Pyruvate prevents the development of age-dependent cognitive deficits in a mouse model of Alzheimer's disease without reducing amyloid and tau pathology

Amyloid-beta (A beta) deposition and tau-dependent pathology are key features of Alzheimer's disease (AD). However, to date, approaches aimed at counteracting these two pathogenic factors have produced only modest therapeutic outcomes. More effective therapies should therefore consider additional pathogenic factors like energy production failure, hyperexcitability and excitotoxicity, oxidative stress, deregulation of metal ion homeostasis, and neuroinflammation. Pyruvate is an energy substrate associated with neuroprotective properties. In this study, we evaluated protective effects of long-term administration of pyruvate in 3xTg-AD mice, a preclinical AD model that develops amyloid-beta- and tau-dependent pathology. Chronic (9 months) treatment with pyruvate inhibited short and long-term memory deficits in 6 and 12 months old 3xTg-AD mice as assessed with the Morris water maze test. Pyruvate had no effects on intraneuronal amyloid-beta accumulation and, surprisingly, the molecule increased deposition of phosphorylated tau. Pyruvate did not change aerobic or anaerobic metabolisms but decreased lipid peroxidation, counteracted neuronal hyperexcitability, decreased baseline levels of oxidative stress, and also reduced reactive oxygen species-driven elevations of intraneuronal Zn2+ as well as glutamate receptor-mediated deregulation of intraneuronal Ca2+. Thus, pyruvate promotes beneficial cognitive effects without affecting AS and tau pathology. The molecule mainly promotes a reduction of hyperexcitability, oxidative stress while favors the regulation of intraneuronal Ca2+ and Zn2+ homeostasis rather than acting as energy substrate. Pyruvate can be therefore a valuable, safe, and affordable pharmacological tool to be associated with classical anti-AS and tau drugs to counteract the development and progression of AD-related cognitive deficits and neuronal loss. (C) 2014 Elsevier Inc. All rights reserved.