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

ABSTRACT: Alzheimer's disease (AD) is the most common cause of age-related dementia. The neuropathological hallmarks of AD include extracellular deposition of amyloid-? peptides and neurofibrillary tangles that lead to intracellular hyperphosphorylated tau in the brain. Soluble amyloid-? 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-? on NSCs derived from various brain regions at different developmental stages. However, the A? effects on NSCs remain poorly understood because of conflicting results. To investigate the effects of amyloid-? oligomers on human NSCs, we established amyloid precursor protein Swedish mutant-expressing cells and identified cell-derived amyloid-? 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-? oligomers decreased dividing potential resulting from senescence through telomere attrition, impaired neurogenesis and promoted gliogenesis, and attenuated mobility. These amyloid-? oligomers modulated the proliferation, differentiation and migration patterns of human NSCs via a glycogen synthase kinase-3?-mediated signaling pathway. These findings contribute to the development of human NSC-based therapy for AD by elucidating the effects of A? oligomers on human NSCs.

SUBMITTER: Lee IS 

PROVIDER: S-EPMC3849574 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature