Malchiodi-Albedi Fiorella, Contrusciere Valentina, Raggi Carla, Fecchi Katia, Rainaldi Gabriella, Paradisi Silvia, Matteucci Andrea, Santini Maria Teresa, Sargiacomo Massimo, Frank Claudio, Gaudiano Maria Cristina, Diociaiuti Marco
Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy.
Biochim Biophys Acta. 2010 Apr;1802(4):406-15. doi: 10.1016/j.bbadis.2010.01.007. Epub 2010 Jan 12.
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 beta oligomers. Immature neurons and the other cell types showed no cytotoxicity. sCTOs caused cytosolic Ca(2+) 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.
特定神经元对淀粉样蛋白毒性的易损性可能是大脑对蛋白质错误折叠疾病易感性的原因。为了研究这个问题，我们比较了鲑鱼降钙素寡聚体（sCTOs）（一种神经毒性淀粉样蛋白）对不同组织发生来源的细胞的影响：成熟和未成熟的原代海马神经元、原代星形胶质细胞、MG63成骨细胞和NIH-3T3成纤维细胞。在成熟神经元中，sCTOs增加了细胞凋亡，并诱导了与β淀粉样寡聚体引起的类似的神经突和突触损伤。未成熟神经元和其他细胞类型未表现出细胞毒性。sCTOs导致成熟神经元而非未成熟神经元及其他细胞类型的胞质Ca(2+)升高。质膜脂质组成的比较表明，成熟神经元的脂筏含量最高，表明它们在神经元对sCTOs的易损性中起关键作用。一致的是，神经节苷脂的消耗可防止sCTO毒性。我们推测，与其他细胞类型相比，脂筏中的高含量使成熟神经元对淀粉样蛋白特别敏感；这可能有助于解释为什么大脑是淀粉样蛋白相关疾病的靶器官。
