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Mesenchymal stem cells enhance autophagy and increase β-amyloid clearance in Alzheimer disease models

Authors
 Jin Young Shin  ;  Hyun Jung Park  ;  Ha Na Kim  ;  Se Hee Oh  ;  Jae-Sung Bae  ;  Hee-Jin Ha  ;  Phil Hyu Lee 
Citation
 AUTOPHAGY, Vol.10(1) : 32-44, 2014 
Journal Title
 AUTOPHAGY 
ISSN
 1554-8627 
Issue Date
2014
MeSH
Alzheimer Disease/metabolism* ; Alzheimer Disease/pathology* ; Amyloid beta-Peptides/metabolism* ; Amyloid beta-Peptides/toxicity ; Animals ; Apoptosis Regulatory Proteins/metabolism ; Autophagy*/drug effects ; Beclin-1 ; CHO Cells ; Cell Line ; Cell Survival/drug effects ; Cricetinae ; Cricetulus ; Disease Models, Animal ; Hippocampus/pathology ; Humans ; Lysosomes/drug effects ; Lysosomes/metabolism ; Lysosomes/ultrastructure ; Membrane Proteins/metabolism ; Mesenchymal Stromal Cells/cytology* ; Mesenchymal Stromal Cells/drug effects ; Mesenchymal Stromal Cells/metabolism ; Mesenchymal Stromal Cells/ultrastructure ; Mice ; Neurons/drug effects ; Neurons/metabolism ; Neurons/pathology ; Neuroprotective Agents/metabolism ; Phagosomes/drug effects ; Phagosomes/metabolism ; Phagosomes/ultrastructure ; Time Factors
Keywords
Alzheimer disease ; BECN1 ; amyloid beta ; autophagy ; mesenchymal stem cell
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.
Full Text
http://www.tandfonline.com/doi/full/10.4161/auto.26508#.VI_bJNKsXTo
DOI
10.4161/auto.26508
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurology (신경과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Ha Na(김하나)
Park, Hyun Jung(박현정)
Shin, Jin Young(신진영)
Oh, Se Hee(오세희)
Lee, Phil Hyu(이필휴) ORCID logo https://orcid.org/0000-0001-9931-8462
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/97936
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