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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\u2010derived 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. A\u03b2 exposure induced significant metabolic alteration of 39, 18, and 28 metabolites in microglial cells, cultured media, and EVs, respectively. A\u03b2 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                    <jats:italic>N<\/jats:italic>\n                    \u2010acetyl aspartic acid displayed the opposite directional change in EVs.\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acetyl aspartic acid decreased 2.3\u2010fold and twofold in microglial cells and media, respectively, but increased 3.5\u2010fold in EVs under A\u03b2 exposure. Moreover, mediation analysis proposed key EV metabolites that were directly affected by the metabolic dysregulation of A\u03b2\u2010exposed microglial cells. The up\u2010regulation of cysteic acid in EVs was mediated by up\u2010regulated IMP in microglial cells. The down\u2010regulation of 1\u201316:0\u2010lysoPE in EVs was mediated by stearoyl\u2010L\u2010carnitine 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.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70030-fig-0006-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70030","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T05:20:54Z","timestamp":1741756854000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Metabolic Reprogramming in Primary Microglial Cell and Extracellular Vesicle Triggered by A\u03b2 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