title: Systemic pyruvate administration markedly reduces neuronal death and cognitive impairment in a rat model of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a major neurodegenerative disease of old age, characterized by progressive cognitive impairment, dementia and atrophy of the central nervous system. Amyloid-β (Aβ) oligomers are derived from proteolytic cleavage of amyloid precursor protein (APP) and recognized as the primary neurotoxic agents in AD. Pyruvate has a protective effect against Aβ oligomer-induced neuronal cell death and inhibition of long-term potentiation (LTP) in hippocampal slice cultures, leading us to investigate the effect of systemic pyruvate administration in an intracerebroventricular Aβ oligomer infusion model. We found that sodium pyruvate (500 mg/kg, intraperitoneally) improved neuron survival and sustained improvement in cognitive function as assessed by the Morris water maze. Pyuvate prevented the Aβ oligomer-induced inhibition of LTP and protein phosphatase 2A (PP2A) activation. Pyruvate suppressed the Aβ oligomer-induced poly[adenosine diphosphate (ADP) ribose] polymerase-1 (PARP-1) activity and ameliorated Aβ oligomer-induced decrease of NAD(+) level. Moreover, pyuvate, but not lactate, decreased reactive oxygen species (ROS) accumulation in hippocampus of Aβ1-42 oligomer-injection rat model. These results suggest that systemic pyruvate administration could significantly ameliorate Aβ oligomer-induced spatial learning and memory impairment by the improvement of neuron survival and prevention of LTP inhibition, and the beneficial effect of pyruvate could be linked, at least in part, to the elimination of ROS accumulation, prevention of PP2A activation, amelioration of NAD(+) level and suppression of PARP-1 activity.
authors.affiliation: Department of Gerontology and Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, China. Electronic address: xiao_nan99@hotmail.com.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Gerontology and Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, China.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Gerontology and Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Saiseikai Nakatsu Hospital, Osaka, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Takata
authors.affiliation: National Center for Geriatrics and Gerontology, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakurai
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000150:complications* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D010446:Peptide Fragments / Q000633:toxicity; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism; D019289:Pyruvic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D065853:Spatial Learning / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D019289:Pyruvic Acid; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C514014:Ppp2ca protein, rat; D054648:Protein Phosphatase 2
keywords: Alzheimer's disease; Long-term potentiation; NAD(+); PARP-1; Protein phosphatase 2A; Pyruvate; ROS