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

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.