Exp Mol Med.  2013 Nov;45(11):e60.

Amyloid-beta oligomers regulate the properties of human neural stem cells through GSK-3beta signaling

• Lee IS
• Jung K
• Kim IS
• Park KI

Abstract

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 Abeta 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-3beta-mediated signaling pathway. These findings contribute to the development of human NSC-based therapy for AD by elucidating the effects of Abeta oligomers on human NSCs.

Keyword

amyloid-beta oligomers; differentiation; glycogen synthase kinase-3beta; human neural stem cells; migration; proliferation

MeSH Terms

Amyloid beta-Peptides/*pharmacology
Animals
Apoptosis
Cell Aging
Cell Movement
Cell Proliferation
Culture Media, Conditioned/chemistry/pharmacology
Fetus/cytology
Glycogen Synthase Kinase 3/*metabolism
HEK293 Cells
Humans
Mice
Mice, Inbred C57BL
Neural Stem Cells/*drug effects/metabolism/physiology
Signal Transduction
Telomere Shortening
Amyloid beta-Peptides
Culture Media, Conditioned
Glycogen Synthase Kinase 3