Constitutive 5-HT7 receptor activity as a target for treatment of tauopathy

组成型 5-HT7 受体活性作为 tau 蛋白病治疗的靶点

基本信息

项目摘要

Multiple neurodegenerative diseases are induced by the formation and deposition of protein aggregates. In particular, aggregation of the microtubule-associated protein, Tau, leads to the development of so-called tauopathies, which are characterized by the aggregation of hyperphosphorylated Tau protein within neurons. We recently showed that the constitutive serotonin 5-HT7 receptor (5-HT7R) activity is required for Tau hyperphosphorylation and formation of highly bundled Tau structures through G12-protein-independent, CDK5-dependent mechanism. Moreover, selective 5-HT7R knockdown in mouse cortex fully abrogated impairments in long-term potentiation and memory induced by the overexpression of pathological human mutant Tau[R406W] associated with frontotemporal dementia (FTD). Within this proposal, we aim to characterize structural requirements for 5-HT7R-CDK5 complex formation. Based on this knowledge, we will specifically interfere with 5-HT7R-CDK5 signaling by expressing the mutated form of 5-HT7R (not binding to CDK5). This would enable us to study the role 5-HT7R-CDK5 signaling in small GTPase activities, actin filament dynamics, spinogenesis and synaptic plasticity under physiological conditions and in two forms of tauopathy induced by neuronal overexpression of either human Tau[R406W] or Tau[P301L] mutants. Since we identified several clinically approved drugs to be potential 5-HT7R inverse agonists, we shall compare their efficacies to prevent Tau hyperphosphorylation and aggregation using a high throughput bimolecular fluorescence complementation (BiFC) technique. The most potent drugs will be then investigated for their ability to abrogate pathological Tau effects both in vitro and in vivo using synergistic combination of cutting edge techniques present in participating labs, including biochemical and molecular biological assays, viral manipulations, quantitative intravital microscopy, FRET measurements, electrophysiological recordings, and behavioral analyses. Moreover, a preregistered double-blind randomized preclinical trial of the most efficient 5-TH7R inverse agonist inhibiting Tau hyperphosphorylation and aggregation will be performed to evaluate its effects on multiple cognitive, social, emotional and locomotor functions in male and female Tg4510 mice, also controlling for potential extrapyramidal side effects. Finally, we will evaluate the role of 5-HT7R/CDK5 signaling using human induced pluripotent stem cells (hiPSCs)-derived neurons, which will help to bridge the genetic and phenotypic gap between animal models and humans. Thus, the outcome of this project is expected to improve our understanding of the physiological and pathophysiological significance of 5-HT7R-CDK5 signaling in neurodegenerative diseases and to identify and characterize the therapeutic effects of 5-HT7R-targeting drug for treatment of tauopathy-related disorders.
多种神经退行性疾病是由蛋白质聚集体的形成和沉积引起的。特别地,微管相关蛋白Tau的聚集导致所谓的Tau病的发展,其特征在于过度磷酸化的Tau蛋白在神经元内的聚集。我们最近发现,组成型5-羟色胺5-HT 7受体(5-HT 7 R)活性是Tau过度磷酸化和通过G12蛋白非依赖性、CDK 5依赖性机制形成高度捆绑的Tau结构所必需的。此外,小鼠皮质中的选择性5-HT 7 R敲低完全消除了与额颞叶痴呆(FTD)相关的病理性人突变体Tau[R406 W]过表达诱导的长时程增强和记忆障碍。在该提案中,我们的目标是表征5-HT 7 R-CDK 5复合物形成的结构要求。基于这一知识,我们将通过表达突变形式的5-HT 7 R(不结合CDK 5)特异性干扰5-HT 7 R-CDK 5信号传导。这将使我们能够研究5-HT 7 R-CDK 5信号传导在生理条件下的小GT α活性、肌动蛋白丝动力学、棘发生和突触可塑性中的作用,以及在由人Tau[R406 W]或Tau[P301 L]突变体的神经元过表达诱导的两种形式的Tau病中的作用。由于我们确定了几种临床批准的药物是潜在的5-HT 7 R反向激动剂,我们将使用高通量双分子荧光互补(BiFC)技术比较它们预防Tau过度磷酸化和聚集的功效。然后将研究最有效的药物在体外和体内消除病理性Tau效应的能力,使用参与实验室中存在的尖端技术的协同组合,包括生物化学和分子生物学测定,病毒操作,定量活体显微镜,FRET测量,电生理记录和行为分析。此外,将进行抑制Tau过度磷酸化和聚集的最有效的5-TH 7 R反向激动剂的预先注册的双盲随机临床前试验,以评估其对雄性和雌性Tg 4510小鼠中的多种认知、社交、情感和运动功能的影响,还控制潜在的锥体外系副作用。最后,我们将使用人类诱导多能干细胞(hiPSC)衍生的神经元评估5-HT 7 R/CDK 5信号传导的作用,这将有助于弥合动物模型和人类之间的遗传和表型差距。因此,该项目的结果有望提高我们对5-HT 7 R-CDK 5信号传导在神经退行性疾病中的生理和病理生理学意义的理解,并鉴定和表征5-HT 7 R靶向药物用于治疗tau蛋白病相关疾病的治疗效果。

项目成果

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Professor Dr. Alexander Dityatev, Ph.D.其他文献

Professor Dr. Alexander Dityatev, Ph.D.的其他文献

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{{ truncateString('Professor Dr. Alexander Dityatev, Ph.D.', 18)}}的其他基金

Role of the Serine/Threonin Kinase Ndr2 in Integrin-mediated Neural Plasticity and Learning
丝氨酸/苏氨酸激酶 Ndr2 在整合素介导的神经可塑性和学习中的作用
  • 批准号:
    264761169
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Funktionelle Analyse der neuronalen Anionenaustauscher mit Hilfe von transgenen Mausmodellen
使用转基因小鼠模型进行神经元阴离子交换器的功能分析
  • 批准号:
    32459114
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Mechanisms of synaptic plasticity mediated by extracellular matrix glycoproteins of the tenascin family
腱蛋白家族细胞外基质糖蛋白介导的突触可塑性机制
  • 批准号:
    5439158
  • 财政年份:
    2004
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Mechanisms of synaptogenesis mediated by the neural cell adhesion molecule NCAM in the central nervous system of mouse
神经细胞粘附分子NCAM介导的小鼠中枢神经系统突触发生机制
  • 批准号:
    5330660
  • 财政年份:
    2001
  • 资助金额:
    --
  • 项目类别:
    Research Grants

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5-HT7 receptor and blood pressure regulation
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