Blockage of GSK3β-mediated Drp1 phosphorylation provides neuroprotection in neuronal and mouse models of Alzheimer's disease
Blockage of GSK3β-mediated Drp1 phosphorylation provides neuroprotection in neuronal and mouse models of Alzheimer's disease
复制标题
阻断 GSK3 β 介导的 Drp1 磷酸化可为阿尔茨海默病的神经元和小鼠模型提供神经保护
DOI：
10.1016/j.neurobiolaging.2014.08.005
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发表时间：
2015-01-01
影响因子：
4.2
通讯作者：
Chen, Zhe-Yu
中科院分区：
文献类型：
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作者：
Yan, Jing;Liu, Xiang-Hua;Chen, Zhe-Yu
众所周知，线粒体断裂在阿尔茨海默病（AD）的发病机制中发挥着关键作用。线粒体分裂由动力相关蛋白 1 (Drp1) 介导，该蛋白在神经系统中高表达，并受到包括磷酸化在内的各种翻译后修饰的调节。我们在 Ser(40) 和 Ser(44) 处发现了糖原合酶激酶 (GSK) 3 β 依赖性 Drp1 磷酸化，这会增加 Drp1 GTPase 活性及其线粒体分布，并可能诱导线粒体断裂。此外，转染Ser(40)Ser(44)拟磷Drp1的神经元显示线粒体碎片增加，并且更容易受到淀粉样蛋白-β(Aβ)诱导的细胞凋亡的影响。因此，阻断GSK3β诱导的Drp1磷酸化可能是保护神经元免受Aβ毒性的有效方法。为了解决这个问题，我们设计并合成了一种名为 TAT-Drp1-SpS 的人工多肽，它可以特异性阻断 GSK3 β 诱导的 Drp1 磷酸化。我们的结果表明，TAT-Drp1-SpS 处理可以显着减少培养神经元中 Aβ 诱导的神经元凋亡。值得注意的是，在海马 Cornu Ammonis 1 (CA1) 区域施用 TAT-Drp1-SpS 显着减轻了 AD 转基因小鼠的 A β 负担并挽救了记忆缺陷。尽管 A beta 有多个靶点来发挥其神经毒性，但我们的研究结果表明，GSK3 beta 诱导的线粒体断裂至少部分是由 Ab 毒性介导的，并有助于 AD 的发病机制。总而言之，GSK3 β 诱导的 Drp1 磷酸化为 AD 中线粒体断裂提供了一种新机制，我们的研究结果提出了一种新的 AD 治疗策略。 (C) 2015 Elsevier Inc. 保留所有权利。
It is well established that mitochondrial fragmentation plays a key role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial fission is mediated by dynamin-related protein 1 (Drp1), which is highly expressed in nervous system and regulated by various posttranslational modifications including phosphorylation. We identified glycogen synthase kinase (GSK) 3 beta-dependent Drp1 phosphorylation at Ser(40) and Ser(44), which increases Drp1 GTPase activity and its mitochondrial distribution and could induce mitochondrial fragmentation. Moreover, neurons transfected with Ser(40)Ser(44) phosphomimic Drp1 showed increased mitochondria fragmentation and were more vulnerable to amyloid-beta (A beta)-induced apoptosis. Therefore, blocking GSK3 beta-induced Drp1 phosphorylation may be an effective way to protect neurons from A beta toxicity. To address this, we designed and synthesized an artificial polypeptide named TAT-Drp1-SpS, which could specifically block GSK3 beta-induced Drp1 phosphorylation. Our results demonstrated that TAT-Drp1-SpS treatment could significantly reduce A beta-induced neuronal apoptosis in cultured neurons. Notably, TAT-Drp1-SpS administration in hippocampus Cornu Ammonis 1 (CA1) region significantly reduced A beta burden and rescued the memory deficits in AD transgenic mice. Although A beta has multiple targets to exert its neurotoxicity, our findings suggested that GSK3 beta-induced mitochondrial fragmentation was, at least partially, mediated by Ab toxicity and contribute to the pathogenesis of AD. Taken together, GSK3 beta-induced Drp1 phosphorylation provides a novel mechanism for mitochondrial fragmentation in AD, and our findings suggested a novel therapeutic strategy for AD. (C) 2015 Elsevier Inc. All rights reserved.