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Macrophage lineage cells-derived migrasomes activate complement-dependent blood-brain barrier damage in cerebral
Mengyan Hu1,2,3, Tiemei Li1, Xiaomeng Ma1
1Department of Neurology, Mental and Neurological Disease Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
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.
Insights
Macrophage-derived migrasomes carrying CD5L adhere to blood vessels in cerebral amyloid angiopathy (CAA), triggering complement activation and blood-brain barrier damage. Complement inhibition offers protection, suggesting migrasomes are therapeutic targets.
Area of Science:
- Neuroscience
- Immunology
- Vascular Biology
Background:
- Cerebral amyloid angiopathy (CAA) involves amyloid beta (Aβ) accumulation, damaging the blood-brain barrier (BBB).
- Macrophages play a role in Aβ clearance and immune modulation.
- Migrasomes are extracellular vesicles released by cells.
Purpose of the Study:
- To investigate the role of macrophage-derived migrasomes in CAA pathogenesis.
- To identify components within migrasomes that contribute to vascular damage.
- To explore the link between migrasomes, complement activation, and BBB integrity in CAA.
Main Methods:
- Analysis of skin biopsy samples from CAA patients and brain tissue from CAA mouse models (Tg-SwDI/B and 5xFAD mice).
- Characterization of macrophage-derived migrasomes and their interaction with blood vessels.
- Assessment of CD5L content in migrasomes and its effect on complement activation.
- Quantification of migrasome production and membrane attack complex (MAC) levels in relation to disease severity.
- Evaluation of complement inhibitory treatment efficacy in a mouse model.
Main Results:
- Aβ40-induced macrophage migrasomes were found to be sticky to blood vessels in CAA patients and mouse models.
- CD5L was identified within these migrasomes and its enrichment impaired resistance to complement activation.
- Increased migrasome production and MAC levels correlated with CAA disease severity.
- Complement inhibition protected against migrasome-mediated BBB injury in Tg-SwDI/B mice.
Conclusions:
- Macrophage-derived migrasomes contribute to BBB injury in CAA through complement activation.
- CD5L within migrasomes plays a role in this process.
- Migrasomes and complement activation represent potential biomarkers and therapeutic targets for CAA.
