Dkk1-Wnt signalling pathway in synapse degeneration: implication for early stages of Alzheimer's disease

阿尔茨海默病(AD)是一种神经退行性疾病，其特征是记忆力下降，丧失形成和保持新记忆的能力。这些认知特征被认为依赖于被称为突触的神经元接触的数量和强度的变化。在AD患者中，可以观察到进行性认知能力下降和大脑中淀粉样β蛋白(A-Beta)斑块的沉积。许多实验室的研究表明，A-Beta可以诱导神经细胞死亡。然而，认知衰退与突触的丢失和功能障碍最相关。因此，保护突触免受脆弱性的影响可能为在认知能力明显下降之前对AD进行早期干预提供一条途径。多年来，我们的实验室一直在通过专注于一种名为Wnts的分泌蛋白家族的功能来研究哺乳动物大脑中控制突触形成、生长和成熟的机制。我们发现，WNTs在发育过程中促进突触的形成，也是成人大脑中突触完整性所必需的。我们实验室和其他实验室的研究强烈表明，A-Beta会损害Wnt蛋白的功能。事实上，我们发现A-β促进分泌的Wnt拮抗剂Dickkopf-1(Dkk1)的合成，该蛋白介导了A-Beta对脑突触的毒性作用(S)。我们最近建立了一个小鼠模型来研究Dkk1的功能。利用这些小鼠，我们证明了Dkk1诱导了海马区突触的丢失和功能障碍，海马区是学习和记忆的关键大脑区域。一直以来，Dkk1在成人大脑中的表达会导致长期记忆缺陷。拟议的研究方案是以这些调查结果为基础的。我们的主要目标是确定与Dkk1诱导的突触变性有关的分子。我们将采用结合细胞、电生理学和行为学方法的多学科策略来加强对这些破坏性病理过程的理解。我们的研究将使我们更好地理解控制突触完整性的原则和触发突触脆弱性的机制。因此，我们的发现将有助于开发旨在改善症状并可能防止AD早期阶段认知能力下降的进展的治疗策略。我们的发现也将有助于识别早期发现AD的生物标志物。

Alzheimer's disease (AD) is a neurodegenerative condition characterised by a failing memory and loss of the ability to form and retain new memories. These cognitive features are recognised to be dependent on changes in the number and strength of neuronal contacts called synapses. In AD patients, a progressive cognitive decline and deposition of Amyloid-Beta (A-Beta) plaques in the brain are observed. Work from many labs has demonstrated that A-Beta induces neuronal cell death. However, cognitive decline is best correlated with the loss and dysfunction of synapses. Thus, protection of synapses against vulnerability could provide an avenue for early intervention in AD before considerable cognitive decline is evident.For many years, our lab has been studying the mechanisms that control synapse formation, growth and maturation in the mammalian brain by focusing on the function of a family of secreted proteins called Wnts. We discovered that Wnts promote the formation of synapses during development and are also required for synapse integrity in the adult brain. Studies from our lab and others strongly suggest that A-Beta compromises the function of Wnt proteins. Indeed, we discovered that A-Beta promotes the synthesis of Dickkopf-1 (Dkk1), a secreted Wnt antagonist and this protein mediates the toxic effect(s) of A-Beta on brain synapses. We recently developed a mouse model to study the function of Dkk1. Using these mice, we demonstrated that Dkk1 induces the loss and dysfunction of synapses in the hippocampus, a brain area crucial for learning and memory. Consistently, Dkk1 expression in the adult brain induces long-term memory defects. The proposed programme of research builds upon these findings. Our main aim is to identify molecules that contribute to synapse degeneration induced by Dkk1. We will employ a multidisciplinary strategy that combines cellular, electrophysiological and behavioural approaches to enhance understanding of these devastating pathological processes.Our studies will lead to a better understanding of the principles that control synapse integrity and the mechanisms that trigger synapse vulnerability. Thus, our findings will permit the development of therapeutic strategies aimed at ameliorating the symptoms and possibly preventing the progression of cognitive decline at the early stages of AD. Our findings would also contribute to the identification of biomarkers for the early detection of AD.