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

  • Immunity. 2026 Jun 9;59(6):1579-1598.e9. doi: 10.1016/j.immuni.2026.03.007.
Jingyan Zhang  1 ,  Yufei Huang  1 ,  Yanbing Chen  1 ,  Yusi Zhang  1 ,  Jianmin Chen  1 ,  Yihong Huang  1 ,  Haizhi Zhong  1 ,  Haobing He  1 ,  Xiaoman Dai  1 ,  Xiaoxin Yan  2 ,  Wanjin Chen  3 ,  Qinyong Ye  1 ,  Xiaochun Chen  4 ,  Jing Zhang  5
Affiliations
  • 1. Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University, Fuzhou 350001, China.
  • 2. Department of Anatomy and Neurobiology, Central South University Xiangya Basic Medical School, Changsha 410013, China.
  • 3. Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China.
  • 4. Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University, Fuzhou 350001, China. Electronic address: [email protected].
  • 5. Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University, Fuzhou 350001, China. Electronic address: [email protected].
PMID: 41962542 DOI: 10.1016/j.immuni.2026.03.007
Abstract

Glial crosstalk surrounding Amyloid-β (Aβ) plaques establishes a self-propagating inflammatory niche fueling Alzheimer's disease (AD), yet the molecular triggers remain incompletely defined. We found that the calcium-dependent enzyme peptidyl-arginine deiminase 2 (PAD2) was selectively upregulated in plaque-associated astrocytes in human AD cortex and multiple APP AD transgenic mouse models. Astrocyte-specific deletion of Padi2 in 5×FAD mice rescued learning and memory, lowered Aβ load, restrained pro-inflammatory microglial activation, and restored microglial phagocytosis. Multi-omics profiling tied these benefits to rewiring of the astrocytic proteome and the microglial transcriptome toward homeostasis. PAD2 converted astrocytic vimentin to citrullinated Cit-Vim175/184. The released Cit-vimentin drove a proinflammatory phenotype while dampening Aβ clearance in microglia-a process dependent on TLR4 signaling. Pharmacological PAD2 inhibition mimicked the genetic rescue, normalizing glial signatures and cognition. These findings identify PAD2-dependent vimentin citrullination as a key inter-glial signaling hub that worsens AD pathology and highlight PAD2 as a promising therapeutic target.

Keywords
Alzheimer’s disease; PAD2; TLR4; astrocyte; citrullination; glial crosstalk; microglia; neuroinflammation; vimentin.
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