title: Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death.
abstract: Amyloid-β (Aβ) oligomers are recognized as the primary neurotoxic agents in Alzheimer's disease (AD). Impaired brain energy metabolism and oxidative stress are implicated in cognitive decline in AD. Nicotinamide adenine dinucleotide (NAD(+)), a coenzyme involved in redox activities in the mitochondrial electron transport chain, has been identified as a key regulator of the lifespan-extending effects, and the activation of NAD(+) expression has been linked with a decrease in Aβ toxicity in AD. One of the key precursors of NAD(+) is nicotinamide mononucleotide (NMN), a product of the nicotinamide phosphoribosyltransferase reaction. To determine whether improving brain energy metabolism will forestall disease progress in AD, the impact of the NAD(+) precursor NMN on Aβ oligomer-induced neuronal death and cognitive impairment were studied in organotypic hippocampal slice cultures (OHCs) and in a rat model of AD. Treatment of intracerebroventricular Aβ oligomer infusion AD model rats with NMN (500mg/kg, intraperitoneally) sustained improvement in cognitive function as assessed by the Morris water maze. In OHCs, Aβ oligomer-treated culture media with NMN attenuated neuronal cell death. NMN treatment also significantly prevented the Aβ oligomer-induced inhibition of LTP. Furthermore, NMN restored levels of NAD(+) and ATP, eliminated accumulation of reactive oxygen species (ROS) in the Aβ oligomer-treated hippocampal slices. All these protective effects were reversed by 3-acetylpyridine, which generates inactive NAD(+). The present study indicates that NMN could restore cognition in AD model rats. The beneficial effect of NMN is produced by ameliorating neuron survival, improving energy metabolism and reducing ROS accumulation. These results suggest that NMN may become a promising therapeutic drug for AD.
authors.affiliation: Department of Gerontology and Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, China. Electronic address: wxiaon9981@yahoo.co.jp.
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: D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000139:chemically induced / Q000150:complications*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D060825:Cognitive Dysfunction / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009537:Nicotinamide Mononucleotide / Q000008:administration & dosage*; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D009243:NAD; D009537:Nicotinamide Mononucleotide; D013481:Superoxides; D000255:Adenosine Triphosphate
keywords: Alzheimer's disease; Cognitive impairment; Neuronal death; Nicotinamide mononucleotide; ROS