Macrophage lineage cells-derived migrasomes activate complement-dependent blood-brain barrier damage in cerebral amyloid angiopathy mouse model

Mengyan Hu, Tiemei Li, Xiaomeng Ma, Sanxin Liu, Chunyi Li, Zhenchao Huang, Yinyao Lin, Ruizhen Wu, Shisi Wang, Danli Lu, Tingting Lu, Xuejiao Men, Shishi Shen, Huipeng Huang, Yuxin Liu, Kangyu Song, Banghao Jian, Yuxuan Jiang, Wei Qiu, Quentin Liu (), Zhengqi Lu () and Wei Cai ()
Additional contact information
Mengyan Hu: The Third Affiliated Hospital of Sun Yat-sen University
Tiemei Li: The Third Affiliated Hospital of Sun Yat-sen University
Xiaomeng Ma: The Third Affiliated Hospital of Sun Yat-sen University
Sanxin Liu: The Third Affiliated Hospital of Sun Yat-sen University
Chunyi Li: The Third Affiliated Hospital of Sun Yat-sen University
Zhenchao Huang: The Third Affiliated Hospital of Sun Yat-Sen University
Yinyao Lin: The Third Affiliated Hospital of Sun Yat-sen University
Ruizhen Wu: The Third Affiliated Hospital of Sun Yat-sen University
Shisi Wang: The Third Affiliated Hospital of Sun Yat-sen University
Danli Lu: The Third Affiliated Hospital of Sun Yat-sen University
Tingting Lu: The Third Affiliated Hospital of Sun Yat-sen University
Xuejiao Men: The Third Affiliated Hospital of Sun Yat-sen University
Shishi Shen: The Third Affiliated Hospital of Sun Yat-sen University
Huipeng Huang: The Third Affiliated Hospital of Sun Yat-sen University
Yuxin Liu: The Third Affiliated Hospital of Sun Yat-sen University
Kangyu Song: The Third Affiliated Hospital of Sun Yat-sen University
Banghao Jian: The Third Affiliated Hospital of Sun Yat-sen University
Yuxuan Jiang: The Third Affiliated Hospital of Sun Yat-sen University
Wei Qiu: The Third Affiliated Hospital of Sun Yat-sen University
Quentin Liu: State Key Laboratory of Oncology in South China
Zhengqi Lu: The Third Affiliated Hospital of Sun Yat-sen University
Wei Cai: The Third Affiliated Hospital of Sun Yat-sen University

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Accumulation of amyloid beta protein (Aβ) in brain vessels damages blood brain barrier (BBB) integrity in cerebral amyloid angiopathy (CAA). Macrophage lineage cells scavenge Aβ and produce disease-modifying mediators. Herein, we report that Aβ40-induced macrophage-derived migrasomes are sticky to blood vessels in skin biopsy samples from CAA patients and brain tissue from CAA mouse models (Tg-SwDI/B and 5xFAD mice). We show that CD5L is packed in migrasomes and docked to blood vessels, and that enrichment of CD5L impairs the resistance to complement activation. Increased migrasome-producing capacity of macrophages and membrane attack complex (MAC) in blood are associated with disease severity in both patients and Tg-SwDI/B mice. Of note, complement inhibitory treatment protects against migrasomes-mediated blood-brain barrier injury in Tg-SwDI/B mice. We thus propose that macrophage-derived migrasomes and the consequent complement activation are potential biomarkers and therapeutic targets in CAA.

Date: 2023
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DOI: 10.1038/s41467-023-39693-x

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