The Neuroprotection of KIBRA in Promoting Neuron Survival and Against Amyloid β-Induced Apoptosis
The Neuroprotection of KIBRA in Promoting Neuron Survival and Against Amyloid β-Induced Apoptosis
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KIBRA 在促进神经元存活和对抗淀粉样蛋白诱导的细胞凋亡中的神经保护作用
DOI：
10.3389/fncel.2019.00137
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发表时间：
2019-04-12
影响因子：
5.3
通讯作者：
Du, Yifeng
中科院分区：
文献类型：
--
作者：
Song, Lin;Tang, Shi;Du, Yifeng
背景：最近的研究发现肾脏和脑表达蛋白(KIBRA)的核苷酸多态性与认知功能有关，提示其在阿尔茨海默病(AD)中起重要作用；然而，Kibra在AD中的潜在分子机制尚不清楚。方法：采用AD动物模型(APP/PS1转基因小鼠)和Kibra基因敲除小鼠(Kibra KO)研究Kibra在体内的病理生理变化。通过Kibra CRISPR/Cas9-sgRNA系统和Kibra在体外过表达慢病毒来探讨其分子机制。结果：老龄APP/PS1小鼠和Kibra KO小鼠海马神经细胞凋亡增加。Kibra缺乏症与脑内神经元丢失密切相关。此外，在Aβ(1-42)寡聚体的压力下，神经细胞系中Kibra基因的敲除抑制了其生长，并提高了凋亡相关蛋白的水平。反之，Kibra过表达显著促进细胞增殖，减少细胞凋亡。此外，通过筛选几条与存活相关的信号通路，我们发现Kibra通过激活Akt通路而不是ERK或PKC通路来抑制细胞凋亡，这一点被Akt特异性抑制剂MK2206进一步证实。结论：Kibra可能是一种神经保护基因，在促进神经元存活和抑制Aβ诱导的神经元凋亡方面发挥作用。
Background: Recent research has identified the nucleotide polymorphisms of KIdney and BRAin expressed protein (KIBRA) to be associated with cognitive performance, suggesting its vital role in Alzheimer's disease (AD); however, the underlying molecular mechanism of KIBRA in AD remains obscure.Methods: The AD animal model (APP/PS1 transgenic mice) and KIBRA knockout (KIBRA KO) mice were used to investigate pathophysiological changes of KIBRA in vivo. Mouse hippocampal cell line (HT22) was used to explore its molecular mechanism through KIBRA CRISPR/Cas9-sgRNA system and KIBRA overexpression lentivirus in vitro.Results: Aged APP/PS1 mice displayed increased neuronal apoptosis in the hippocampus, as did KIBRA KO mice. KIBRA deficiency was closely related to neuronal loss in the brain. In addition, knockdown of KIBRA in neuronal cell lines suppressed its growth and elevated apoptosis-associated protein levels under the stress of A beta(1-42) oligomers. On the contrary, overexpression of KIBRA significantly promoted cell proliferation and reduced its apoptosis. Moreover, through screening several survival-related signaling pathways, we found that KIBRA inhibited apoptosis by activating the Akt pathway other than ERK or PKC pathways, which was further confirmed by Akt-specific inhibitor MK2206.Conclusion: Our data indicate that KIBRA may function as a neuroprotective gene in promoting neuron survival and inhibiting A beta-induced neuronal apoptosis.