Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Veterans Affairs Medical Center, Baltimore, MD 21201, USA.
Int J Mol Sci. 2020 May 26;21(11):3756. doi: 10.3390/ijms21113756.
Diabetes predisposes to cognitive decline leading to dementia and is associated with decreased brain NAD levels. This has triggered an intense interest in boosting nicotinamide adenine dinucleotide (NAD) levels to prevent dementia. We tested if the administration of the precursor of NAD, nicotinamide mononucleotide (NMN), can prevent diabetes-induced memory deficits. Diabetes was induced in Sprague-Dawley rats by the administration of streptozotocin (STZ). After 3 months of diabetes, hippocampal NAD levels were decreased ( = 0.011). In vivo localized high-resolution proton magnetic resonance spectroscopy (MRS) of the hippocampus showed an increase in the levels of glucose ( < 0.001), glutamate ( < 0.001), gamma aminobutyric acid ( = 0.018), -inositol ( = 0.018), and taurine ( < 0.001) and decreased levels of -acetyl aspartate ( = 0.002) and glutathione ( < 0.001). There was a significant decrease in hippocampal CA1 neuronal volume ( < 0.001) and neuronal number ( < 0.001) in the Diabetic rats. Diabetic rats showed hippocampal related memory deficits. Intraperitoneal NMN (100 mg/kg) was given after induction and confirmation of diabetes and was provided on alternate days for 3 months. NMN increased brain NAD levels, normalized the levels of glutamate, taurine, N-acetyl aspartate (NAA), and glutathione. NMN-treatment prevented the loss of CA1 neurons and rescued the memory deficits despite having no significant effect on hyperglycemic or lipidemic control. In hippocampal protein extracts from Diabetic rats, SIRT1 and PGC-1α protein levels were decreased, and acetylation of proteins increased. NMN treatment prevented the diabetes-induced decrease in both SIRT1 and PGC-1α and promoted deacetylation of proteins. Our results indicate that NMN increased brain NAD, activated the SIRT1 pathway, preserved mitochondrial oxidative phosphorylation (OXPHOS) function, prevented neuronal loss, and preserved cognition in Diabetic rats.
糖尿病易导致认知能力下降，进而导致痴呆症，并且与大脑 NAD 水平降低有关。这引发了人们强烈的兴趣，希望通过提高烟酰胺腺嘌呤二核苷酸（NAD）水平来预防痴呆症。我们测试了烟酰胺单核苷酸（NMN），即 NAD 的前体，是否可以预防糖尿病引起的记忆障碍。通过给予链脲佐菌素（STZ），诱导 Sprague-Dawley 大鼠发生糖尿病。3 个月糖尿病后，海马体 NAD 水平降低（=0.011）。海马体的体内局部高分辨率质子磁共振波谱（MRS）显示，葡萄糖（<0.001）、谷氨酸（<0.001）、γ-氨基丁酸（=0.018）、肌醇（=0.018）和牛磺酸（<0.001）水平升高，而乙酰天门冬氨酸（<0.001）和谷胱甘肽（<0.001）水平降低。糖尿病大鼠的海马 CA1 神经元体积（<0.001）和神经元数量（<0.001）显著减少。糖尿病大鼠表现出海马相关的记忆障碍。糖尿病诱导和确认后，给予腹腔内 NMN（100mg/kg），隔天给予 3 个月。NMN 增加了大脑 NAD 水平，使谷氨酸、牛磺酸、N-乙酰天门冬氨酸（NAA）和谷胱甘肽的水平正常化。尽管对高血糖或血脂控制没有显著影响，但 NMN 治疗可防止 CA1 神经元丢失并挽救记忆障碍。在糖尿病大鼠的海马体蛋白提取物中，SIRT1 和 PGC-1α 蛋白水平降低，蛋白乙酰化增加。NMN 治疗可预防糖尿病引起的 SIRT1 和 PGC-1α 减少，并促进蛋白去乙酰化。我们的结果表明，NMN 增加了大脑 NAD，激活了 SIRT1 通路，维持了线粒体氧化磷酸化（OXPHOS）功能，防止了神经元丢失，并维持了糖尿病大鼠的认知能力。
