Astrocytic EAAT1 suppression by EV-ACLY underlies glutamate imbalance and cognitive impairment in POCD.

Postoperative cognitive dysfunction (POCD) is common in older surgical patients, yet its mechanistic underpinnings remain incompletely defined. Building on the premise that immune-cell metabolism shapes inflammatory signaling, we investigated whether microglia export metabolic instructions through extracellular vesicles (EVs) to remodel astrocytic function. We show that plasma EVs from POCD patients and EVs from activated microglia are enriched for ATP citrate lyase (ACLY) and are efficiently taken up by astrocytes. EV-delivered ACLY increases acetyl-CoA availability and enhances NF-κB p65 acetylation, which in turn suppresses the astrocytic glutamate transporter EAAT1 (SLC1A3). This program diminishes glutamate clearance, leading to synaptic dysfunction and cognitive impairment. In aged mice, systemic or hippocampal EV administration recapitulated microgliosis/astrogliosis, dendritic spine loss, impaired long-term potentiation, and deficits in the Morris water maze and novel object recognition. Chromatin immunoprecipitation confirmed acetyl-p65 occupancy at the SLC1A3 promoter, linking ACLY activity to direct transcriptional repression of EAAT1. Interventions that blocked EV biogenesis/uptake or reduced ACLY (genetically or pharmacologically) attenuated p65 acetylation, restored EAAT1 expression and glutamate uptake, and improved synaptic and behavioral outcomes. These findings identify a microglia-to-astrocyte ACLY-p65-EAAT1 axis that couples immunometabolism to excitatory neurotransmitter dysregulation and cognitive decline in POCD, highlighting ACLY and EV pathways as actionable therapeutic targets.