A disease with a sweet tooth: exploring the Warburg effect in Alzheimer's disease.
After more than 80 years 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 β-amyloid (Aβ)-dependent apoptosis. However, in the late phase, while most AD brain cells die in response to Aβ toxicity, only small populations of neurons, exhibiting increased glucose uptake and glycolytic flux, are able to survive as they are resistant to Aβ. 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 Aβ toxicity is an AD hallmark-are sent into quiescence, this likely contributing to activate mechanisms of resistance to Aβ-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 Aβ-induced neurotoxicity and leading to cell death and dementia. The understanding of how certain nerve cells become resistant to Aβ toxicity, while the majority dies, is an attractive challenge toward the identification of novel possible targets for AD therapy.
Institute of Biomembranes and Bioenergetics (IBBE), National Research Council (CNR), Via G. Amendola 165/A, 70126, Bari, Italy. a.atlante@ibbe.cnr.it.
Anna
0000-0001-6577-6414
A
Atlante
Institute of Biomembranes and Bioenergetics (IBBE), National Research Council (CNR), Via G. Amendola 165/A, 70126, Bari, Italy.
Lidia
L
de Bari
Institute of Biomembranes and Bioenergetics (IBBE), National Research Council (CNR), Via G. Amendola 165/A, 70126, Bari, Italy.
Antonella
A
Bobba
Institute of Translational Pharmacology (IFT), National Research Council (CNR), Via Fosso del Cavaliere 100, 00133, Rome, Italy.
Giuseppina
G
Amadoro
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D017209:Apoptosis; D005947:Glucose / Q000378:metabolism; D006801:Humans; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption
D016229:Amyloid beta-Peptides; D005947:Glucose
Alzheimer; Glycolytic pathway; Lactate; Mitochondria; Warburg effect; βeta-amyloid