Cytotoxic effects of G(M1) ganglioside and amyloid beta-peptide on mouse embryonic neural stem cells.
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AbstractAD (Alzheimer's disease) is a neurodegenerative disease and the most common form of dementia. One of the pathological hallmarks of AD is the aggregation of extracellular Abetas (amyloid beta-peptides) in senile plaques in the brain. The process could be initiated by seeding provided by an interaction between G(M1) ganglioside and Abetas. Several reports have documented the bifunctional roles of Abetas in NSCs (neural stem cells), but the precise effects of G(M1) and Abeta on NSCs have not yet been clarified. We evaluated the effect of G(M1) and Abeta-(1-40) on mouse NECs (neuroepithelial cells), which are known to be rich in NSCs. No change of cell number was detected in NECs cultured in the presence of either G(M1) or Abeta-(1-40). On the contrary, a decreased number of NECs were cultured in the presence of a combination of G(M1) and Abeta-(1-40). The exogenously added G(M1) and Abeta-(1-40) were confirmed to incorporate into NECs. The Ras-MAPK (mitogen-activated protein kinase) pathway, important for cell proliferation, was intact in NECs simultaneously treated with G(M1) and Abeta-(1-40), but caspase 3 was activated. NECs treated with G(M1) and Abeta-(1-40) were positive in the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay, an indicator of cell death. It was found that G(M1) and Abeta-(1-40) interacted in the presence of cholesterol and sphingomyelin, components of cell surface microdomains. The cytotoxic effect was found also in NSCs prepared via neurospheres. These results indicate that Abeta-(1-40) and G(M1) co-operatively exert a cytotoxic effect on NSCs, likely via incorporation into NEC membranes, where they form a complex for the activation of cell death signalling.
CitationASN Neuro. 2010 Mar 15; 2(1):e00029
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