Decreased Amyloid-β Pathologies by Intracerebral Loading of Glycosphingolipid-enriched Exosomes in Alzheimer Model Mice

Background: Exosome, a type of extracellular vesicles, can associate with A in vitro. Results: Intracerebrally injected exosomes trapped A on surface glycosphingolipids and transported it into microglia in AD mouse brains, resulting in reductions in A pathology. Conclusion: Exogenous exosomes act as potent scavengers for A in mouse brains. Significance: The findings provide a novel therapeutic approach for AD. Elevated levels of amyloid- peptide (A) in the human brain are linked to the pathogenesis of Alzheimer disease. Recent in vitro studies have demonstrated that extracellular A can bind to exosomes, which are cell-secreted nanovesicles with lipid membranes that are known to transport their cargos intercellularly. Such findings suggest that the exosomes are involved in A metabolism in brain. Here, we found that neuroblastoma-derived exosomes exogenously injected into mouse brains trapped A and with the associated A were internalized into brain-resident phagocyte microglia. Accordingly, continuous intracerebral administration of the exosomes into amyloid- precursor protein transgenic mice resulted in marked reductions in A levels, amyloid depositions, and A-mediated synaptotoxicity in the hippocampus. In addition, we determined that glycosphingolipids (GSLs), a group of membrane glycolipids, are highly abundant in the exosomes, and the enriched glycans of the GSLs are essential for A binding and assembly on the exosomes both in vitro and in vivo. Our data demonstrate that intracerebrally administered exosomes can act as potent scavengers for A by carrying it on the exosome surface GSLs and suggest a role of exosomes in A clearance in the central nervous system. Improving A clearance by exosome administration would provide a novel therapeutic intervention for Alzheimer disease.