Ross Sean P, Baker Kelly E, Fisher Amanda, Hoff Lee, Pak Elena S, Murashov Alexander K
Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, United States.
Front Cell Neurosci. 2018 Mar 28;12:87. doi: 10.3389/fncel.2018.00087. eCollection 2018.
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.
突触丧失被公认为是阿尔茨海默病（AD）发展过程中记忆功能逐渐衰退的根本原因。最近的观察结果表明，Wnt拮抗剂Dickkopf-1（Dkk1）在AD大脑中的积累在触发突触退化中起关键作用。从机制上讲，Dkk1与其跨膜受体Kremen1（Krm1）协同作用，阻断Wnt/β-连环蛋白信号通路。在此，我们表明，用miR-431沉默Krm1可防止从三重转基因3xTg-AD小鼠分离的皮质-海马培养物中淀粉样β蛋白介导的突触丧失。暴露于AβDDL（一种淀粉样β蛋白衍生的扩散配体）或Dkk1会减少原代神经元培养物中突触前和突触后小点的数量，而用miR-431处理可防止突触丧失。此外，用miR-431处理还可防止神经突退化。我们的研究结果表明，在AD细胞培养模型中，miR-431可保护突触和神经突免受Aβ毒性影响，可能是一个有前景的治疗靶点。
