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

Alzheimer’s disease (AD) is the most common cause of age-related dementia. The neuropathological hallmarks of AD include extracellular deposition of amyloid-β peptides and neurofibrillary tangles that lead to intracellular hyperphosphorylated tau in the brain. Soluble amyloid-β 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-β on NSCs derived from various brain regions at different developmental stages. However, the Aβ effects on NSCs remain poorly understood because of conflicting results. To investigate the effects of amyloid-β oligomers on human NSCs, we established amyloid precursor protein Swedish mutant-expressing cells and identified cell-derived amyloid-β 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-β oligomers decreased dividing potential resulting from senescence(definition) through telomere(definition) attrition, impaired neurogenesis and promoted gliogenesis, and attenuated mobility. These amyloid-β oligomers modulated the proliferation, differentiation and migration patterns of human NSCs via a glycogen synthase kinase-3β-mediated signaling pathway. These findings contribute to the development of human NSC-based therapy for AD by elucidating the effects of Aβ oligomers on human NSCs. Aggregates of the protein amyloid-β - responsible for Alzheimer's disease - appear to modulate the properties of neural stem cells (NSCs), self-renewing precursors of different types of brain cell. The finding should be considered when designing cell therapies for the neurodegenerative disorder. Kook In Park and colleagues from the Yonsei University College of Medicine in Seoul, South Korea, treated human NSCs with clumps of amyloid-β protein similar to those commonly found in the brains of Alzheimer's patients. The researchers observed that amyloid-β exposure reduced the dividing potential of the stem cells as well as restricted their proliferation, differentiation and migration abilities. These effects were mediated in part by glycogen synthase kinase-3β (GSK-3β), an enzyme activated by amyloid-β. The amyloid-β assemblies also accelerated the shortening of chromosomal caps (called telomeres) in the NSCs, leading to premature cell aging.