Exposure to Manganese Induces Autophagy–Lysosomal Pathway Dysfunction-Mediated Tauopathy by Activating the cGAS–STING Pathway in the Brain

Manganese (Mn) exposure leads to pathological accumulation of Tau-associated neurodegenerative disease and has become a major public health concern. However, the precise mechanism underlying this effect remains unclear. Here, the mechanism by which Mn induces dysfunction of autophagy–lysosomal pathway-mediated tauopathy by activating the cGAS–STING pathway was explored both in vitro and in vivo. Mn exposure induced tauopathy in microglia and in mice while activating the cGAS–STING pathway, inducing type I interferon production, and impairing the degradation function of the autophagy–lysosomal pathway. Importantly, inactivation of the cGAS–STING pathway rescued the degradation activity of the autophagy–lysosomal pathway, while tauopathy was markedly attenuated, as shown in both cGAS-knockout and STING-knockout BV2 microglia and in mice. Moreover, the autophagy inhibitor 3-methyladenine (3-MA) restored the impaired degradation activity of the autophagy–lysosomal pathway by inactivating the cGAS–STING pathway, thereby clearing Tau aggregation. Taken together, these results indicate that Mn exposure induces tauopathy by impairing the function of the autophagy–lysosomal pathway through the activation of the cGAS–STING pathway. Thus, this study identifies a novel mechanism by which Mn exposure induces Tau aggregation, which in turn triggers potential neurotoxicity, providing a foundation for future drug target research.