RESUMEN
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.
Asunto(s)
Amiloide/efectos adversos , Apoptosis/efectos de los fármacos , Hipocampo/metabolismo , Microdominios de Membrana/metabolismo , Neuritas/metabolismo , Amiloide/farmacología , Animales , Astrocitos/metabolismo , Astrocitos/patología , Hipocampo/patología , Microdominios de Membrana/patología , Ratones , Células 3T3 NIH , Neuritas/patología , Osteoblastos/metabolismo , Osteoblastos/patología , RatasRESUMEN
The higher risk for amyotrophic lateral sclerosis (ALS) among professional soccer players, recently reported in Italy, has stimulated investigations in the search for environmental factors that may be at the origin of the increased susceptibility to the disease. Here we studied if high concentrations of branched-chain amino acids (BCAAs), widely used among athletes as dietary integrators to improve physical performance, may be related to an excitotoxic neuronal cell damage. Our results show that (i) high concentrations of BCAAs are neurotoxic and increase excitotoxicity in cortical neurons; (ii) neurotoxicity is brain area specific, being detected in cortical, but not in hippocampal neurons; (iii) it is related to NMDA receptor overstimulation, since it is abolished in the presence of MK-801, a specific NMDA channel blocker; (iv) it depends on the presence of astrocytes. We describe here a possible biological link between an environmental factor (high dietary intake of BCAAs) and the increased risk of ALS among soccer players.