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

• Published in: Neurochemistry international Vol. 59; no. 5; pp. 648 - 655
• Main Authors: Kreutz, Fernando, Frozza, Rudimar L., Breier, Ana Carolina, de Oliveira, Valeska A., Horn, Ana Paula, Pettenuzzo, Letícia F., Netto, Carlos Alexandre, Salbego, Christianne Gazzana, Trindade, Vera Maria Treis
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.10.2011; Elsevier
• Subjects: Alzheimer’s disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - toxicity; Amyloid β-peptide (Aβ); Animals; Biological and medical sciences; Blotting, Western; Cell Death - drug effects; Chromatography, Thin Layer; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Fundamental and applied biological sciences. Psychology; G(M1) Ganglioside - pharmacology; Gangliosides; Gangliosides - biosynthesis; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; GM1; GSK3β; Hippocampus - drug effects; Hippocampus - metabolism; Lipid Metabolism - drug effects; Male; Medical sciences; Neurofibrils - drug effects; Neurofibrils - metabolism; Neurology; Neuroprotection; Neuroprotective Agents; Organ Culture Techniques; Organotypic culture; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - toxicity; Phosphorylation; Rats; Rats, Wistar; Vertebrates: nervous system and sense organs; Neuroprotection; GSK3β; Alzheimer’s disease; Organotypic culture; Amyloid β-peptide (Aβ); GM1; Gangliosides; Nervous system diseases; Enzyme; Alzheimer disease; Toxicity; Transferases; Cerebral disorder; Ganglioside; Glycogen synthase kinase-3β; β Amyloid protein; Central nervous system disease; Degenerative disease; Alzheimer's disease
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2011.06.007

► Aβ25–35 affected ganglioside expression in organotypic hippocampal cultures. ► Fibrillar Aβ25–35 increased GM3 labeling and reduced GD1b labeling. ► Non-fibrillar form of Aβ25–35 enhanced GM1 expression. ► Gangliosides could participate in the development of Alzheimer’s disease. ► GM1 exhibited a neuroprotective effect against Aβ-induced toxicity in organotypic model. The effect of Aβ25–35 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 Aβ25–35 affected ganglioside expression, depending on the peptide aggregation state, that is, fibrillar Aβ25–35 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 10μM was able to prevent the toxicity triggered by the fibrillar Aβ25–35, 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 24h) upon the Aβ-induced alterations on GSK3β dephosphorylation/activation state. Results demonstrated an important effect after 24-h incubation, with GM1 preventing the Aβ-induced dephosphorylation (activation) of GSK3β, 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 Aβ-induced toxicity. This may be useful for designing new therapeutic strategies for Alzheimer’s treatment.