Air pollutants as drivers of cellular stress in neurons and microglia in the brain

Air pollution is a growing global health concern, with increasing evidence linking exposure to particulate matter (PM) to neurodegenerative diseases such as Alzheimer’s disease (AD). PM exposure contributes to oxidative stress, neuroinflammation, and cellular dysfunction, processes that align with key pathological features of AD, including amyloid-beta (Aβ) aggregation, tau hyperphosphorylation, and synaptic impairment. Despite these associations, the precise molecular mechanisms through which PM drives neurodegeneration remain insufficiently understood.

This thesis investigates how air pollution, particularly diesel exhaust particles (DEP), affects neuronal and microglial function. Our findings demonstrate that PM does not directly induce neuronal death but significantly enhances ferroptosis—a form of iron-dependent cell death—when combined with ferroptotic inducers. DEP exposure leads to increased lipid peroxidation, calcium dysregulation, and mitochondrial fragmentation, effects that can be mitigated by ferroptosis inhibitors. Furthermore, we explore the role of cAMP/EPAC1 and soluble adenylyl cyclase (sAC) signaling in PM-induced ferroptosis, identifying potential therapeutic targets to counteract oxidative damage.

Additionally, our research highlights microglial dysfunction under PM exposure, showing impaired phagocytosis, lysosomal alkalinization, and increased neuroinflammation. These disruptions mirror pathological mechanisms seen in AD, suggesting that air pollution exacerbates neurodegenerative disease progression by impairing key cellular homeostatic processes.The findings deepen our understanding of how environmental pollutants contribute to brain aging and neurodegenerative processes, emphasizing the complex and multifaceted impact of air pollution on brain health.

Dissertation: https://hdl.handle.net/11370/2decfa6e-54fb-4a3e-a5c7-e0d0a12a446d