Amyloid-[beta] induced toxicity involves ganglioside expression and is sensitive to GM1 neuroprotective action

Abstract

The effect of Ab25–35 peptide, in its fibrillar and non-fibrillar forms, on ganglioside expression in organotypic hippocampal slice cultures was investigated. Gangliosides were endogenously labeled with D-[1-C14] galactose and results showed that Ab25–35 affected ganglioside expression, depending on the peptide aggregation state, that is, fibrillar Ab25–35 caused an increase in GM3 labeling and a reduction in GD1b labeling, whereas the non-fibrillar form was able to enhance GM1 expression. Interestingly, GM1 exhibited a neuroprotective effect in this organotypic model, since pre-treatment of the hippocampal slices with GM1 10 lM was able to prevent the toxicity triggered by the fibrillar Ab25–35, when measured by propidium iodide uptake protocol. With the purpose of further investigating a possible mechanism of action, we analyzed the effect of GM1 treatment (1, 6, 12 and 24 h) upon the Ab-induced alterations on GSK3b dephosphorylation/activation state. Results demonstrated an important effect after 24-h incubation, with GM1 preventing the Ab-induced dephosphorylation (activation) of GSK3b, a signaling pathway involved in apoptosis triggering and neuronal death in models of Alzheimer’s disease. Taken together, present results provide a new and important support for ganglioside participation in development of Alzheimer’s disease experimental models and suggest a protective role for GM1 in Ab-induced toxicity. This may be useful for designing new therapeutic strategies for Alzheimer’s treatment.