Metabolic Reprogramming in Primary Microglial Cell and Extracellular Vesicle Triggered by Aβ Exposure

Microglia, key immune cells in the brain, play a pivotal role in brain homeostasis and immune responses. Emerging evidence suggests their critical involvement in Alzheimer's disease (AD) pathogenesis and propagation. The propagation of AD pathology is related to the extracellular matrix of microglia, including extracellular vesicles (EV). Recently, microglia-derived EVs are implicated in inflammatory processes and neuronal death. This study aimed to extensively profile and propose the metabolic role of microglial EVs in AD. Accordingly, we determined the significant alterations of the EV metabolome associated with the metabolites in primary microglial cells. Aβ exposure induced significant metabolic alteration of 39, 18, and 28 metabolites in microglial cells, cultured media, and EVs, respectively. Aβ exposure triggered common alteration of key metabolic pathways between microglial cells and EVs, including purine, amino acid, and fatty acid metabolisms. While most of the common metabolites showed the same directional changes among the microglial system, N-acetyl aspartic acid displayed the opposite directional change in EVs. N-acetyl aspartic acid decreased 2.3-fold and twofold in microglial cells and media, respectively, but increased 3.5-fold in EVs under Aβ exposure. Moreover, mediation analysis proposed key EV metabolites that were directly affected by the metabolic dysregulation of Aβ-exposed microglial cells. The up-regulation of cysteic acid in EVs was mediated by up-regulated IMP in microglial cells. The down-regulation of 1-16:0-lysoPE in EVs was mediated by stearoyl-L-carnitine in microglial cells. Our study sheds new light on the role of microglia and EVs in neurodegenerative diseases, offering promising avenues for future therapeutic interventions.