MicroRNA-155-5p Targets SKP2, Activates IKKβ, Increases Aβ Aggregation, and Aggravates a Mouse Alzheimer Disease Model.
MicroRNA-155-5p Targets SKP2, Activates IKKβ, Increases Aβ Aggregation, and Aggravates a Mouse Alzheimer Disease Model.
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DOI：
10.1093/jnen/nlab116
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发表时间：
2021-12
影响因子：
3.2
通讯作者：
Wei Wang;Xunhu Gu;Min Li;Zhi Cheng;Sheng Tian;Ying Liao;Xu Liu
中科院分区：
文献类型：
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作者：
Wei Wang;Xunhu Gu;Min Li;Zhi Cheng;Sheng Tian;Ying Liao;Xu Liu
核因子-κ B（NF-κB）通路及NF-κB激酶β抑制剂（IKKβ）参与了阿尔茨海默病（AD）的发病机制。本研究探讨了APP.PS1小鼠中IKKβ介导的Aβ聚集和神经元再生的机制。将腺病毒转导颗粒注射到小鼠海马CA 1区以敲低或抑制靶基因。Morris水迷宫检测小鼠认知功能。通过组织学检查确定Aβ沉积。将sh-IKKβ质粒和microRNA（miR）-155-5p抑制剂转染Aβ1-42诱导的N2 a细胞。Western blot检测AD相关蛋白的表达。免疫共沉淀法检测S期激酶相关蛋白2（SKP 2）与IKKβ的相互作用。IKKβ敲除（KD）和miR-155- 5 p抑制可改善APP/PS1小鼠的认知障碍，改善神经元再生，并减少Aβ沉积。SKP 2 KD加重小鼠认知功能障碍，抑制神经元再生，促进Aβ沉积。SKP 2通过泛素化作用调节IKKβ蛋白的稳定性。MiR-155- 5 p通过靶向SKP 2调节N2 a细胞中Aβ沉积和Aβ生成相关蛋白的表达。这些结果表明，miR-155- 5 p/SKP 2/IKKβ轴对于该AD模型中的发病机制至关重要，并表明miR-155- 5 p作为AD治疗靶点的潜力。
The nuclear factor kappa B (NF-κB) pathway and inhibitor of NF-κB kinase β (IKKβ) are involved in Alzheimer disease (AD) pathogenesis. This study explored the mechanisms underlying IKKβ-mediated Aβ aggregation and neuron regeneration in APP.PS1 mice. Adenoviral transduction particles were injected into the hippocampal CA1 region of the mice to knock down or inhibit target genes. Morris water maze was performed to evaluate the cognitive function of the mice. Aβ deposition was determined by histological examination. sh-IKKβ plasmids and microRNA (miR)-155-5p inhibitor were transfected into Aβ1-42-induced N2a cells. The expressions of AD-related proteins were detected by Western blot. The interaction between S-phase kinase-associated protein 2 (SKP2) and IKKβ was assessed by co-immunoprecipitation. IKKβ knockdown (KD) and miR-155-5p inhibition ameliorated cognitive impairment, improved neuron regeneration, and attenuated Aβ deposition in APP/PS1 mice. SKP2 KD aggravated cognitive impairment, inhibited neuron regeneration, and promoted Aβ deposition in the mice. SKP2 regulated the stability of IKKβ protein via ubiquitination. MiR-155-5p regulates Aβ deposition and the expression of Aβ generation-related proteins in N2a cells via targeting SKP2. These results indicate that the miR-155-5p/SKP2/IKKβ axis was critical for pathogenesis in this AD model and suggest the potential of miR-155-5p as a target for AD treatment.