期刊
EXPERIMENTAL AND MOLECULAR MEDICINE
卷 45, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/emm.2013.125
关键词
amyloid-beta oligomers; differentiation; glycogen synthase kinase-3 beta; human neural stem cells; migration; proliferation
资金
- Korea Healthcare Technology RD Project [A091159, A121943]
- Ministry for Health and Welfare
- National Research Foundation of Korea [2010-0020289]
- Ministry of Science and Technology
- Faculty Grant of Yonsei University College of Medicine, Republic of Korea [6-2006-0017]
- Korea Health Promotion Institute [A091159] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Alzheimer's disease (AD) is the most common cause of age-related dementia. The neuropathological hallmarks of AD include extracellular deposition of amyloid-beta peptides and neurofibrillary tangles that lead to intracellular hyperphosphorylated tau in the brain. Soluble amyloid-beta oligomers are the primary pathogenic factor leading to cognitive impairment in AD. Neural stem cells (NSCs) are able to self-renew and give rise to multiple neural cell lineages in both developing and adult central nervous systems. To explore the relationship between AD-related pathology and the behaviors of NSCs that enable neuroregeneration, a number of studies have used animal and in vitro models to investigate the role of amyloid-beta on NSCs derived from various brain regions at different developmental stages. However, the A beta effects on NSCs remain poorly understood because of conflicting results. To investigate the effects of amyloid-beta oligomers on human NSCs, we established amyloid precursor protein Swedish mutant-expressing cells and identified cell-derived amyloid-beta oligomers in the culture media. Human NSCs were isolated from an aborted fetal telencephalon at 13 weeks of gestation and expanded in culture as neurospheres. Human NSCs exposure to cell-derived amyloid-beta oligomers decreased dividing potential resulting from senescence through telomere attrition, impaired neurogenesis and promoted gliogenesis, and attenuated mobility. These amyloid-beta oligomers modulated the proliferation, differentiation and migration patterns of human NSCs via a glycogen synthase kinase-3 beta-mediated signaling pathway. These findings contribute to the development of human NSC-based therapy for AD by elucidating the effects of Ab oligomers on human NSCs.
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