Molecular Mechanism of Wnt/Planar Cell Polarity Signaling

摘要 阿尔茨海默病(AD)是衰老过程中最常见的神经退行性疾病，是一种未被满足的 医学挑战。AD是一种复杂的多因素疾病，临床特征是认知能力下降 细胞外β-淀粉样蛋白(A-β)斑块和细胞内积聚的功能和病理定义 神经原纤维缠结(NFTs)。AD既可由遗传缺陷引起，也可由环境因素引起。 突变和风险因素已被确定为导致或改变疾病进展的因素。蜂窝 以及神经细胞、星形胶质细胞、小胶质细胞/免疫细胞和内皮/血管细胞的分子变化 修改AD脑内的病理标志一直是研究的重点。Wnt信号通路 已发现与AD的发病有关。然而，大多数研究都是 主要集中在Wnt/b-连环蛋白途径。Wnt/平面细胞极性(PCP)信号通路在AD中的作用 虽然很重要，但没有得到充分的研究。Wnt/PCP通路是一种高度保守的细胞定位调节因子 在上皮细胞平面内，已被发现对大脑发育和功能是必不可少的。 有趣的是，Wnt-PCP通路在大脑中调节轴突的生长，而不是神经元的极性 脊椎动物和果蝇的发育。尽管果蝇的Wnt/PCP信号是保守的 对于哺乳动物来说，脊椎动物中PCP的调控更加复杂，功能多样，需要额外的 监管方案和脊椎动物特有的PCP成分，如Ror2。已有研究发现，PCP信号转导 成分在谷氨酸能突触形成和Wnt/PCP信号转导中的重要作用 与被切割成β的淀粉样前体蛋白(APP)相互作用，这种相互作用会改变 WNT/PCP信号，它驱动tau病理和神经元死亡导致AD。大多数AD临床试验 都专注于减少抗体负荷，不幸的是，到目前为止，这些试验都没有成功。因此，有 迫切需要寻求其他疾病修改机制和治疗方法。在我们之前的研究中 在父母资助的支持下，我们对Vangl2的调控有了新的发现 Wnt5a和Ror2的磷酸化，这在苍蝇进化为哺乳动物时表现出根本的不同。我们 将扩大我们对体内Vangl2磷酸化在发病机制中的功能需求的研究 两种APP/Ab基因小鼠模型(5XFAD Tg6799)中AD的研究进展 和tau蛋白过度磷酸化(PS19)。我们还将确定APP在Wnt5a诱导的PCP中的作用 信号体。在此过程中，我们将获得对病理生理机制至关重要的新见解。 AD中潜在的WNT/PCP信号，以及确定操纵WNT/PCP信号的潜在目标 治疗阿尔茨海默病的方法。

Abstract Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder during aging and an unmet medical challenge. AD is a complex multi-factorial disease clinically characterized by a decline in cognitive function and pathologically defined by the accumulation of extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). AD can be caused by both genetic defects and environmental factors and genetic mutations and risk factors have been identified that are either causal or modify the disease progression. Cellular and molecular alterations in the neuronal, astroglial, microglial/immune, and endothelial/vascular cells that modify the AD pathological hallmarks in the brain have been the focus of studies. The Wnt signaling pathways have been found to be involved causatively in the pathogenesis of AD. However, most of the research has been focused on the Wnt/b-catenin pathway. The role of the Wnt/planar cell polarity (PCP) signaling pathway in AD, though important, was understudied. The Wnt/PCP pathway is a highly conserved regulator of cellular orientation within the plane of an epithelium and has been found to be essential for brain development and function. Intriguingly, the Wnt-PCP pathway regulates axon outgrowth rather than neuronal polarity during brain development of both vertebrates and Drosophila. Despite the conservation of Wnt/PCP signaling from Drosophila to mammals, PCP regulation in vertebrates is more complex, functionally diverse and requires additional regulatory schemes and vertebrate-specific PCP component such as Ror2. It has been found that PCP signaling components play essential roles in glutamatergic synapse formation in development and Wnt/PCP signaling interacts with the amyloid precursor protein (APP) that is cleaved to become Aβ and such interaction alters Wnt/PCP signaling, which drives tau pathology and neuronal death causing AD. The majority of AD clinical trials have focused on reducing Ab load and unfortunately, these trials have been unsuccessful so far. Thus, there is an urgent need to pursue other disease modifying mechanisms and therapies. In our previous studies before and after the support of the parental grant, we have made the novel discovery for the regulation of Vangl2 phosphorylation by Wnt5a and Ror2, which exhibits fundamental difference when flies evolve to mammals. We will expand our investigation of functional requirement of Vangl2 phosphorylation in vivo in pathogenesis and progression of AD in two genetic mouse models focused respectively on APP/Ab production (5XFAD Tg6799) and tau hyper-phosphorylation (PS19). We will also determine the role of APP in Wnt5a-induced PCP signalosome. In so doing, we will gain critically important new insights into the pathophysiological mechanism underlying Wnt/PCP signaling in AD, as well as identify potential targets for manipulating Wnt/PCP signaling as an approach for AD treatment.