miRNA-431 Prevents Amyloid-β-Induced Synapse Loss in Neuronal Cell Culture Model of Alzheimer's Disease by Silencing Kremen1.
miRNA-431 Prevents Amyloid-β-Induced Synapse Loss in Neuronal Cell Culture Model of Alzheimer's Disease by Silencing Kremen1.
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DOI：
10.3389/fncel.2018.00087
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发表时间：
2018
影响因子：
5.3
通讯作者：
Murashov AK
中科院分区：
文献类型：
--
作者：
Ross SP;Baker KE;Fisher A;Hoff L;Pak ES;Murashov AK
突触丢失被认为是阿尔茨海默病（AD）发展过程中记忆功能进行性下降的根本原因。最近的观察表明，AD脑中Wnt拮抗剂Dickkopf-1（Dkk 1）的积累在触发突触变性中起着关键作用。在机制上，Dkk 1与其跨膜受体Kremen 1（Krm 1）合作，阻断Wnt/β-catenin信号通路。在这里，我们表明，沉默Krm 1与miR-431防止淀粉样蛋白-β-介导的突触丢失在皮质海马培养分离自三重转基因3xTg-AD小鼠。暴露于Aβ 1（一种淀粉样蛋白-β衍生的扩散配体）或Dkk 1减少了原代神经元培养物中突触前和突触后斑点的数量，而miR-431处理可防止突触丢失。此外，用miR-431处理也防止了神经突变性。我们的研究结果表明，miR-431在AD细胞培养模型中保护突触和神经突免受Aβ毒性，可能是一个有前途的治疗靶点。
Synapse loss is well regarded as the underlying cause for the progressive decline of memory function over the course of Alzheimer's disease (AD) development. Recent observations suggest that the accumulation of the Wnt antagonist Dickkopf-1 (Dkk1) in the AD brain plays a critical role in triggering synaptic degeneration. Mechanistically, Dkk1 cooperates with Kremen1 (Krm1), its transmembrane receptor, to block the Wnt/β-catenin signaling pathway. Here, we show that silencing Krm1 with miR-431 prevents amyloid-β-mediated synapse loss in cortico-hippocampal cultures isolated from triple transgenic 3xTg-AD mice. Exposure to AβDDL (an amyloid-β derived diffusive ligand) or Dkk1 reduced the number of pre- and post-synaptic puncta in primary neuronal cultures, while treatment with miR-431 prevented synapse loss. In addition, treatment with miR-431 also prevented neurite degeneration. Our findings demonstrate that miR-431 protects synapses and neurites from Aβ-toxicity in an AD cell culture model and may be a promising therapeutic target.
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影响因子：
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