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.

阿尔茨海默氏病（AD）是一种神经退行性疾病，其特征在于记忆力下降以及形成和保留新记忆的能力丧失。这些认知特征被认为依赖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，观察到进行性认知下降和脑中淀粉样蛋白-β（A-Beta）斑块的沉积。许多实验室的工作表明，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相关。因此，在AD患者出现认知功能明显下降之前，保护突触免受损伤可能为早期干预AD提供一条途径。多年来，本实验室一直致力于研究哺乳动物大脑中控制突触形成、生长和成熟的机制，重点关注一个名为Wnts的分泌蛋白家族的功能。我们发现Wnt在发育过程中促进突触的形成，并且也是成年大脑中突触完整性所必需的。我们实验室和其他人的研究强烈表明，A-β损害了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（Dkk 1）的合成，并且该蛋白质介导A-β对脑突触的毒性作用。我们最近开发了一种小鼠模型来研究Dkk 1的功能。使用这些小鼠，我们证明了Dkk 1诱导海马体中突触的丧失和功能障碍，海马体是学习和记忆的关键大脑区域。因此，Dkk 1在成年人大脑中的表达诱导了长期记忆缺陷。拟议的研究方案以这些调查结果为基础。我们的主要目的是确定分子，有助于Dkk 1诱导的突触变性。我们将采用多学科的策略，结合细胞，电生理和行为的方法，以提高对这些破坏性的病理过程的理解。我们的研究将导致更好地了解控制突触完整性的原则和触发突触脆弱性的机制。因此，我们的研究结果将允许开发治疗策略，旨在改善症状，并可能在AD的早期阶段预防认知能力下降的进展。我们的研究结果也将有助于识别早期发现AD的生物标志物。

项目成果

Striatal Synapse Degeneration and Dysfunction Are Reversed by Reactivation of Wnt Signaling.

• DOI: 10.3389/fnsyn.2021.670467
• 发表时间: 2021
• 期刊: Frontiers in synaptic neuroscience
• 影响因子: 3.7
• 作者: Galli S;Stancheva SH;Dufor T;Gibb AJ;Salinas PC
• 通讯作者: Salinas PC

Single-Cell Quantification of mRNA Expression in The Human Brain

人脑 mRNA 表达的单细胞定量

• DOI: 10.5167/uzh-174534
• 发表时间: 2019
• 作者: Jolly, Sarah

Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus.

• DOI: 10.1016/j.cub.2016.07.024
• 发表时间: 2016-10-10
• 期刊: CURRENT BIOLOGY
• 影响因子: 9.2
• 作者: Marzo, Aude;Galli, Soledad;Lopes, Douglas;McLeod, Faye;Podpolny, Marina;Segovia-Roldan, Margarita;Ciani, Lorenza;Purro, Silvia;Cacucci, Francesca;Gibb, Alasdair;Salinas, Patricia C.
• 通讯作者: Salinas, Patricia C.

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

更正：Bardet-Biedl 综合征蛋白的丢失会导致主要神经元的突触畸变。

• DOI: 10.1371/journal.pbio.3000520
• 发表时间: 2019
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Haq N

Miro1-dependent mitochondrial dynamics in parvalbumin interneurons.

• DOI: 10.7554/elife.65215
• 发表时间: 2021-06-30
• 期刊: eLife
• 影响因子: 7.7
• 作者: Kontou G;Antonoudiou P;Podpolny M;Szulc BR;Arancibia-Carcamo IL;Higgs NF;Lopez-Domenech G;Salinas PC;Mann EO;Kittler JT
• 通讯作者: Kittler JT