Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Medical Center, Jerusalem, Israel; Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Department of Genetic and Metabolic Diseases, Hadassah Medical Center, Jerusalem Israel, Jerusalem, Israel; Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Neurobiol Aging. 2022 Feb;110:77-87. doi: 10.1016/j.neurobiolaging.2021.11.001. Epub 2021 Nov 11.
Advanced age is the main risk factor for the manifestation of late onset neurodegenerative diseases. Metformin, an anti-diabetic drug, was shown to extend longevity, and to ameliorate the activity of recognized aging hallmarks. Here, we compared the clinical, pathologic and biochemical effects of Metformin to those of Nano-PSO (Granagard), a brain targeted anti-oxidant shown by us to delay disease advance in transgenic mice mimicking for genetic Creutzfeldt Jacob disease (CJD) linked to the E200KPrP mutation. We demonstrate that both Metformin and Nano-PSO reduced aging hallmarks activities such as activated AMPK, the main energy sensor of cells as well as Nrf2 and COX IV1, regulators of oxidation, and mitochondrial activity. Both compounds reduced inflammation and increased stem cells production, however did not decrease PrP accumulation. As opposed to Nano-PSO, Metformin neither delayed clinical disease advance in these mice nor reduced the accumulation of sulfated glycosaminoglycans, a pathologic feature of prion disease. We conclude that elevation of anti-aging markers may not be sufficient to delay the fatal advance of genetic CJD.
年龄增长是引发迟发性神经退行性疾病的主要风险因素。二甲双胍是一种治疗糖尿病的药物，已被证明可以延长寿命，并改善公认的衰老标志的活性。在这里，我们将二甲双胍与 Nano-PSO（Granagard）的临床、病理和生化作用进行了比较，Nano-PSO 是一种我们之前研究过的靶向大脑的抗氧化剂，它可以延缓模拟与 E200KPrP 突变相关的遗传克雅氏病（CJD）的转基因小鼠的疾病进展。我们证明，二甲双胍和 Nano-PSO 都能降低衰老标志物的活性，如激活 AMPK，这是细胞的主要能量传感器，以及氧化和线粒体活性的调节因子 Nrf2 和 COX IV1。这两种化合物都能减少炎症和增加干细胞的产生，但不能减少 PrP 的积累。与 Nano-PSO 不同，二甲双胍既不能延缓这些小鼠的临床疾病进展，也不能减少硫酸化糖胺聚糖的积累，硫酸化糖胺聚糖是朊病毒病的一种病理特征。我们的结论是，提高抗衰老标志物的水平可能不足以延缓遗传性 CJD 的致命进展。
