近日，南京大学华子春及其研究组发现，一种新型的Annexin二聚体靶向小胶质细胞对星形胶质细胞的吞噬作用，来保护脑血屏障免受脑缺血后的损伤。这一研究成果于2024年12月11日在线发表在国际学术期刊《中国药理学报》上。

研究人员表示，尽管星形胶质细胞在维持血脑屏障（BBB）完整性方面发挥着重要作用，但它们作为缺血性卒中引起的屏障破坏治疗靶点的潜力仍未得到充分研究。研究人员之前报告了星形胶质细胞膜上磷脂酰丝氨酸（PS）的外翻现象，与神经元中PS外翻的出现相伴随。星形胶质细胞的PS外翻诱导了小胶质细胞对星形胶质细胞的吞噬作用，导致星形胶质细胞与血管的耦合减少，进而引发BBB破坏。Annexin A5（ANXA5）属于钙（Ca²⁺）和磷脂结合蛋白的超家族。

研究人员报告了人类ANXA5的两种X射线结构，包括单体ANXA5（1.42 Å）和二聚体ANXA5（1.80 Å）。通过分子对接和功能分析的结合，研究人员探讨了ANXA5在卒中治疗中的作用机制。此外，研究人员观察到随着ANXA5与PS的亲和力增加，治疗效果明显增强。总之，小胶质细胞吞噬PS外翻的星形胶质细胞已成为缺血后BBB破坏的关键机制。

该发现为ANXA5作为一种创新药理靶点提供了宝贵的结构见解，以保护缺血性卒中后的血脑屏障完整性。这些见解可能有助于开发新型的PS靶向药物，旨在提高疗效并减少副作用。

附：英文原文

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

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

Issue&Volume: 2024-12-11

Abstract: 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 (Ca2+)- and phospholipid-binding proteins. Here, we report two X-ray structures of human ANXA5, including monomeric ANXA5 (1.42) and dimeric ANXA5 (1.80). 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.

DOI: 10.1038/s41401-024-01432-3

Source: https://www.nature.com/articles/s41401-024-01432-3