwide in 2019, 89% of which occurred in low- and middle-income countries. It is thus imperative to investigate whether the exposure to airborne PM-derived MNPs may pose a risk to human health. The causes reported for these premature deaths are mostly cardiovascular diseases, ischaemia and cancers (WHO, air quality guidelines, 2021). Nevertheless, to date, a bunch of clinical and epidemiological studies are increasingly demonstrating also the adverse association between TRAPs and neurological diseases (Gómez-Budia M et al., 2020). Indeed, recent studies have shown that in highly trafficked and industrialised urban areas (e.g. Mexico City, Manchester) dementia cases at a younger age increased (Maher BA et al., 2019). Airborne particulate matter (PM) pollution is considered as an important environmental risk factor for neurotoxicity and may potentiate the risk of developing neurodegenerative diseases such as Alzheimer's disease (AD). Neurodegenerative diseases are constantly increasing as the world’s population ages. In the early stages, these diseases can be triggered by different types of stimuli, all leading to chronic oxidative stress. Among TRAPs, PM2.5, which include MNPs, can be inhaled and directly reach the brain promoting the formation of reactive oxygen species (ROS) and inducing oxidative stress, one of the hallmarks of AD (Jankowska-Kieltyka M et al., 2021). In this work we focussed our attention on the biological impact of magnetite nanoparticles pollution on the promotion and development of neurodegenerative diseases, while also exploring the potential role of astrocytes in this context. In light of these considerations, the effects of MNPs and Amyloid-β (Aβ1-42) were evaluated on human astroglial and neuronal cell models. Firstly, we demonstrated that MNPs do not directly affect neuronal viability, whereas astrocyte viability is impaired. Otherwise, amyloid impairs the viability of both astrocytes and neurons. The interaction between magnetite nanoparticles and amyloid has a dual impact on astrocytes: in addition to reducing the viability of these cells, MNPs and amyloid also exert a synergistic effect when used in combination. In the brain, astrocytes can efficiently counteract oxidative stress through the activation of an antioxidant response (Baxter PS et al., 2016) and are crucial for neuronal function. Indeed, they provide structural and metabolic support to neurons, maintaining homeostasis of the extracellular space of the brain parenchyma (Durkee CA et al., 2019). Moreover, glial cells play a pivotal role in iron homeostasis in the central nervous system through the action of ferroportin (Fpn), the only known mammalian iron exporter, and ceruloplasmin (Cp), an enzyme with ferroxidase activity (Hohnholt MC and Dringen R, 2013). Cp is required for Fpn function; indeed, it is thought that this protein may play a protective role in neurodegenerative diseases. In this study we demonstrated that astrocytes activate a response that culminates in the up-regulation of System Xc- and ceruloplasmin, while the iron exporter ferroportin is not up-regulated. These modifications may precipitate an elevation in extracellular glutamate release, impaired iron efflux, thereby leading to an augmented intracellular labile iron pool and diminished cellular viability. Taken together these data suggest a potential correlation between iron homeostasis, oxidative stress and cytotoxicity in this context. Given the numerous essential functions that astrocytes fulfil, any dysfunction in these cells has the potential to contribute to the development of several neurological disorders, including neurodegenerative diseases such as AD (Sofroniew MV et al., 2010). Therefore, following an evaluation of the impact of magnetite nanoparticles and amyloid on astrocyte behaviour, it was essential to ascertain whether the observed alterations in astrocytes could potentially influence neurons, as part of this research project. The results show that astrocyte supernatant has a harmful impact on neuronal viability that lasts over time. The synergistic effect of MNPs and amyloid on neuronal death may be due to the release of soluble factors by astrocytes that accumulate over time, highlighting the exacerbating effect that MNPs may have in chronic conditions. Nevertheless, it is important to acknowledge that under identical experimental conditions, the viability of astrocytes is also adversely affected. Consequently, the reduction in neuronal viability may likewise be attributable to the diminished trophic support rendered by astrocytes. Our findings collectively suggest that while exposure of neurons to MNPs does not directly affect their viability, it can potentially induce neurotoxicity through the action of astrocytes. The role of astrocytes may be attributed to their capacity to produce and release soluble factors that affect neuronal function. In conclusion, these findings suggest that airborne pollution-derived magnetite nanoparticles may contribute to the increased prevalence of neurodegenerative diseases observed in highly trafficked and industrialised urban areas.