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

Zheng Qi1,2, Lan Ding3, Yingying Zhao1,2

  • 1Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China.

Communications Biology
|March 20, 2026
PubMed

Insights

Microglia release extracellular vesicles (EVs) carrying ATP citrate lyase (ACLY) that impair astrocyte function, leading to cognitive decline in postoperative cognitive dysfunction (POCD). Targeting this pathway may improve brain function after surgery.

Area of Science:

  • Neuroscience
  • Immunology
  • Metabolism

Background:

  • Postoperative cognitive dysfunction (POCD) is a common complication in older adults undergoing surgery, with unclear underlying mechanisms.
  • Immune cell metabolism is known to influence inflammatory signaling, but its role in POCD is not fully understood.

Purpose of the Study:

  • To investigate if microglia-derived extracellular vesicles (EVs) transmit metabolic signals to astrocytes, affecting cognitive function.
  • To elucidate the specific molecular mechanisms linking microglial metabolism to astrocytic function and cognitive impairment in POCD.

Main Methods:

  • Analysis of plasma EVs from POCD patients and EVs from activated microglia for ATP citrate lyase (ACLY) content.
  • In vitro studies using astrocytes to assess EV uptake and the functional consequences of EV-delivered ACLY.
  • In vivo experiments in aged mice involving EV administration and assessment of neuroinflammation, synaptic function, and cognitive behaviors.
  • Chromatin immunoprecipitation to confirm transcriptional regulation of EAAT1.

Main Results:

  • EVs from POCD patients and activated microglia are enriched in ACLY and taken up by astrocytes.
  • EV-delivered ACLY enhances NF-κB p65 acetylation, suppressing astrocytic glutamate transporter EAAT1 (SLC1A3) expression and impairing glutamate clearance.
  • Systemic or hippocampal EV administration in aged mice induced POCD-like symptoms, including neuroinflammation, synaptic deficits, and cognitive impairment.
  • Genetic or pharmacological inhibition of EV pathways or ACLY restored EAAT1 expression, glutamate uptake, and cognitive function.

Conclusions:

  • A novel microglia-to-astrocyte signaling axis involving ACLY delivered via EVs contributes to cognitive decline in POCD.
  • This pathway couples microglial immunometabolism to excitatory neurotransmitter dysregulation, offering potential therapeutic targets.
  • Targeting ACLY and EV pathways presents a promising strategy for mitigating POCD and associated cognitive deficits.

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