Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
J Mol Cell Biol. 2014 Feb;6(1):75-80. doi: 10.1093/jmcb/mjt049. Epub 2014 Jan 20.
The molecular mechanisms that regulate synapse formation have been well documented. However, little is known about the factors that modulate synaptic stability. Synapse loss is an early and invariant feature of neurodegenerative diseases including Alzheimer's (AD) and Parkinson's disease. Notably, in AD the extent of synapse loss correlates with the severity of the disease. Hence, understanding the molecular mechanisms that underlie synaptic maintenance is crucial to reveal potential targets that will allow the development of therapies to protect synapses. Wnts play a central role in the formation and function of neuronal circuits. Moreover, Wnt signaling components are expressed in the adult brain suggesting their role in synaptic maintenance in the adult. Indeed, blockade of Wnts with the Wnt antagonist Dickkopf-1 (Dkk1) causes synapse disassembly in mature hippocampal cells. Dkk1 is elevated in brain biopsies from AD patients and animal models. Consistent with these findings, Amyloid-β (Aβ) oligomers induce the rapid expression of Dkk1. Importantly, Dkk1 neutralizing antibodies protect synapses against Aβ toxicity, indicating that Dkk1 is required for Aβ-mediated synapse loss. In this review, we discuss the role of Wnt signaling in synapse maintenance in the adult brain, particularly in relation to synaptic loss in neurodegenerative diseases.
调节突触形成的分子机制已得到充分证实。然而，对于调节突触稳定性的因素知之甚少。突触丢失是包括阿尔茨海默病（AD）和帕金森病在内的神经退行性疾病的早期和普遍特征。值得注意的是，在 AD 中，突触丢失的程度与疾病的严重程度相关。因此，了解支持突触维持的分子机制对于揭示潜在的靶点至关重要，这些靶点将允许开发保护突触的疗法。Wnts 在神经元回路的形成和功能中发挥核心作用。此外，Wnt 信号成分在成年大脑中表达，表明它们在成年期的突触维持中发挥作用。事实上，用 Wnt 拮抗剂 Dickkopf-1（Dkk1）阻断 Wnts 会导致成熟海马细胞中的突触解体。AD 患者和动物模型的脑活检中 Dkk1 水平升高。与这些发现一致，淀粉样β（Aβ）寡聚体诱导 Dkk1 的快速表达。重要的是，Dkk1 中和抗体可防止突触免受 Aβ毒性的侵害，表明 Dkk1 是 Aβ介导的突触丢失所必需的。在这篇综述中，我们讨论了 Wnt 信号在成年大脑中的突触维持中的作用，特别是与神经退行性疾病中的突触丢失有关。
