title: Degradation of amyloid beta by human induced pluripotent stem cell-derived macrophages expressing Neprilysin-2.
abstract: The purpose of this study was to evaluate the therapeutic potential of human induced pluripotent stem (iPS) cell-derived macrophage-like cells for Alzheimer's disease (AD). In previous studies, we established the technology to generate macrophage-like myeloid lineage cells with proliferating capacity from human iPS cells, and we designated the cells iPS-ML. iPS-ML reduced the level of Aβ added into the culture medium, and the culture supernatant of iPS-ML alleviated the neurotoxicity of Aβ. We generated iPS-ML expressing the Fc-receptor-fused form of a single chain antibody specific to Aβ. In addition, we made iPS-ML expressing Neprilysin-2 (NEP2), which is a protease with Aβ-degrading activity. In vitro, expression of NEP2 but not anti-Aβ scFv enhanced the effect to reduce the level of soluble Aβ oligomer in the culture medium and to alleviate the neurotoxicity of Aβ. To analyze the effect of iPS-ML expressing NEP2 (iPS-ML/NEP2) in vivo, we intracerebrally administered the iPS-ML/NEP2 to 5XFAD mice, which is a mouse model of AD. We observed significant reduction in the level of Aβ in the brain interstitial fluid following administration of iPS-ML/NEP2. These results suggested that iPS-ML/NEP2 may be a potential therapeutic agent in the treatment of AD.
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; CREST, Japan Science and Technology Agency, Kawaguchi, Japan. Electronic address: taktr@fc.kuh.kumamoto-u.ac.jp.
authors.forename: Koutaro
authors.initials: K
authors.lastname: Takamatsu
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; CREST, Japan Science and Technology Agency, Kawaguchi, Japan.
authors.forename: Tokunori
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; CREST, Japan Science and Technology Agency, Kawaguchi, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Haruta
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; CREST, Japan Science and Technology Agency, Kawaguchi, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Matsumura
authors.affiliation: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ogi
authors.affiliation: Division of Reproductive Engineering, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Nakagata
authors.affiliation: Department of Neurology, Jonan Hospital, Kumamoto, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Uchino
authors.affiliation: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ando
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; CREST, Japan Science and Technology Agency, Kawaguchi, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Senju
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000637:transplantation; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D016229:Amyloid beta-Peptides; D015703:Antigens, CD; C436550:MMEL1 protein, human; D015260:Neprilysin