Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom.
J Neurosci. 2012 Mar 7;32(10):3492-8. doi: 10.1523/JNEUROSCI.4562-11.2012.
Extensive evidence supports a central role for amyloid-β (Aβ) in the pathogenesis of Alzheimer's disease (AD). Synaptic loss mediated by Aβ in early stages of the disease might contribute to cognitive impairments. However, little is known about the mechanism by which Aβ induces the loss of synapses. The expression of the Wnt antagonist Dickkopf-1 (Dkk1) is increased in brains of AD patients and in AD transgenic mouse models, suggesting that dysfunction of Wnt signaling could contribute to AD pathology. Here we report that acute exposure to Aβ oligomers induces Dkk1 expression together with the loss of synaptic sites. Importantly, Dkk1-neutralizing antibodies suppress Aβ-induced synapse loss in mouse brain slices. In mature rat hippocampal neurons, Dkk1 decreases the number of synapses without affecting cell viability. Ultrastructural analyses revealed that Wnt blockade decreases the size of presynaptic and postsynaptic terminals. Time-lapse recordings of RFP-labeled stable synaptic sites demonstrate that Dkk1 induces the dispersal of synaptic components. These findings identify Dkk1 as a potential therapeutic target for the treatment of AD.
大量证据表明β淀粉样蛋白（Aβ）在阿尔茨海默病（AD）的发病机制中起核心作用。疾病早期 Aβ介导的突触丧失可能导致认知障碍。然而，目前对于 Aβ 诱导突触丧失的机制知之甚少。AD 患者和 AD 转基因小鼠模型的大脑中，Wnt 拮抗剂 Dickkopf-1（Dkk1）的表达增加，表明 Wnt 信号功能障碍可能导致 AD 病理学。本文报道，急性暴露于 Aβ 寡聚体可诱导 Dkk1 表达和突触位点丧失。重要的是，Dkk1 中和抗体可抑制 Aβ 诱导的小鼠脑片突触丧失。在成熟的大鼠海马神经元中，Dkk1 减少了突触的数量，而不影响细胞活力。超微结构分析显示，Wnt 阻断减少了突触前和突触后末端的大小。RFP 标记的稳定突触位点的延时记录表明，Dkk1 诱导了突触成分的分散。这些发现表明 Dkk1 可能是治疗 AD 的潜在治疗靶点。
