Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cognitive Sciences and Behavior Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Prog Neuropsychopharmacol Biol Psychiatry. 2019 Mar 8;89:322-334. doi: 10.1016/j.pnpbp.2018.10.005. Epub 2018 Oct 5.
Alzheimer's disease (AD) by progressive neurodegenerative pattern is associated with autophagy stress which is suggested as a potential cause of amyloid β (Aβ) aggregation and neural loss. Apelin-13, a neuropeptide with modulatory effect on autophagy, has been shown the beneficial effects on neural cell injuries. We investigated the effect of Apelin-13 on Aβ-induced memory deficit as well as autophagy and apoptosis processes. We performed bilateral intra-CA1 injection of Aβ25-35 alone or in combination with Apelin-13. Spatial reference and working memory was evaluated using the Morris water maze (MWM) and Y-maze tests. Hippocampus was harvested on 2, 5, 10 and 21 days after Aβ injection. The light chain 3 (LC3II/I) ratio, histone deacetylase 6 (HDAC6) level, Caspase-3 cleavage, and mTOR phosphorylation were assessed using western blot technique. Intra-CA1 injection of Aβ caused impairment of working and spatial memory. We observed higher LC3II/I ratio, cleaved caspase-3 and lower HDAC6, and p-mTOR/mTOR ratio in Aβ-treated animals. Apelin-13 provided significant protection against the destructive effects of Aβ on working and spatial memory. Apelin-13 prevented the increase of LC3II/I ratio and cleaved caspase-3 on days 10 and 21 after injection of Aβ. It also limited the Aβ-induced reduction in HDAC6 expression. This implies that Apelin-13 has suppressed both autophagy and apoptosis. Our findings suggested that the neuroprotection of Apelin-13 may be in part related to autophagy and apoptosis inhibition via the mTOR signaling pathway. Apelin-13 may be a promising approach to improve memory impairment and potentially pave the way for new therapeutic plans in AD.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，与自噬应激有关，自噬应激被认为是淀粉样β（Aβ）聚集和神经丢失的潜在原因。阿肽素-13 是一种具有自噬调节作用的神经肽，已显示出对神经细胞损伤的有益作用。我们研究了阿肽素-13 对 Aβ 诱导的记忆缺陷以及自噬和细胞凋亡过程的影响。我们通过双侧 CA1 内注射 Aβ25-35 或与阿肽素-13 联合注射来进行实验。使用 Morris 水迷宫（MWM）和 Y 迷宫测试评估空间参考和工作记忆。在 Aβ 注射后 2、5、10 和 21 天收获海马。使用 Western blot 技术评估 LC3II/I 比值、组蛋白去乙酰化酶 6（HDAC6）水平、Caspase-3 切割和 mTOR 磷酸化。CA1 内注射 Aβ可导致工作记忆和空间记忆受损。我们观察到 Aβ 处理动物的 LC3II/I 比值升高、Caspase-3 切割增加、HDAC6 和 p-mTOR/mTOR 比值降低。阿肽素-13 对 Aβ 对工作和空间记忆的破坏作用提供了显著的保护作用。阿肽素-13 可防止 LC3II/I 比值和 Caspase-3 在注射 Aβ 后 10 和 21 天增加。它还限制了 Aβ 诱导的 HDAC6 表达减少。这表明阿肽素-13 抑制了自噬和细胞凋亡。我们的研究结果表明，阿肽素-13 的神经保护作用可能部分与通过 mTOR 信号通路抑制自噬和细胞凋亡有关。阿肽素-13 可能是改善记忆障碍的一种有前途的方法，并可能为 AD 的新治疗方案铺平道路。
