Consequences of dietary manganese and copper imbalance on neuronal apoptosis in a murine model of scrapie.

R. Bolea, P. Hortells, I. Martin-Burriel, A. Vargas, B. Ryffel, M. Monzon and J. J. Badiola (2010) Neuropathology and Applied Neurobiology36, 300–311 Consequences of dietary manganese and copper imbalance on neuronal apoptosis in a murine model of scrapie Aims: Copper and manganese levels are altered in mice both lacking PrPc and prion-infected brains. The aim of this study was to analyse the effects of manganese and copper imbalance on neuronal apoptosis in a scrapie-infected Tga20 mouse model. Methods: Immunoreactivities for the apoptotic proteins Bax and active caspase-3 were evaluated in nine regions of the brain of scrapie-infected and control Tga20 mice treated with one of several diets: depleted cooper (−Cu), loaded manganese (+Mn), depleted copper/loaded manganese (−Cu+Mn) and regular diet. Immunohistochemical determination of NeuN was used to detect possible neuronal loss. Results: Intracellular Bax detection was significantly decreased in animals fed with modified diets, particularly in those treated with copper-depleted diets. A decrease in active caspase-3 was primarily observed in animals fed with enhanced manganese diets. Our results show that the −Cu, −Cu+Mn and +Mn diets protected against apoptosis in scrapie-infected mice. However, NeuN immunolabelling quantification revealed that no diet was sufficient to arrest neuronal death. Conclusions: With regard to apoptosis induction, the response of Tga20 mice to prion infection was similar to that reported for other mice models. Our results demonstrate the neuroprotective effects of –Cu, −Cu+Mn and +Mn diets in a murine model of scrapie. However, neuronal death induced by infection with prions seems to be independent of apoptosis marker signalling. Moreover, copper-modified diets were neuroprotective against the possible toxicity of the prion transgene in Tga20 control and infected mice even though manganese supplementation could not counteract this toxicity.