Enhanced activity of superoxide dismutase is a common response to dietary and genetically induced increased cholesterol levels

Objectives: Hypercholesterolaemia has been implicated in the pathogenesis of neurodegenerative diseases. In this work, we tested whether cholesterol-mediated neurodegeneration induced either by cholesterol-rich diet or genetic mutation may share a common mechanism involving increased oxidative stress and mitochondria oxidant status. Additionally, we analysed whether upon cholesterol-rich diet, different brain regions (prefrontal cortex, cortex, hippocampus, and cerebellum) show distinct vulnerability to an oxidative stress response. Methods: Oxidative stress parameters were measured both in vivo (in the liver and in different brain regions) in cholesterol-fed mice and in vitro in genetically induced cholesterol accumulation in NPC1-null cells. Results: Increased superoxide dismutase (SOD) activity was a common feature of cholesterol-mediated antioxidant response in both models. Moreover, upon high-cholesterol diet, all four brain regions analysed responded via somewhat different capacity of antioxidant defence, hippocampus showing the highest basal activity of SOD. Increased activity of SOD upon cholesterol accumulation in vitro involves mitochondrial SOD2. We found that SOD/SOD2 activities are modulated by cholesterol levels. Discussion: Hypercholesterolaemia could potentiate brain dysfunction and neurodegenerative processes via oxidative stress, and activity of mitochondrial SOD2 may play a key role in this process. Our findings suggest that preventing/reducing mitochondrial oxidative stress may represent a common approach against neurodegenerative diseases.