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

Overview

Authors: Qiuzhi Zhou1,2,3, Fei Sun1, Yao Zhang4, Xiaojian Cao2,3, Mengzhu Li1,5, Haitao Yu1, Tao Jiang1, Shihong Li1, Weixia Wang1, Jiazhao Xie1, Ting He1, Yanchao Liu1,6, Dan Ke1, Xiao-Chuan Wang1, Peng Xu7, Enjie Liu8, Hong Chen2,3, Jian-Zhi Wang1,9
ORCID iDs: Fei Sun, Haitao Yu, Tao Jiang, Xiao-Chuan Wang, Peng Xu, Enjie Liu, Jian-Zhi Wang
  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
  9. Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University,Wuhan, China
Institutions: Huazhong University of Science and Technology (China); Southeast University (China); First Affiliated Hospital of Zhengzhou University (China); Jianghan University (China)
Journal: Nature communications, volume 17, issue 1, article 7217
Dates: received 29 October 2025; accepted 27 May 2026; published online 5 June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41467-026-74037-5 · PMID 42248891 · PMCID PMC13396677 · OpenAlex W7163656190
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), mouse (organism), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions
Keywords: Alzheimer's disease
MeSH: Alzheimer Disease*, Amyloid beta-Peptides*, Microglia*, Platelet Endothelial Cell Adhesion Molecule-1*, Animals, Astrocytes, Brain, Disease Models, Animal, Female, Gene Knockdown Techniques, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 11, STAT3 Transcription Factor (* major topic)
Topic: Neuroinflammation and Neurodegeneration Mechanisms (Neurology, Neuroscience), according to OpenAlex
Funding: National Natural Science Foundation of China (National Science Foundation of China) (82230041, 82301620, 82001134, 31730035, 81721005)
Citations: not cited yet (Europe PMC); 60 references in the paper
Research resources: Wild-type C57BL/6J mice RRID:IMSR_JAX:000664, Cx3cr1-Cre mice RRID:IMSR_JAX:025524, 5×FAD transgenic mice RRID:MMRRC_034848-JAX

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

Data availability

Raw sequencing data generated in this study have been deposited in the Gene Expression Omnibus (GEO) under accession codes GSE331294 (snRNA-seq; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE331294) and GSE331306 (bulk RNA-seq; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE331306), and are publicly available. Publicly available datasets reanalyzed in this study include human AD cortex single-cell RNA-seq data accessed through AlzData (http://www.alzdata.org/), mouse brain single-cell RNA-seq data accessed through the Broad Institute Single Cell Portal (https://singlecell.broadinstitute.org/), and the Allen Brain Atlas mouse brain reference dataset used for cell-type label transfer in snRNA-seq annotation. STAT3 position weight matrices were retrieved from the JASPAR database (https://jaspar.genereg.net/), and STAT3 transcription factor–target gene relationships were retrieved from the hTFtarget database (http://bioinfo.life.hust.edu.cn/hTFtarget/). The mm10-2020-A mouse reference genome was used for sequencing read alignment. Antibody information, single-cell DEG and cluster marker tables, statistical details, and other supporting tabular data are provided in Supplementary Data 1–4. Source data are provided with this paper. Raw data are available on request. Source data are provided with this paper.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 18 authors, 1 keyword, 18 MeSH terms, 1 funder, 60 references, 3 RRIDs.

Cite

This paper

Zhou, Q., Sun, F., Zhang, Y., Cao, X., Li, M., Yu, H., Jiang, T., Li, S., Wang, W., Xie, J., He, T., Liu, Y., Ke, D., Wang, X.-C., Xu, P., Liu, E., Chen, H., & Wang, J.-Z. (2026). Microglial CD31 suppresses Aβ clearance and promotes Alzheimer pathology in 5×FAD mice. Nature communications, 17(1), 7217. https://doi.org/10.1038/s41467-026-74037-5

BibTeX

@article{zhou2026microglial,
author = {Zhou, Qiuzhi and Sun, Fei and Zhang, Yao and Cao, Xiaojian and Li, Mengzhu and Yu, Haitao and Jiang, Tao and Li, Shihong and Wang, Weixia and Xie, Jiazhao and He, Ting and Liu, Yanchao and Ke, Dan and Wang, Xiao-Chuan and Xu, Peng and Liu, Enjie and Chen, Hong and Wang, Jian-Zhi},
title = {{Microglial CD31 suppresses Aβ clearance and promotes Alzheimer pathology in 5×FAD mice}},
journal = {Nature communications},
year = {2026},
month = jun,
volume = {17},
number = {1},
pages = {7217},
publisher = {Nature Publishing Group},
issn = {2041-1723},
doi = {10.1038/s41467-026-74037-5},
url = {https://doi.org/10.1038/s41467-026-74037-5},
pmid = {42248891},
pmcid = {PMC13396677}
}

RIS

TY - JOUR
AU - Zhou, Qiuzhi
AU - Sun, Fei
AU - Zhang, Yao
AU - Cao, Xiaojian
AU - Li, Mengzhu
AU - Yu, Haitao
AU - Jiang, Tao
AU - Li, Shihong
AU - Wang, Weixia
AU - Xie, Jiazhao
AU - He, Ting
AU - Liu, Yanchao
AU - Ke, Dan
AU - Wang, Xiao-Chuan
AU - Xu, Peng
AU - Liu, Enjie
AU - Chen, Hong
AU - Wang, Jian-Zhi
TI - Microglial CD31 suppresses Aβ clearance and promotes Alzheimer pathology in 5×FAD mice
T2 - Nature communications
J2 - Nat Commun
PY - 2026
DA - 2026/06/05
VL - 17
IS - 1
SP - 7217
SN - 2041-1723
PB - Nature Publishing Group
DO - 10.1038/s41467-026-74037-5
UR - https://doi.org/10.1038/s41467-026-74037-5
LA - en
ER -

CSL-JSON

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