title: Mesenchymal stem cells enhance autophagy and increase β-amyloid clearance in Alzheimer disease models.
abstract: Current evidence suggests a central role for autophagy in Alzheimer disease (AD), and dysfunction in the autophagic system may lead to amyloid-β (Aβ) accumulation. Using in vitro and in vivo AD models, the present study investigated whether mesenchymal stem cells (MSCs) could enhance autophagy and thus exert a neuroprotective effect through modulation of Aβ clearance In Aβ-treated neuronal cells, MSCs increased cellular viability and enhanced LC3-II expression compared with cells treated with Aβ only. Immunofluorescence revealed that MSC coculture in Aβ-treated neuronal cells increased the number of LC3-II-positive autophagosomes that were colocalized with a lysosomal marker. Ultrastructural analysis revealed that most autophagic vacuoles (AVs) in Aβ-treated cells were not fused with lysosomes, whereas a large portion of autophagosomes were conjoined with lysosomes in MSCs cocultured with Aβ-treated neuronal cells. Furthermore, MSC coculture markedly increased Aβ immunoreactivity colocalized within lysosomes and decreased intracellular Aβ levels compared with Aβ-treated cells. In Aβ-treated animals, MSC administration significantly increased autophagosome induction, final maturation of late AVs, and fusion with lysosomes. Moreover, MSC administration significantly reduced the level of Aβ in the hippocampus, which was elevated in Aβ-treated mice, concomitant with increased survival of hippocampal neurons. Finally, MSC coculture upregulated BECN1/Beclin 1 expression in AD models. These results suggest that MSCs significantly enhance autolysosome formation and clearance of Aβ in AD models, which may lead to increased neuronal survival against Aβ toxicity. Modulation of the autophagy pathway to repair the damaged AD brain using MSCs would have a significant impact on future strategies for AD treatment.
authors.affiliation: Department of Neurology and Brain Research Institute; Yonsei University College of Medicine; Seoul, Korea; Severance Biomedical Science Institute; Yonsei University; Seoul, Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Shin
authors.affiliation: Department of Neurology and Brain Research Institute; Yonsei University College of Medicine; Seoul, Korea; Severance Biomedical Science Institute; Yonsei University; Seoul, Korea.
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Department of Neurology and Brain Research Institute; Yonsei University College of Medicine; Seoul, Korea; Severance Biomedical Science Institute; Yonsei University; Seoul, Korea.
authors.forename: Ha Na
authors.initials: HN
authors.lastname: Kim
authors.affiliation: Department of Neurology and Brain Research Institute; Yonsei University College of Medicine; Seoul, Korea; Severance Biomedical Science Institute; Yonsei University; Seoul, Korea.
authors.forename: Se Hee
authors.initials: SH
authors.lastname: Oh
authors.affiliation: Department of Physiology; School of Medicine; Kyungpook National University; Daegu, Korea.
authors.forename: Jae-Sung
authors.initials: JS
authors.lastname: Bae
authors.affiliation: College of Pharmacy; Sungkyunkwan University; Suwon, Korea.
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Ha
authors.affiliation: Department of Neurology and Brain Research Institute; Yonsei University College of Medicine; Seoul, Korea; Severance Biomedical Science Institute; Yonsei University; Seoul, Korea.
authors.forename: Phil Hyu
authors.initials: PH
authors.lastname: Lee
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D016466:CHO Cells; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008565:Membrane Proteins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D008565:Membrane Proteins; D018696:Neuroprotective Agents
keywords: Alzheimer disease; BECN1; amyloid beta; autophagy; mesenchymal stem cell