小胶质细胞CD31抑制5×FAD小鼠的Aβ清除并促进阿尔茨海默病病理
Microglial CD31 suppresses Aβ clearance and promotes Alzheimer pathology in 5×FAD mice.
摘要(中文译文)
小胶质细胞在阿尔茨海默病（AD）中发挥关键作用，但其分子机制尚不清楚。本研究发现，公认的内皮标志物CD31主要表达于小胶质细胞，而非神经元或星形胶质细胞，并且在AD患者和模型小鼠脑内显著升高。在5xFAD小鼠中小胶质细胞特异性敲低CD31可显著减轻失调的转录网络，抑制小胶质细胞过度激活及疾病相关小胶质细胞（DAM），减轻Aβ沉积和炎症，并最终改善小鼠的认知功能。机制上，CD31敲低破坏了Src同源磷酸酶2（SHP2）与STAT3的同步募集，导致转录因子STAT3去磷酸化减少、活化增强。STAT3活化增加了膜金属内肽酶（MME）的转录并促进Aβ清除。总之，本研究鉴定出小胶质细胞CD31通过调控SHP2-STAT3-MME轴在AD发病机制中发挥作用，靶向CD31在AD药物开发中具有前景。
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.
如何引用
AMA
Qiuzhi Zhou, Fei Sun, Yao Zhang, Xiaojian Cao, Mengzhu Li, Haitao Yu, et al. Microglial CD31 suppresses Aβ clearance and promotes Alzheimer pathology in 5×FAD mice.. Nature communications. 2026; doi:10.1038/s41467-026-74037-5.
APA
Qiuzhi Zhou, Fei Sun, Yao Zhang, Xiaojian Cao, Mengzhu Li, Haitao Yu, et al (2026). Microglial CD31 suppresses Aβ clearance and promotes Alzheimer pathology in 5×FAD mice.. Nature communications. https://doi.org/10.1038/s41467-026-74037-5
GB/T 7714
Qiuzhi Zhou, Fei Sun, Yao Zhang, Xiaojian Cao, Mengzhu Li, Haitao Yu, et al. Microglial CD31 suppresses Aβ clearance and promotes Alzheimer pathology in 5×FAD mice.[J]. Nature communications, 2026 doi:10.1038/s41467-026-74037-5.
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