Amyloid-β induced toxicity involves ganglioside expression and is sensitive to GM1 neuroprotective action

The effect of A beta 25-35 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-C-14] galactose and results showed that A beta 25-35 affected ganglioside expression, depending on the peptide aggregation state, that is, fibrillar A beta 25-35 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 mu M was able to prevent the toxicity triggered by the fibrillar A beta 25-35, 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 A beta-induced alterations on GSK3 beta dephosphorylation/activation state. Results demonstrated an important effect after 24-h incubation, with GM1 preventing the A beta-induced dephosphorylation (activation) of GSK3 beta, 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 A beta-induced toxicity. This may be useful for designing new therapeutic strategies for Alzheimer's treatment. (C) 2011 Elsevier B.V. All rights reserved.