A disease with a sweet tooth: exploring the Warburg effect in Alzheimer's disease.

After more than 80years from the revolutionary discoveries of Otto Warburg, who observed high glucose dependency, with increased glycolysis and lactate production regardless of oxygen availability in most cancer cells, the 'Warburg effect' returns to the fore in neuronal cells affected by Alzheimer's disease (AD). Indeed, it seems that, in the mild phase of AD, neuronal cells "prefer" to use the energetically inefficient method of burning glucose by glycolysis, as in cancer, proving to become resistant to beta-amyloid (Abeta)-dependent apoptosis. However, in the late phase, while most AD brain cells die in response to Abeta toxicity, only small populations of neurons, exhibiting increased glucose uptake and glycolytic flux, are able to survive as they are resistant to Abeta. Here we draw an overview on the metabolic shift for glucose utilization from oxidative phosphorylation to glycolysis, focusing on the hypothesis that, as extreme attempt to oppose the impending death, mitochondria-whose dysfunction and central role in Abeta toxicity is an AD hallmark-are sent into quiescence, this likely contributing to activate mechanisms of resistance to Abeta-dependent apoptosis. Finally, the attempt turns out fruitless since the loss of the adaptive advantage afforded by elevated aerobic glycolysis exacerbates the pathophysiological processes associated with AD, making the brain susceptible to Abeta-induced neurotoxicity and leading to cell death and dementia. The understanding of how certain nerve cells become resistant to Abeta toxicity, while the majority dies, is an attractive challenge toward the identification of novel possible targets for AD therapy.