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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
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Microglia-to-neuron signaling increases lipid droplet metabolism, enhancing neuronal network activity

Ana P Verduzco Espinoza1, Na Na1, Loraine Campanati1

  • 1Department of Neuroscience, The Scripps Research Institute, La Jolla, San Diego, CA, USA.

Biorxiv : the Preprint Server for Biology
|August 6, 2025
PubMed

Insights

Inflammatory microglia alter neuronal function, with APOE4 increasing excitability. Microglia-derived exosomes and lipid droplet metabolism mediate this communication, impacting neurodegenerative diseases like Alzheimer's.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Neuroinflammation

Background:

  • Microglia are crucial for neuronal circuit plasticity; their dysfunction contributes to neuroinflammation and neurodegenerative diseases like Alzheimer's disease (AD).
  • The apolipoprotein E4 (APOE4) genotype is the strongest genetic risk factor for AD, influencing microglial activation and neuronal excitability.
  • The precise mechanisms of microglial communication with neurons during inflammation and the role of APOE4 in this process remain unclear.

Purpose of the Study:

  • To investigate how microglial inflammatory states affect neuronal circuit function.
  • To determine the independent contribution of APOE genotype in microglia and neurons to microglial regulation of neuronal activity during inflammation.
  • To elucidate the role of lipid metabolism and intercellular communication in mediating these effects.

Main Methods:

  • Utilized human induced pluripotent stem cell (iPSC)-derived microglial and neuronal monocultures.
  • Assessed neuronal network activity using calcium imaging in response to conditioned media (CM) from lipopolysaccharide (LPS)-stimulated microglia.
  • Analyzed the impact of APOE genotype on microglial CM, neuronal responses, exosome-mediated communication, and lipid droplet (LD) metabolism.

Main Results:

  • CM from LPS-stimulated microglia increased neuronal network activity; APOE4 microglial CM induced higher firing rates than APOE3 CM.
  • Both APOE3 and APOE4 neurons responded to CM, but APOE4 neurons showed increased presynaptic puncta with APOE4 microglial CM.
  • Microglial-derived exosomes mediated increased network activity, which was linked to increased lipid droplet metabolism; blocking LD metabolism abolished activity.

Conclusions:

  • Microglia-to-neuron communication drives inflammation-induced changes in neuronal circuit function.
  • Neuronal lipid droplets play a role in regulating network activity.
  • APOE4 may increase neuronal excitability through altered microglial communication and lipid metabolism, contributing to AD pathogenesis.
Keywords:
APOE4DDHD2Inflammatory microgliaexosomeshyperexcitabilitynetwork activityneuronal lipid droplets

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