Lipid raft disruption protects mature neurons against amyloid oligomer toxicity |
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Authors: | Fiorella Malchiodi-Albedi Valentina Contrusciere Carla Raggi Katia Fecchi Gabriella Rainaldi Silvia Paradisi Andrea Matteucci Maria Teresa Santini Massimo Sargiacomo Claudio Frank Maria Cristina Gaudiano Marco Diociaiuti |
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Affiliation: | 1. Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, viale Regina Elena, 299 - 00161 Rome, Italy;2. Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena, 299 - 00161 Rome, Italy;3. Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, viale Regina Elena, 299 - 00161 Rome, Italy;4. Department of Technology and Health, Istituto Superiore di Sanità, viale Regina Elena, 299 - 00161 Rome, Italy;5. National Center for Rare Diseases, Istituto Superiore di Sanità, viale Regina Elena, 299 - 00161 Rome, Italy |
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Abstract: | A specific neuronal vulnerability to amyloid protein toxicity may account for brain susceptibility to protein misfolding diseases. To investigate this issue, we compared the effects induced by oligomers from salmon calcitonin (sCTOs), a neurotoxic amyloid protein, on cells of different histogenesis: mature and immature primary hippocampal neurons, primary astrocytes, MG63 osteoblasts and NIH-3T3 fibroblasts. In mature neurons, sCTOs increased apoptosis and induced neuritic and synaptic damages similar to those caused by amyloid β oligomers. Immature neurons and the other cell types showed no cytotoxicity. sCTOs caused cytosolic Ca2+ rise in mature, but not in immature neurons and the other cell types. Comparison of plasma membrane lipid composition showed that mature neurons had the highest content in lipid rafts, suggesting a key role for them in neuronal vulnerability to sCTOs. Consistently, depletion in gangliosides protected against sCTO toxicity. We hypothesize that the high content in lipid rafts makes mature neurons especially vulnerable to amyloid proteins, as compared to other cell types; this may help explain why the brain is a target organ for amyloid-related diseases. |
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