Elliott Christina, Jackson Joshua, Findlay Jane, Williams Gareth, Ghosh Anshua, Ribe Elena, Ulmschneider Martin, Khan Ayesha, Ballard Clive, Aarsland Dag, Baillie George S, Harte Michael, Killick Richard
King's College London, Centre for Healthy Brain Aging, The Institute of Psychiatry, Psychology and Neuroscience, Denmark Hill, London, UK; Newcastle University, School of Biomedical, Nutritional and Sport Sciences, Faculty of Medical Sciences, Newcastle-upon-Tyne, UK.
University of Manchester, Faculty of Biology, Medicine and Health, Division of Pharmacy and Optometry, Manchester, UK.
Cell Signal. 2025 Jul;131:111716. doi: 10.1016/j.cellsig.2025.111716. Epub 2025 Mar 6.
Synapse loss driven by amyloid-β (Aβ) is an early event in Alzheimer's disease (AD). Although the mechanism by which Aβ drives synapse loss remain poorly understood data indicate that a disruption of Wnt signalling plays an important part. We have shown that Aβ exerts its effects on synapses through Dickkopf-1 (Dkk1), a secreted protein that acts upon Wnt signalling via a direct interaction with the canonical Wnt pathway co-receptor proteins, LRP5 and LRP6, preventing their interaction with the receptor Frizzled. This antagonises canonical, Wnt/β-catenin, signalling and allows concomitant activation of non-canonical signalling pathways. We contend that it is the switch from canonical to non-canonical Wnt signalling activity that drives synapse loss and subsequent cognitive impairment in AD, driven by Aβ and mediated by Dkk1. Preventing the Dkk1-LRP5/6 interaction could protect synapses and cognition against Aβ by maintaining canonical Wnt signalling. To test this, we mapped the Dkk1-LRP6 interaction by peptide array and identified a small peptide able to disrupt the Dkk1-LRP6 interaction. This Dkk1-LRP6 'disruptor' peptide dose dependently restores canonical Wnt signalling in the presence of Dkk1; blocks Dkk1-driven dendritic spine loss in primary rat cortical cultures and the accompanying increase in endogenous Aβ production; and when administered intracerebroventricularly to a rat acute Aβ model, blocks Aβ-driven cognitive impairment. These data support our contention that the ability of Aβ to induce Dkk1 and the effects of Dkk1 on LRP6 are an important element in AD aetiopathology and establish Dkk1 as a therapeutic target for protecting synapse and cognition in AD.
由淀粉样β蛋白（Aβ）驱动的突触丧失是阿尔茨海默病（AD）的早期事件。尽管Aβ驱动突触丧失的机制仍知之甚少，但数据表明Wnt信号通路的破坏起着重要作用。我们已经表明，Aβ通过Dickkopf-1（Dkk1）对突触发挥作用，Dkk1是一种分泌蛋白，通过与经典Wnt通路共受体蛋白LRP5和LRP6直接相互作用作用于Wnt信号通路，阻止它们与受体卷曲蛋白相互作用。这拮抗了经典的Wnt/β-连环蛋白信号通路，并允许非经典信号通路的同时激活。我们认为，正是从经典Wnt信号活动向非经典Wnt信号活动的转变驱动了AD中的突触丧失和随后的认知障碍，这由Aβ驱动并由Dkk1介导。通过维持经典Wnt信号通路，阻止Dkk1-LRP5/6相互作用可以保护突触和认知免受Aβ的影响。为了验证这一点，我们通过肽阵列绘制了Dkk1-LRP6相互作用图谱，并鉴定出一种能够破坏Dkk1-LRP6相互作用的小肽。这种Dkk1-LRP6“破坏”肽在有Dkk1存在的情况下剂量依赖性地恢复经典Wnt信号通路；在原代大鼠皮质培养物中阻断Dkk1驱动的树突棘丧失以及内源性Aβ产生的伴随增加；并且当脑室内注射到大鼠急性Aβ模型中时，阻断Aβ驱动的认知障碍。这些数据支持了我们的观点，即Aβ诱导Dkk1的能力以及Dkk1对LRP6的作用是AD发病机制中的一个重要因素，并将Dkk1确立为保护AD中突触和认知的治疗靶点。
