Ozone (O3) is a significant global air pollutant. Recent epidemiological studies have established a correlation between O3 exposure and an increased risk of neurological disorders. However, the underlying mechanisms by which O3 induces cognitive deficits remain unclear. This study demonstrated that exposure to environmentally relevant O3 levels resulted in significant cognitive impairment in mice. These deficits arose from hippocampal synaptic injury, characterized by reduced dendritic spine density, disrupted synaptic ultrastructure, and impaired long-term potentiation. Mechanistically, O3 activated the liver complement pathway, leading to increased levels of complement component 3 (C3) and its subsequent release into the bloodstream. Furthermore, O3 compromised the integrity of the blood–brain barrier, allowing peripheral C3 to infiltrate the hippocampus. Notably, C3 served as a key signal that triggered local pro-inflammatory microglial activation and enhanced their phagocytosis of excitatory synapses, ultimately resulting in synaptic loss and cognitive decline. Importantly, both the microglial inhibitor minocycline and liver-specific C3 knockdown suppressed pro-inflammatory microglial activation and restored synaptic plasticity and cognitive function. These findings systematically reveal a novel liver–brain axis in O3 neurotoxicity, whereby peripheral C3 drives central microglial phagocytosis of excitatory synapses, offering new mechanistic insights and potential therapeutic targets for O3-related neurological diseases.
Wang et al. (Thu,) studied this question.