Yao Zhiwen, Yang Wenhao, Gao Zhiqiang, Jia Peng
Department of Neurology, YangPu Hospital, Tongji University School of Medicine, Shanghai 200092, China.
Department of Neurology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China.
Neurosci Lett. 2017 Apr 24;647:133-140. doi: 10.1016/j.neulet.2017.03.027. Epub 2017 Mar 19.
Amyloid-β (Aβ) oligomers have been accepted as major neurotoxic agents in the therapy of Alzheimer's disease (AD). It has been shown that the activity of nicotinamide adenine dinucleotide (NAD+) is related with the decline of Aβ toxicity in AD. Nicotinamide mononucleotide (NMN), the important precursor of NAD+, is produced during the reaction of nicotinamide phosphoribosyl transferase (Nampt). This study aimed to figure out the potential therapeutic effects of NMN and its underlying mechanisms in APPswe/PS1dE9 (AD-Tg) mice. We found that NMN gave rise to a substantial improvement in behavioral measures of cognitive impairments compared to control AD-Tg mice. In addition, NMN treatment significantly decreased β-amyloid production, amyloid plaque burden, synaptic loss, and inflammatory responses in transgenic animals. Mechanistically, NMN effectively controlled JNK activation. Furthermore, NMN potently progressed nonamyloidogenic amyloid precursor protein (APP) and suppressed amyloidogenic APP by mediating the expression of APP cleavage secretase in AD-Tg mice. Based on our findings, it was suggested that NMN substantially decreases multiple AD-associated pathological characteristically at least partially by the inhibition of JNK activation.
淀粉样β蛋白（Aβ）寡聚体已被公认为是阿尔茨海默病（AD）治疗中的主要神经毒性因子。研究表明，烟酰胺腺嘌呤二核苷酸（NAD+）的活性与AD中Aβ毒性的降低有关。烟酰胺单核苷酸（NMN）是NAD+的重要前体，在烟酰胺磷酸核糖基转移酶（Nampt）反应过程中产生。本研究旨在探究NMN在APPswe/PS1dE9（AD-Tg）小鼠中的潜在治疗作用及其潜在机制。我们发现，与对照AD-Tg小鼠相比，NMN使认知障碍的行为指标有了显著改善。此外，NMN治疗显著降低了转基因动物的β淀粉样蛋白生成、淀粉样斑块负荷、突触损失和炎症反应。从机制上讲，NMN有效控制了JNK激活。此外，NMN通过介导AD-Tg小鼠中APP裂解分泌酶的表达，有力地促进了非淀粉样生成性淀粉样前体蛋白（APP）的生成，并抑制了淀粉样生成性APP。基于我们的研究结果，提示NMN至少部分地通过抑制JNK激活，显著降低了多种与AD相关的病理特征。
