title: Decreased amyloid-β pathologies by intracerebral loading of glycosphingolipid-enriched exosomes in Alzheimer model mice.
abstract: Elevated levels of amyloid-β peptide (Aβ) in the human brain are linked to the pathogenesis of Alzheimer disease. Recent in vitro studies have demonstrated that extracellular Aβ 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 Aβ metabolism in brain. Here, we found that neuroblastoma-derived exosomes exogenously injected into mouse brains trapped Aβ and with the associated Aβ were internalized into brain-resident phagocyte microglia. Accordingly, continuous intracerebral administration of the exosomes into amyloid-β precursor protein transgenic mice resulted in marked reductions in Aβ levels, amyloid depositions, and Aβ-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 Aβ 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 Aβ by carrying it on the exosome surface GSLs and suggest a role of exosomes in Aβ clearance in the central nervous system. Improving Aβ clearance by exosome administration would provide a novel therapeutic intervention for Alzheimer disease.
authors.affiliation: From the Laboratory of Biomembrane and Biofunctional Chemistry, Graduate School of Advanced Life Science, and Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo 001-0021, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Yuyama
authors.affiliation: From the Laboratory of Biomembrane and Biofunctional Chemistry, Graduate School of Advanced Life Science, and Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo 001-0021, Japan.
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.affiliation: From the Laboratory of Biomembrane and Biofunctional Chemistry, Graduate School of Advanced Life Science, and Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo 001-0021, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Sakai
authors.affiliation: From the Laboratory of Biomembrane and Biofunctional Chemistry, Graduate School of Advanced Life Science, and Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo 001-0021, Japan, Department of Applied Biochemistry and Food Science, Faculty of Agriculture, Saga University, Saga 840-8502, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Mitsutake
authors.affiliation: Department of Cellular and Molecular Biology, Graduate School of Biomedical Science, Hiroshima University, Hiroshima 734-8553, Japan, and.
authors.forename: Megumi
authors.initials: M
authors.lastname: Okada
authors.affiliation: Department of Cellular and Molecular Biology, Graduate School of Biomedical Science, Hiroshima University, Hiroshima 734-8553, Japan, and.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Tahara
authors.affiliation: Laboratory of Medical and Functional Glycomics, Graduate School of Advanced Life Science, and Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo 001-0021, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Furukawa
authors.affiliation: Laboratory of Medical and Functional Glycomics, Graduate School of Advanced Life Science, and Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo 001-0021, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Fujitani
authors.affiliation: Laboratory of Medical and Functional Glycomics, Graduate School of Advanced Life Science, and Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo 001-0021, Japan.
authors.forename: Yasuro
authors.initials: Y
authors.lastname: Shinohara
authors.affiliation: From the Laboratory of Biomembrane and Biofunctional Chemistry, Graduate School of Advanced Life Science, and Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo 001-0021, Japan, yigarash@pharm.hokudai.ac.jp.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Igarashi
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D045744:Cell Line, Tumor; D055354:Exosomes / Q000378:metabolism*; D006028:Glycosphingolipids / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D006028:Glycosphingolipids
keywords: Alzheimer Disease; Amyloid-β (AB); Exosome; Glycolipid; Microglia