Neuroprotection Through Rapamycin-Induced Activation of Autophagy and PI3K/Akt1/mTOR/CREB Signaling Against Amyloid-β-Induced Oxidative Stress, Synaptic/Neurotransmission Dysfunction, and Neurodegeneration in Adult Rats
Neuroprotection Through Rapamycin-Induced Activation of Autophagy and PI3K/Akt1/mTOR/CREB Signaling Against Amyloid-β-Induced Oxidative Stress, Synaptic/Neurotransmission Dysfunction, and Neurodegeneration in Adult Rats
复制标题
DOI：
10.1007/s12035-016-0129-3
复制
发表时间：
2017-10-01
影响因子：
5.1
通讯作者：
Rizvi, Syed Ibrahim
中科院分区：
文献类型：
--
作者：
Singh, Abhishek Kumar;Kashyap, Mahendra Pratap;Rizvi, Syed Ibrahim
自噬是一种分解代谢过程，涉及持续清除有毒蛋白质聚集体和细胞器，以维持细胞的动态平衡和功能完整性。在神经退行性疾病的发展过程中，自噬介导的神经保护机制的理解仍然难以捉摸。在此，我们研究了雷帕霉素诱导的自噬激活和PI3K/Akt1/mTor/CREB通路(S)在淀粉样β蛋白(Aβ1-42)诱导的阿尔茨海默病(AD)样表型大鼠海马神经元保护中的潜在作用。单次海马区注射Aβ1-42可破坏氧化还原平衡，显著诱导成年大鼠突触功能障碍、神经传递功能障碍和认知功能障碍，并抑制促生存信号。给予雷帕霉素后，mTOR复合体1在Ser2481位的磷酸化水平显著降低，而微管相关蛋白-1轻链-3(Lc3)、Beclin1、隔离小体-1/p62、UNC-51样蛋白1(ULK1)等自噬标志物水平显著升高。此外，雷帕霉素诱导自噬的激活，进一步激活了Aβ1-42处理的大鼠的p-PI3K、p-Akt1(Ser473)和p-CREB(Ser183)的表达。激活的自噬显著逆转了Aβ1-42诱导的氧化还原动态平衡，降低了促氧化剂ROS的生成、细胞内钙通量和LPO的水平，增加了抗氧化剂SOD、过氧化氢酶和GSH的水平。激活的自噬还通过增加突触素-I、突触素和PSD95的表达，以及通过增加CHRM2、DAD2受体、NMDA受体和AMPA受体的水平，对Aβ1-42诱导的突触功能障碍和神经传递功能障碍提供显著的神经保护，最终改善大鼠的认知能力。给予Wortmannin显著降低自噬标志物p-PI3K、p-Akt1和p-CREB的表达以及自噬介导的神经保护作用。我们的研究表明，自噬可能是促生存信号(PI3K/Akt1/mTor/CREB)的一个组成部分，自噬激活可以恢复氧化防御机制(S)、神经退行性损伤，并维持突触和神经传递的完整性。
Autophagy is a catabolic process involved in the continuous removal of toxic protein aggregates and cellular organelles to maintain the homeostasis and functional integrity of cells. The mechanistic understanding of autophagy mediated neuroprotection during the development of neurodegenerative disorders remains elusive. Here, we investigated the potential role of rapamycin-induced activation of autophagy and PI3K/Akt1/mTOR/CREB pathway(s) in the neuroprotection of amyloid-beta (A beta 1-42)-insulted hippocampal neurons in rat model of Alzheimer's disease (AD) like phenotypes. A single intra-hippocampal injection of A beta 1-42 impaired redox balance and markedly induced synaptic dysfunction, neurotransmission dysfunction, and cognitive deficit, and suppressed pro-survival signaling in the adult rats. Rapamycin administration caused a significant reduction of mTOR complex 1 phosphorylation at Ser2481 and a significant increase in levels of autophagy markers such as microtubule-associated protein-1 light chain-3 (LC3), beclin1, sequestosome-1/p62, unc-51-like kinase 1 (ULK1). In addition, rapamycin induced the activation of autophagy that further activated p-PI3K, p-Akt1 (Ser473), and p-CREB (Ser183) expression in A beta 1-42-treated rats. The activated autophagy markedly reversed A beta 1-42-induced impaired redox homeostasis by decreasing the levels of prooxidants-ROS generation, intracellular Ca2+ flux and LPO, and increasing the levels of antioxidants-SOD, catalase, and GSH. The activated autophagy also provided significant neuroprotection against A beta 1-42-induced synaptic dysfunction by increasing the expression of synapsin-I, synaptophysin, and PSD95; and neurotransmission dysfunction by increasing the levels of CHRM2, DAD2 receptor, NMDA receptor, and AMPA receptor; and ultimately improved cognitive ability in rats. Wortmannin administration significantly reduced the expression of autophagy markers, p-PI3K, p-Akt1, and p-CREB, as well as the autophagy mediated neuroprotective effect. Our study demonstrate that autophagy can be an integrated part of pro-survival (PI3K/Akt1/mTOR/CREB) signaling and autophagic activation restores the oxidative defense mechanism(s), neurodegenerative damages, and maintains the integrity of synapse and neurotransmission in rat model of AD.