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Astrocytic calcium-dependent enzyme PAD2 governs microglia activity to exacerbate amyloid pathology via citrullinated

Jingyan Zhang1, Yufei Huang1, Yanbing Chen1

  • 1Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University, Fuzhou 350001, China.

Immunity
|April 10, 2026
PubMed

Insights

Researchers discovered that the enzyme peptidyl-arginine deiminase 2 (PAD2) drives Alzheimer's disease (AD) inflammation by altering astrocyte proteins. Inhibiting PAD2 improved cognition and reduced AD pathology in mouse models.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Immunology

Background:

  • Glial cells (astrocytes and microglia) form a pro-inflammatory environment around amyloid-β (Aβ) plaques, contributing to Alzheimer's disease (AD) progression.
  • The precise molecular mechanisms initiating this detrimental glial crosstalk are not fully understood.

Purpose of the Study:

  • To investigate the role of peptidyl-arginine deiminase 2 (PAD2) in AD pathogenesis.
  • To identify PAD2 as a potential therapeutic target for AD.

Main Methods:

  • Examined PAD2 expression in human AD brain tissue and APP AD transgenic mouse models.
  • Utilized astrocyte-specific Padi2 gene deletion in 5×FAD mice.
  • Performed multi-omics profiling (proteomics and transcriptomics).
  • Investigated the effect of PAD2 inhibition on glial cells and AD pathology.

Main Results:

  • PAD2 was upregulated in astrocytes near Aβ plaques in human AD cortex and mouse models.
  • Astrocyte-specific deletion of Padi2 in 5×FAD mice improved learning/memory, reduced Aβ load, and restored microglial phagocytosis.
  • PAD2 citrullinated vimentin in astrocytes, generating Cit-Vim175/184, which promoted inflammation and impaired microglial Aβ clearance via TLR4 signaling.
  • Pharmacological PAD2 inhibition replicated genetic rescue effects, normalizing glial function and cognition.

Conclusions:

  • PAD2-mediated vimentin citrullination acts as a critical inter-glial signaling pathway exacerbating AD pathology.
  • Targeting PAD2 offers a promising therapeutic strategy for Alzheimer's disease.
Keywords:
Alzheimer’s diseasePAD2TLR4astrocytecitrullinationglial crosstalkmicroglianeuroinflammationvimentin

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