Defining the role of Wnt-Fz7 signalling in long-term plasticity in health and disease

定义 Wnt-Fz7 信号在健康和疾病长期可塑性中的作用

• 批准号: MR/S012125/1
• 负责人: Patricia Salinas
• 金额: $ 86.77万
• 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: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS012125%2F1
• 关键词: Defining; role; Wnt; Fz7; signalling

Efficient communication between brain cells or neurons is a fundamental process required for brain function. This is achieved through specialised contacts between neurons called synapses. The level of communication between synapses varies according to the stimuli received by the neuron. Modulation of this synaptic communication is called synaptic plasticity, a process that underlies crucial functions such as learning and memory. One mode of synaptic plasticity, called long-term potentiation (LTP), increases the strength of synaptic communication. A critical molecule in this process is the neurotransmitter glutamate which binds to receptors, molecules that act as surface antennas at synapses to convey information to the inside of the cell. Binding of glutamate to specific receptors located at the synapse, called NMDA receptors, has profound effects on the connectivity of neurons and on synaptic potentiation. This process is involved in fundamental brain functions such as learning and memory. In Alzheimer's disease (AD), the connectivity between neurons at synapses is profoundly affected in early stages of the disease. Several studies suggest that the weakening of synapses contributes to the loss of these tiny structures, resulting in memory impairment and difficulties in performing basic tasks in patients. Despite the extensive progress made in recent years in scientific research studying the mechanisms that control synaptic connectivity, our understanding of how synapses are modulated in the healthy brain and in conditions such as AD remains very limited. Our research group has been studying the function of a group of proteins called Wnts. These molecules are released by cells and promote the formation of connections between neurons. We recently found that Wnt proteins are present at the synapse and modulate the formation and size of synapses in the hippocampus, a brain area that plays a central role in learning and memory. Our latest work has also demonstrated that Wnts are important modulators of synaptic plasticity that depends on NMDA receptors. Furthermore, our studies have led to the identification of a Wnt receptor that mediates this form of synaptic plasticity. However, the precise molecular mechanisms by which Wnts influence synaptic plasticity through these receptors are not well understood. In the current project, we will address this central question to advance scientific knowledge in this area. Our recent studies demonstrate that the receptor for Wnts at the synapse is decreased in the brain of mouse models of AD, which have been developed to mimic the disease. This finding is in agreement with the hypothesis that deficiency in Wnt molecules contributes to synaptic defects, resulting in memory impairment in AD. In this project, we will also investigate the contribution of this Wnt receptor to synaptic defects in AD mouse models and to test whether modulation of this receptor restores memory. Our studies could have important implications for developing strategies to restore memory in Alzheimer's disease.

脑细胞或神经元之间的有效通信是大脑功能所需的基本过程。这是通过称为突触的神经元之间的专门接触来实现的。突触之间的交流水平根据神经元接收到的刺激而变化。这种突触通讯的调节被称为突触可塑性，这是一个关键功能（如学习和记忆）的基础过程。突触可塑性的一种模式，称为长时程增强（LTP），增加突触通信的强度。在这个过程中，一个关键的分子是神经递质谷氨酸，它与受体结合，这些分子在突触处充当表面天线，将信息传递到细胞内部。谷氨酸与位于突触的特定受体（称为NMDA受体）的结合对神经元的连接性和突触增强具有深远的影响。这个过程涉及大脑的基本功能，如学习和记忆。在阿尔茨海默病（AD）中，突触处神经元之间的连接在疾病的早期阶段受到深刻影响。几项研究表明，突触的减弱导致这些微小结构的丧失，导致患者记忆障碍和执行基本任务的困难。尽管近年来在研究控制突触连接的机制的科学研究方面取得了广泛的进展，但我们对健康大脑和AD等疾病中突触如何调节的理解仍然非常有限。我们的研究小组一直在研究一组称为Wnts的蛋白质的功能。这些分子由细胞释放，促进神经元之间连接的形成。我们最近发现Wnt蛋白存在于突触处，并调节海马中突触的形成和大小，海马是在学习和记忆中起核心作用的脑区。我们的最新工作也证明了Wnt是依赖于NMDA受体的突触可塑性的重要调节剂。此外，我们的研究已经导致Wnt受体介导这种形式的突触可塑性的鉴定。然而，Wnt通过这些受体影响突触可塑性的确切分子机制还不清楚。在本项目中，我们将解决这一核心问题，以推进这一领域的科学知识。我们最近的研究表明，在AD小鼠模型的大脑中，突触处的Wnts受体减少，该模型已被开发用于模拟该疾病。这一发现与Wnt分子缺陷导致突触缺陷，导致AD记忆障碍的假设一致。在这个项目中，我们还将研究这种Wnt受体对AD小鼠模型中突触缺陷的贡献，并测试这种受体的调节是否可以恢复记忆。我们的研究可能对开发恢复阿尔茨海默病记忆的策略具有重要意义。

项目成果

A genetic variant of the Wnt receptor LRP6 accelerates synapse degeneration during aging and in Alzheimer's disease.

• DOI: 10.1126/sciadv.abo7421
• 发表时间: 2023-01-13
• 期刊: Science advances
• 影响因子: 13.6

Wnt-Frizzled Signaling Regulates Activity-Mediated Synapse Formation.

WNT爆发的信号传导调节活动介导的突触形成。

• DOI: 10.3389/fnmol.2021.683035
• 发表时间: 2021
• 期刊: Frontiers in molecular neuroscience
• 影响因子: 4.8
• 作者: Teo S;Salinas PC
• 通讯作者: Salinas PC

Wnt Signaling Through Nitric Oxide Synthase Promotes the Formation of Multi-Innervated Spines.

• DOI: 10.3389/fnsyn.2020.575863
• 发表时间: 2020
• 期刊: Frontiers in synaptic neuroscience
• 影响因子: 3.7
• 作者: McLeod F;Boyle K;Marzo A;Martin-Flores N;Moe TZ;Palomer E;Gibb AJ;Salinas PC
• 通讯作者: Salinas PC

Downregulation of Dickkopf-3, a Wnt antagonist elevated in Alzheimer's disease, restores synapse integrity and memory in a disease mouse model

Dickkopf-3（一种在阿尔茨海默病中升高的 Wnt 拮抗剂）的下调可恢复疾病小鼠模型中的突触完整性和记忆

• DOI: 10.7554/elife.89453.3
• 发表时间: 2024
• 期刊: eLife
• 影响因子: 7.7
• 作者: Podpolny M

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