Microglial CD31 suppresses Aβ clearance and promotes Alzheimer pathology in 5×FAD mice

  • Nat Commun. 2026 Jun 5. doi: 10.1038/s41467-026-74037-5.
Qiuzhi Zhou  #  1  2  3 ,  Fei Sun  #  1 ,  Yao Zhang  4 ,  Xiaojian Cao  2  3 ,  Mengzhu Li  1  5 ,  Haitao Yu  1 ,  Tao Jiang  1 ,  Shihong Li  1 ,  Weixia Wang  1 ,  Jiazhao Xie  1 ,  Ting He  1 ,  Yanchao Liu  1  6 ,  Dan Ke  1 ,  Xiao-Chuan Wang  1 ,  Peng Xu  7 ,  Enjie Liu  8 ,  Hong Chen  9  10 ,  Jian-Zhi Wang  11  12
Affiliations
  • 1. Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2. Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3. Stem Cell Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4. Department of Endocrinology, Key Laboratory of Ministry of Education for Neurological Disorders, Li Yuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5. Department of Neurosurgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 6. Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 7. Center of Clinical Laboratory Medicine, Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health, Southeast University, Nanjing, China.
  • 8. Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. [email protected].
  • 9. Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 10. Stem Cell Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 11. Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 12. Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University, Wuhan, China. [email protected].
  • # Contributed equally.
PMID: 42248891 DOI: 10.1038/s41467-026-74037-5
Abstract

Microglia play crucial roles in Alzheimer's disease (AD), yet the molecular mechanisms are unclear. Here, we show that CD31, a recognized endothelial marker, is predominantly expressed in microglia but not in neurons or astrocytes, and it is significantly elevated in the brains of AD patients and mouse models. Microglia-specific CD31 knockdown in 5xFAD mice substantially attenuated the dysregulated transcription networks, suppressed microglia hyperactivation and the disease-associated microglia (DAM), mitigated Aβ deposition and inflammation, and eventually improved cognitive functions in mice. Mechanistically, CD31 knockdown damaged the simultaneous recruitment of Src homology Phosphatase 2 (SHP2) and STAT3, leading to a reduced dephosphorylation and enhanced activation of STAT3, a transcription factor. STAT3 activation increased transcription of membrane metalloendopeptidase (MME) and promoted Aβ clearance. Collectively, this study identifies microglial CD31, by regulating SHP2-STAT3-MME axis, plays a role in AD pathogenesis and targeting CD31 is promising in AD drug development.

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