Department of Neurology, Yangpu Hospital, Tongji University School of Medicine, Shanghai, 200090, China.
J Mol Neurosci. 2021 Jul;71(7):1467-1472. doi: 10.1007/s12031-020-01781-8. Epub 2021 Jan 14.
Nigrostriatal pathway disturbance is one of the major pathogenic factors in Alzheimer's disease (AD). Dopaminergic neuron dysfunction results in bradykinesia and akinesia (inability to initiate movement), indicating a significant risk factor for substantia nigra pars compacta lesions. Furthermore, the nicotinamide adenine dinucleotide (NAD) is associated with Aβ toxicity decline in AD therapy. Nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1) is an essential enzyme that preserves normal neuronal function and protects neurons from insult. This study aimed to investigate the potential therapeutic effects of Nmnat1 and its underlying mechanisms in a triple-transgenic mouse model of AD (3xTgAD). Results showed that Nmnat1 improved the substantial behavioral measures of cognitive impairments compared with the 3xTgAD control. Additionally, Nmnat1 overexpression significantly increased tyrosine hydroxylase-positive neurons and anti-apoptotic protein Bcl2 and caspase-3 expression levels in 3xTgAD mice. Nmnat1 also effectively controlled SOD1 activation. In conclusion, Nmnat1 substantially decreases multiple AD-associated pathological characteristics at least partially by the increase of caspase-3 activation.
黑质纹状体通路紊乱是阿尔茨海默病（AD）的主要致病因素之一。多巴胺能神经元功能障碍导致运动迟缓（无法启动运动），这表明中脑黑质致密部损伤的一个重要危险因素。此外，烟酰胺腺嘌呤二核苷酸（NAD）与 AD 治疗中 Aβ毒性的下降有关。烟酰胺单核苷酸腺嘌呤二核苷酸转移酶 1（Nmnat1）是一种必需的酶，可维持正常神经元功能并保护神经元免受损伤。本研究旨在探讨 Nmnat1 在 AD 三转基因小鼠模型（3xTgAD）中的潜在治疗作用及其潜在机制。结果表明，与 3xTgAD 对照组相比，Nmnat1 改善了认知障碍的显著行为测量。此外，Nmnat1 的过表达显著增加了 3xTgAD 小鼠中酪氨酸羟化酶阳性神经元和抗凋亡蛋白 Bcl2 和 caspase-3 的表达水平。Nmnat1 还能有效控制 SOD1 的激活。总之，Nmnat1 通过增加 caspase-3 的激活，至少部分地显著降低了多种与 AD 相关的病理特征。
