福建医科大学张静小组在研究中取得进展。他们开发出星形胶质细胞钙依赖性酶PAD2通过瓜氨酸化波形蛋白控制小胶质细胞活性，从而加剧淀粉样蛋白病理。这一研究成果发表在2026年4月9日出版的国际学术期刊《免疫学》上。

该课题组研究人员发现钙依赖性酶肽精氨酸脱亚胺酶2 （PAD2）在人类AD皮层斑块相关星形胶质细胞和多个APP AD转基因模位模型中选择性上调。5×FAD小鼠星形胶质细胞特异性缺失Padi2可恢复学习和记忆，降低Aβ负荷，抑制促炎小胶质细胞激活，恢复小胶质细胞吞噬。多组学分析将这些益处与星形细胞蛋白质组和小胶质细胞转录组向稳态方向的重新布线联系起来。PAD2将星形细胞波形蛋白转化为瓜氨酸化的Cit-Vim175/184。释放的Cit-vimentin驱动促炎表型，同时抑制小胶质细胞中aβ的清除-这是一个依赖于TLR4信号传导的过程。药物抑制PAD2模拟基因拯救，使神经胶质特征和认知正常化。这些发现确定了PAD2依赖的静脉蛋白瓜氨酸化是恶化AD病理的关键胶质间信号中枢，并强调了PAD2是一个有希望的治疗靶点。

据悉，淀粉样蛋白-β (Aβ)斑块周围的神经胶质串扰建立了一个自我传播的炎症生态位，助长了阿尔茨海默病（AD），但其分子触发因素仍未完全确定。

附：英文原文

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

Author: Jingyan Zhang, Yufei Huang, Yanbing Chen, Yusi Zhang, Jianmin Chen, Yihong Huang, Haizhi Zhong, Haobing He, Xiaoman Dai, Xiaoxin Yan, Wanjin Chen, Qinyong Ye, Xiaochun Chen, Jing Zhang

Issue&Volume: 2026-04-09

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.

DOI: 10.1016/j.immuni.2026.03.007

Source: https://www.cell.com/immunity/abstract/S1074-7613(26)00118-4