Paraquat exposure triggers amyloid-β and α-synuclein aggregation in the prefrontal cortex of mice: Suppression of microglial phagocytosis via IL-17A

Paraquat (PQ), an environmental neurotoxin, has been demonstrated to induce pathological protein aggregation and thus neurotoxicity. Nevertheless, the exact mechanisms remain elusive. In this investigation, we explored the involvement of interleukin-17A (IL-17 A) in the aggregation of amyloid-β (Aβ) and α-synuclein (α-syn) induced by PQ. Combining in vitro and in vivo, we explored whether PQ leads to Aβ and α-syn aggregation through IL-17 A-mediated reduction in microglia phagocytosis, thereby aggravating neurotoxicity. The results demonstrated that low-dose PQ continuous exposure significantly elevated IL-17 A levels in the peripheral blood serum and prefrontal cortical regions of mice. It also suppressed microglial phagocytosis of pathological proteins and promoted the aggregation of Aβ and α-syn in the prefrontal cortex. These changes ultimately resulted in depression, anxiety, and cognitive impairments. Mechanistically, IL-17 A inhibited the expression of the microglial phagocytic receptor CD36, impairing the microglial ability to clear Aβ and α-syn. Furthermore, administering an anti-IL-17 A effectively restored microglial phagocytosis in PQ-exposed mice, reduced Aβ and α-syn aggregation in prefrontal cortical areas, and alleviated behavioral deficits. In conclusion, this paper highlights IL-17 A as a pivotal mediator in PQ-induced neurotoxicity. It provides a potential target for developing novel therapeutic strategies against neurodegenerative pathologies induced by such environmental toxicants.