Cuello A Claudio, Hall Hélène, Do Carmo Sonia
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
Front Pharmacol. 2019 Mar 4;10:189. doi: 10.3389/fphar.2019.00189. eCollection 2019.
This Mini Review discusses the merits and shortfalls of transgenic (tg) rodents modeling aspects of the human Alzheimer's disease (AD) pathology and their application to evaluate experimental therapeutics. It addresses some of the differences between mouse and rat tg models for these investigations. It relates, in a condensed fashion, the experience of our research laboratory with the application of anti-inflammatory compounds and S-adenosylmethionine (SAM) at the earliest stages of AD-like amyloid pathology in tg mice. The application of SAM was intended to revert the global brain DNA hypomethylation unleashed by the intraneuronal accumulation of amyloid-β-immunoreactive material, an intervention that restored levels of DNA methylation including of the gene. This review also summarizes experimental pharmacology observations made in the McGill tg rat model of AD-like pathology by applying "nano-lithium" or a drug with allosteric M1 muscarinic and sigma 1 receptor agonistic properties (AF710B). Extremely low doses of lithium (up to 400 times lower than used in the clinic) had remarkable beneficial effects on lowering pathology and improving cognitive functions in tg rats. Likewise, AF710B treatment, even at advanced stages of the pathology, displayed remarkable beneficial effects. This drug, in experimental conditions, demonstrated possible "disease-modifying" properties as pathology was frankly diminished and cognition improved after a month of "wash-out" period. The Mini-Review ends with a discussion on the predictive value of similar experimental pharmacological interventions in current rodent tg models. It comments on the validity of some of these approaches for early interventions at preclinical stages of AD, interventions which may be envisioned once definitive diagnosis of AD before clinical presentation is made possible.
本综述讨论了转基因（tg）啮齿动物模型在模拟人类阿尔茨海默病（AD）病理方面的优点和不足，以及它们在评估实验性治疗方法中的应用。文中阐述了在这些研究中，小鼠和大鼠tg模型之间的一些差异。简要介绍了我们研究实验室在tg小鼠出现类似AD的淀粉样蛋白病理早期阶段应用抗炎化合物和S-腺苷甲硫氨酸（SAM）的经验。应用SAM旨在逆转由淀粉样β免疫反应性物质在神经元内积累所引发的全脑DNA低甲基化，这种干预恢复了包括该基因在内的DNA甲基化水平。本综述还总结了在麦吉尔AD样病理tg大鼠模型中，通过应用“纳米锂”或具有变构M1毒蕈碱和σ1受体激动特性的药物（AF710B）所取得的实验药理学观察结果。极低剂量的锂（比临床使用剂量低多达400倍）对降低tg大鼠的病理变化和改善认知功能具有显著的有益作用。同样，即使在病理晚期，AF710B治疗也显示出显著的有益效果。在实验条件下，这种药物表现出可能的“疾病修饰”特性，因为在一个月的“洗脱”期后，病理变化明显减轻，认知功能得到改善。本综述最后讨论了当前啮齿动物tg模型中类似实验药理学干预的预测价值。评论了其中一些方法在AD临床前阶段进行早期干预的有效性，这些干预措施有望在AD临床表现前实现明确诊断时实施。
