Extracellular vesicles carrying the tenascin-C protein participate in glucose metabolism in neurodegenerative injury via inhibiting the AKT/GLUT1 pathway.

Abstract

Extracellular vesicles (EVs) serve as key mediators of intercellular communication within the nervous system. An adequate glucose supply is essential for normal brain function; however, cerebral glucose metabolism is progressively impaired in Parkinson's disease (PD). Here, we show that EVs released by microglia exposed to 40 μM paraquat (PQ) are internalized by dopaminergic neurons, where they impair glucose metabolism and induce neurodegenerative injury through the intercellular transfer of tenascin-C (TNC). TNC, which has been proposed as a potential indicator of disease severity, is upregulated following neurological injury and has been implicated in neuronal apoptosis and neuroinflammation. EVs released by microglia exposed to 40 μM PQ reduced neuronal glucose uptake, disrupted glucose metabolism, and exacerbated mitochondrial dysfunction. Proteomic analysis revealed that EVs derived from PQ-exposed microglia were enriched in TNC. Co-immunoprecipitation analysis further demonstrated an interaction between EV-transferred TNC and protein kinase B (AKT) in recipient neurons. Both depletion of TNC from EVs and pharmacological activation of AKT restored glucose uptake in recipient neurons. Collectively, these findings demonstrate that, under PQ exposure, activated microglia impair neuronal glucose metabolism by releasing TNC-enriched EVs. The EV-mediated TNC-AKT/ glucose transporter 1 (GLUT1) axis may therefore contribute to PQ-induced dopaminergic neurotoxicity and represent a potential therapeutic target for PD.