title: Pyruvate prevents the development of age-dependent cognitive deficits in a mouse model of Alzheimer's disease without reducing amyloid and tau pathology.
abstract: Amyloid-β (Aβ) 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-β- 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-β 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 Zn(2+) as well as glutamate receptor-mediated deregulation of intraneuronal Ca(2+). Thus, pyruvate promotes beneficial cognitive effects without affecting Aβ and tau pathology. The molecule mainly promotes a reduction of hyperexcitability, oxidative stress while favors the regulation of intraneuronal Ca(2+) and Zn(2+) homeostasis rather than acting as energy substrate. Pyruvate can be therefore a valuable, safe, and affordable pharmacological tool to be associated with classical anti-Aβ and tau drugs to counteract the development and progression of AD-related cognitive deficits and neuronal loss.
authors.affiliation: Molecular Neurology Unit, Center of Excellence on Aging (Ce.S.I.), "G. d'Annunzio" University, Chieti, 66100, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Isopi
authors.affiliation: Molecular Neurology Unit, Center of Excellence on Aging (Ce.S.I.), "G. d'Annunzio" University, Chieti, 66100, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Granzotto
authors.affiliation: Molecular Neurology Unit, Center of Excellence on Aging (Ce.S.I.), "G. d'Annunzio" University, Chieti, 66100, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Corona
authors.affiliation: Molecular Neurology Unit, Center of Excellence on Aging (Ce.S.I.), "G. d'Annunzio" University, Chieti, 66100, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Bomba
authors.affiliation: Molecular Neurology Unit, Center of Excellence on Aging (Ce.S.I.), "G. d'Annunzio" University, Chieti, 66100, Italy; School of Human and Social Science, "Kore" University of Enna, Enna, 94100, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Ciavardelli
authors.affiliation: Department of Biological and Environmental Science, University of Sannio, Benevento, 82100, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Curcio
authors.affiliation: Department of Biological and Environmental Science, University of Sannio, Benevento, 82100, Italy.
authors.forename: Lorella M T
authors.initials: LM
authors.lastname: Canzoniero
authors.affiliation: Department of Neuroscience and Imaging, "G. d'Annunzio" University, Chieti, 66100, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Navarra
authors.affiliation: Department of Clinical and Experimental Sciences, "G. d'Annunzio" University, Chieti, 66100, Italy.
authors.forename: Rossano
authors.initials: R
authors.lastname: Lattanzio
authors.affiliation: Department of Clinical and Experimental Sciences, "G. d'Annunzio" University, Chieti, 66100, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Piantelli
authors.affiliation: Molecular Neurology Unit, Center of Excellence on Aging (Ce.S.I.), "G. d'Annunzio" University, Chieti, 66100, Italy; Department of Neuroscience and Imaging, "G. d'Annunzio" University, Chieti, 66100, Italy; Departments of Neurology and Pharmacology, Institute for Memory Impairments and Neurological Disorders, University of California-Irvine, Irvine, 92697, CA, USA. Electronic address: ssensi@uci.edu.
authors.forename: Stefano L
authors.initials: SL
authors.lastname: Sensi
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003072:Cognition Disorders / Q000209:etiology* / Q000517:prevention & control*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006649:Histocompatibility Antigens / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D019289:Pyruvic Acid / Q000627:therapeutic use*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D006649:Histocompatibility Antigens; D018696:Neuroprotective Agents; D016875:tau Proteins; D019289:Pyruvic Acid; D002118:Calcium
keywords: 3xTg-AD mice; Alzheimer's disease; Amyloid; Brain metabolism; Oxidative stress; Pyruvate; Tau; Zinc