Bone marrow mesenchymal stem cells protect against cerebral amyloid angiopathy by enhancing neutrophil mitocytosis

Current treatments for cerebral amyloid angiopathy are mainly symptomatic and have limited efficacy, and there is a lack of targeted therapies. Mesenchymal stem cell transplantation improves cognitive and motor function in conditions such as Alzheimer's disease, acute ischemic stroke, and Parkinson's disease. In addition, mesenchymal stem cell therapy modulates the immune system, reduces neuroinflammation, and improves resolution of brain lesions by cells of the macrophage lineage. Cerebral amyloid angiopathy and Alzheimer's disease share similar pathologic changes involving amyloid-beta deposition, which contributes to the progression of both diseases and exacerbates cognitive deficits through impaired vascular integrity and neuroinflammation. Therefore, we hypothesized that mesenchymal stem cell therapy could also ameliorate the pathological changes seen in cerebral amyloid angiopathy by modulating the immune response. In this study, we show that bone marrow mesenchymal stem cells have a protective effect in a mouse model of cerebral amyloid angiopathy (Tg-SwDI/B). Bone marrow mesenchymal stem cell treatment improved cognitive function, reduced neuroinflammation, and maintained blood-brain barrier integrity in Tg-SwDI/B mice. Mechanistically, bone marrow mesenchymal stem cell treatment enhanced the expulsion of damaged mitochondria from neutrophils via migrasomes, in a process known as mitocytosis, thereby preserving mitochondrial quality within the neutrophils. Mitochondrial damage in neutrophils leads to cellular injury, including the generation of Reactive Oxygen Species and the formation of neutrophil extracellular traps. Neutrophils activate mitocytosis to promote mitochondrial renewal, which further enhances their own clearance by macrophage lineage cells. Our findings demonstrate that bone marrow mesenchymal stem cells are a promising therapeutic candidate for cerebral amyloid angiopathy, as they play a significant role in migrasome-dependent mitochondrial quality control in neutrophils.

bone marrow mesenchymal stem cell; cerebral amyloid angiopathy; cognitive decline; migrasome; mitochondria; neutrophil mitocytosis.