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

突触变性中的 Dkk1-Wnt 信号通路：对阿尔茨海默病早期阶段的影响

• 批准号: MR/M024083/1
• 负责人: Patricia Salinas
• 金额: $ 155.15万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM024083%2F1
• 关键词: Dkk1; Wnt; signalling; pathway; synapse

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.

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以及形成和保留新记忆的能力丧失。人们认为这些认知特征取决于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以及大脑中淀粉样蛋白 (A-Beta) 斑块的沉积。许多实验室的工作表明 A-Beta 会诱导神经细胞死亡。然而，认知能力下降与突触的丧失和功能障碍最相关。因此，保护​​突触免受脆弱性的影响，可以在明显的认知能力明显下降之前，为 AD 的早期干预提供途径。多年来，我们的实验室一直致力于研究控制哺乳动物大脑中突触形成、生长和成熟的机制。称为 Wnts 的分泌蛋白家族的功能。我们发现 Wnt 促进发育过程中突触的形成，并且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-Beta 促进 Dickkopf-1 (Dkk1)（一种分泌性 Wnt 拮抗剂）的合成，并且该蛋白介导 A-Beta 对脑突触的毒性作用。我们最近开发了一个小鼠模型来研究 Dkk1 的功能。使用这些小鼠，我们证明 Dkk1 会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。一致地，成人大脑中的 Dkk1 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。我们的主要目标是识别导致 Dkk1 诱导的突触退化的分子。我们将采用结合细胞、电生理学和行为方法的多学科策略来增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脆弱性的机制。因此，我们的研究结果将有助于制定旨在改善症状并可能预防 AD 早期认知能力下降的治疗策略。我们的研究结果还将有助于识别早期检测 AD 的生物标志物。

项目成果

Miro1-dependent mitochondrial dynamics in parvalbumin interneurons.

小清蛋白中间神经元中 Miro1 依赖性线粒体动力学。

• DOI: http://dx.10.7554/elife.65215
• 发表时间: 2021
• 期刊: eLife
• 影响因子: 7.7
• 作者: Kontou G

Loss of Bardet-Biedl syndrome proteins causes synaptic aberrations in principal neurons.

Bardet-Biedl 综合征蛋白的缺失会导致主要神经元的突触畸变。

• DOI: http://dx.10.1371/journal.pbio.3000414
• 发表时间: 2019
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Haq N

Deficient Wnt Signaling and Synaptic Vulnerability in Alzheimer's Disease: Emerging Roles for the LRP6 Receptor.

阿尔茨海默病中 Wnt 信号传导缺陷和突触脆弱性：LRP6 受体的新兴作用。

• DOI: http://dx.10.3389/fnsyn.2018.00038
• 发表时间: 2018
• 期刊: Frontiers in synaptic neuroscience
• 作者: Buechler J

Hippocampus: Activity-Driven Maturation of Neural Circuits for Navigation.

海马：活动驱动的导航神经回路的成熟。

• DOI: http://dx.10.1016/j.cub.2017.04.006
• 发表时间: 2017
• 期刊: CB
• 作者: Cacucci F

Wnt7b signalling through Frizzled-7 receptor promotes dendrite development by coactivating CaMKII and JNK.

通过 Frizzled-7 受体的 Wnt7b 信号传导通过共激活 CaMKII 和 JNK 促进树突发育。

• DOI: http://dx.10.1242/jcs.216101
• 发表时间: 2018
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Ferrari ME