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，其特征是记忆力减退，丧失形成和保持新记忆的能力。这些认知特征被认为是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，观察到进行性认知能力下降和大脑中淀粉样蛋白- β (a - β)斑块沉积。许多实验室的研究表明，a - β诱导神经元细胞死亡。然而，认知能力下降与突触的丧失和功能障碍最为相关。因此，在认知能力明显下降之前，保护突触免受脆弱性可能为阿尔茨海默病的早期干预提供了途径。多年来，我们的实验室一直在研究控制哺乳动物大脑突触形成、生长和成熟的机制，重点关注Wnts家族分泌蛋白的功能。我们发现wnt在发育过程中促进突触的形成，并且也是成人大脑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 - β会损害Wnt蛋白的功能。事实上，我们发现a - β促进Dickkopf-1 （Dkk1）的合成，Dkk1是一种分泌的Wnt拮抗剂，该蛋白介导a - β对脑突触的毒性作用。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诱导海马体突触的丧失和功能障碍，海马体是对学习和记忆至关重要的大脑区域。成人大脑中Dkk1的表达会导致长期记忆缺陷。拟议的研究计划建立在这些发现的基础上。我们的主要目的是确定有助于Dkk1诱导的突触变性的分子。我们将采用多学科策略，结合细胞，电生理和行为方法来加强对这些破坏性病理过程的理解。我们的研究将有助于更好地理解控制突触完整性的原理和触发突触易感性的机制。因此，我们的研究结果将允许开发旨在改善症状的治疗策略，并可能防止阿尔茨海默病早期认知能力下降的进展。我们的发现也将有助于识别早期检测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.