A novel annexin dimer targets microglial phagocytosis of astrocytes to protect the brain-blood barrier after cerebral ischemia  

作　　者：Wei Tang Rong Cheng Meng-yue Gao Min-jin Hu Lu Zhang Qiang Wang Xin-yu Li Wei Yan Xiao-ying Wang Hai-mei Yang Jian Cheng Zi-chun Hua 

机构地区：[1]The State Key Laboratory of Pharmaceutical Biotechnology,School of Life Sciences,Nanjing University,Nanjing,210093,China [2]Clinical Research Center of Neurological Disease,The Second Affiliated Hospital of Soochow University,Suzhou,215123,China [3]Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Pharmacology,College of Pharmaceutical Sciences,Soochow University,Suzhou,215123,China [4]Changzhou High-Tech Research Institute of Nanjing University and Jiangsu TargetPharma Laboratories Inc.,Changzhou,213164,China [5]Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience,Soochow University,Suzhou,215123,China [6]Faculty of Pharmaceutical Sciences,Xinxiang Medical University,Xinxiang,453003,China

出　　处：《Acta Pharmacologica Sinica》2025年第4期852-866,共15页中国药理学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(82071469,32271033);the Priority Academic Program Development of the Jiangsu Higher Education Institutions(PAPD);Jiangsu Department of Science and Technology(BK20230164,BK20230165,BE2023695,BK20231136 and BK20243001);Changzhou Municipal Department of Science and Technology(2022169,CJ2023001,CJ20220019,and CJ20235009);the Suzhou Clinical Research Center of Neurological Disease(Szzx201503)and the Jiangsu Key Laboratory Grant(BM2013003).

摘　　要：Despite the vital role of astrocytes in preserving blood-brain barrier(BBB)integrity,their therapeutic potential as targets in ischemic stroke-induced barrier disruption remains underexplored.We previously reported externalization of phosphatidylserine(PS)on astrocytic membranes concurrent with the emergence of PS externalization in neurons.PS externalization of astrocytes induced microglial phagocytosis of astrocytes,resulting in reduced astrocyte-vascular coupling and subsequent BBB breakdown.Annexin A5(ANXA5)belongs to the superfamily of calcium(Ca^(2+))-and phospholipid-binding proteins.Here,we report two X-ray structures of human ANXA5,including monomeric ANXA5(1.42Å)and dimeric ANXA5(1.80Å).Through the combination of molecular docking and functional analysis,we explored the mechanism of action of ANXA5 in stroke treatment.In addition,we observed a clear increase in therapeutic efficacy corresponding to the increased affinity of ANXA5 for PS.In summary,the phagocytosis of PS-externalized astrocytes by microglia has emerged as a critical mechanism driving BBB breakdown after ischemia.Our findings offer valuable structural insight into ANXA5 as an innovative pharmacological target for safeguarding blood-brain barrier integrity after cerebral ischemia.These insights may facilitate the development of novel PS-targeting medications aimed at achieving enhanced efficacy with minimal side effects.

关 键 词：cerebral ischemia blood-brain barrier ASTROCYTES PHOSPHATIDYLSERINE Annexin A5 

分 类 号：R743.3[医药卫生—神经病学与精神病学]