Song Lin, Tang Shi, Dong Lingling, Han Xiaolei, Cong Lin, Dong Jixin, Han Xiaojuan, Zhang Qinghua, Wang Yongxiang, Du Yifeng
Department of Neurology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China.
Department of Neurology, Dongying People's Hospital, Dongying, China.
Front Cell Neurosci. 2019 Apr 12;13:137. doi: 10.3389/fncel.2019.00137. eCollection 2019.
: 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. : The AD animal model (APP/PS1 transgenic mice) and KIBRA knockout (KIBRA KO) mice were used to investigate pathophysiological changes of KIBRA . Mouse hippocampal cell line (HT22) was used to explore its molecular mechanism through KIBRA CRISPR/Cas9-sgRNA system and KIBRA overexpression lentivirus . : 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 Aβ 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. : Our data indicate that KIBRA may function as a neuroprotective gene in promoting neuron survival and inhibiting Aβ-induced neuronal apoptosis.
近期研究已确定肾脏和大脑表达蛋白（KIBRA）的核苷酸多态性与认知能力有关，表明其在阿尔茨海默病（AD）中起着至关重要的作用；然而，KIBRA在AD中的潜在分子机制仍不清楚。使用AD动物模型（APP/PS1转基因小鼠）和KIBRA基因敲除（KIBRA KO）小鼠来研究KIBRA的病理生理变化。使用小鼠海马细胞系（HT22）通过KIBRA CRISPR/Cas9-sgRNA系统和KIBRA过表达慢病毒来探索其分子机制。衰老的APP/PS1小鼠海马中的神经元凋亡增加，KIBRA KO小鼠也是如此。KIBRA缺乏与大脑中的神经元丢失密切相关。此外，在神经元细胞系中敲低KIBRA会抑制其生长，并在Aβ寡聚体应激下提高凋亡相关蛋白水平。相反，KIBRA的过表达显著促进细胞增殖并减少其凋亡。此外，通过筛选几种与生存相关的信号通路，我们发现KIBRA通过激活Akt通路而非ERK或PKC通路来抑制凋亡，这一点通过Akt特异性抑制剂MK2206得到进一步证实。我们的数据表明，KIBRA可能作为一种神经保护基因，在促进神经元存活和抑制Aβ诱导的神经元凋亡中发挥作用。
