Characterizing Wnt Signaling Pathways in Axon Guidance

总结/摘要 阿尔茨海默病（AD）的特征在于Aβ斑块和Tau缠结，其负面地影响了阿尔茨海默病（AD）的治疗。 突触稳定性和突触可塑性并导致神经元死亡和记忆丧失。载脂蛋白E4 载脂蛋白E4（apoE 4）是晚发性AD的主要遗传危险因素。最近的研究表明，apoE 4具有深远的影响， 主要AD病理学，包括淀粉样蛋白-β、tau病理学、神经炎症和神经网络 功能障碍，提示AD发病机制的共同靶点。我们实验室的工作表明， 极性（PCP）在发育中突触的形成中起着重要作用。我们还发现， Aβ与Celsr 3结合，减弱Celsr 3和Frizzled 3之间的相互作用，并协助Vangl 2在细胞内表达。 分解突触PCP信号的调节因子Ryk也是Aβ诱导的突触丢失所必需的 与Vangl 2一起运行。在阿尔茨海默病的5XFAD小鼠模型中，Ryk条件性敲除 在神经元中或脑室内输注功能阻断性单克隆Ryk抗体保护突触 并保留了认知功能我们的新的初步结果表明，一个新的功能的PCP在突触。我们 发现PCP成分Dvl 2和Vangl 2，它们不是突触维持所必需的，但调节突触的形成。 可塑性。此外，Dvl 2在5XFAD小鼠的突触体中下调。询问PCP是否 PCP通路也可能是ApoE的病理靶点，我们检测了ApoE 3和ApoE 4中PCP蛋白的水平 敲入是他与加州大学弗朗西斯科分校格莱斯顿研究所的黄亚东（Yadong Huang）合作，我们发现 在年龄较大的动物（19-19.9个月大）中，ApoE 4动物的突触数量显著减少 与ApoE 3相比，突触中的一些PCP蛋白有减少的趋势。在年幼的动物中 （5.8-5.9个月大），没有明显的突触损失，而电生理变化已经 可检测的我们的初步结果表明，有一个选择性的损失突触的特定组成， PCP蛋白。在这个补充中，我们提出了一组试点实验，以询问Dvl 2的损失是否是 导致突触可塑性丧失并最终失去稳定性。我们将测试不同的成分 突触中PCP蛋白的含量在ApoE模型中表现出不同的易损性。结果从拟议的 实验将使我们不仅能够为未来的突触变性研究提出假设， 阿尔茨海默病，而且还获得了PCP蛋白如何正常调节阿尔茨海默病的形成和功能的线索。 突触以及它们如何调节突触的再生以实现脊髓损伤后的功能恢复， 这也是我们家长资助的目的之一

Summary/Abstract Alzheimer's disease (AD) is characterized by Aβ plaques and Tau tangles, which negatively impact synaptic stability and synaptic plasticity and cause neuronal death and loss of memory. Apolipoprotein E4 (apoE4) is the major genetic risk factor for late-onset AD. Recent work suggests that apoE4 has profound effects on prominent AD pathologies, including amyloid-β, tau pathology, neuroinflammation, and neural network dysfunction, suggesting a common target for pathogenesis of AD. Work from our lab showed that planar cell polarity (PCP) plays an essential role in synapses formation in development. We also showed that oligomeric Aβ binds to Celsr3 and weakens the interaction between Celsr3 and Frizzled3 and assists Vangl2 in disassembling synapses. A regulator of PCP signaling, Ryk, is also required for Aβ-induced synapse loss functioning together with Vangl2. In the 5XFAD mouse model of Alzheimer’s disease, Ryk conditional knockout in neurons or intracerebroventricular infusion of a function-blocking monoclonal Ryk antibody protected synapses and preserved cognitive function. Our new preliminary results suggest a novel function of PCP in synapses. We found that PCP components, Dvl2 and Vangl2, which are not require for synapse maintenance, regulate synaptic plasticity. In addition, Dvl2 is down regulated in the synaptosome of the 5XFAD mice. To ask whether PCP pathway may also be the pathological target of ApoE, we tested the levels of PCP proteins in ApoE3 and ApoE4 knockin mice in collaboration with Yadong Huang of the Gladstone Institute at UC San Francisco. We found that in older animals (19-19.9 months old), there is a dramatic reduction of synapse numbers in ApoE4 animals compared to ApoE3 and a trend of reduction of some of the PCP proteins in the synapses. In younger animals (5.8-5.9 months old), there was no significant loss of synapses, while electrophysiological changes are already detectable. Our preliminary results show that there is a selective loss of synapses with specific compositions of PCP proteins. In this supplement, we propose a set of pilot experiments to ask whether the loss of Dvl2 is responsible for the loss of synaptic plasticity and eventually stability. We will test whether different compositions of PCP proteins in the synapses show different vulnerability in the ApoE model. The results from the proposed experiments will allow us to not only formulate hypothesis for future studies of synapse degeneration in Alzheimer’s disease but also obtain clues of how PCP proteins normally regulate the formation and function of synapses and how they regulate the regeneration of synapses for functional recovery after spinal cord injury, which is one of the aims of our parent grant.