Roles of the glycogen synthase kinase 3 alpha isoform in Alzheimers disease pathophysiology

项目摘要/摘要 阿尔茨海默病(AD)是一种与衰老相关的多因素神经退行性疾病，其特征是 认知障碍和突触衰竭。阿尔茨海默病分子信号转导途径的阐明 可以为这种毁灭性的神经退行性变的病因和潜在的治疗策略提供见解 疾病。越来越多的证据表明，糖原合成酶激酶3(GSK3)的异常过度活性与多发性 阿尔茨海默病的病理生理学方面。同时，基于GSK3抑制的治疗方法的发展 由于缺乏对异构体特异性神经元效应的了解，特别是对于Gsk3α，它具有 与Gsk3β相比，它在很大程度上被忽视了。开发GSK3异构体选择性抑制剂面临的挑战 存在另一层困难，因为抑制α和β亚型都可能导致显著的毒性。 本研究旨在探讨GSK3在AD发病机制中的亚型特异性作用。我们有选择地 用遗传学方法抑制阿尔茨海默病模型小鼠脑内Gsk3α或β亚型。此外，我们还将测试 GSK3在AD模型中的一级异构体选择性拮抗剂。基于以前的工作和初步的 研究表明，需要检验的中心假设是，Gsk3亚型的破坏，特别是Gsk3α，代表着 阿尔茨海默病相关认知损害的关键分子信号机制。一共有三个 明确的目标。目的1阐明GSK3α亚型在AD相关突触可塑性损伤中的作用。 目的2确定GSK3亚型特异性抑制对阿尔茨海默病模型小鼠认知障碍的影响。 目的3是确定与GSK3亚型在AD中的特定作用相关的分子机制。该项目 包括使用多种实验方法的深入分析，包括突触电生理学、 药理学、成像、小鼠遗传学、蛋白质组学/磷蛋白质组学和行为测试。派生的数据 可能揭示以前未知的GSK3信号的异构体特定的作用 阿尔茨海默病病因学中的失调。多学科方法将使我们能够确定详细的机制。 与阿尔茨海默病发病机制中异常的GSK3异构体信号有关，从而为有效 阿尔茨海默病和其他衰老相关认知综合征的治疗靶点和诊断生物标志物。

Project Summary/Abstract Alzheimer’s disease (AD) is an aging-related multifactorial neurodegenerative disorder characterized by cognitive impairment and synaptic failure. Elucidation of the molecular signaling pathways that go awry in AD could provide insights into etiology and potential therapeutic strategies for this devastating neurodegenerative disease. Mounting evidence has linked abnormal over-activity of glycogen synthase kinase 3 (GSK3) to multiple aspects of AD pathophysiology. Meanwhile, the development of therapies based on GSK3 inhibition has been hindered by the lack of understanding of isoform-specific neuronal effects, particularly for GSK3α, which has been largely overlooked compared to GSK3β. Challenges in developing isoform-selective inhibitors for GSK3 present another layer of difficulties since inhibition of both α and β isoforms could result in significant toxicity. This project is aimed to investigate the isoform-specific roles of GSK3 in AD pathogenesis. We have selectively suppressed GSK3α or β isoform in the brain of AD model mice using genetic approaches. Moreover, we will test the first-in-class isoform-selective antagonists of GSK3 in AD models. Based on previous work and preliminary studies, the central hypothesis to be tested is that disruption of GSK3 isoforms, particularly GSK3α, represents a key molecular signaling mechanism underpinning AD-associated cognitive impairment. There are three specific aims. Aim 1 seeks to elucidate roles of GSK3α isoform in AD-associated synaptic plasticity impairments. Aim 2 is to determine the effects of GSK3 isoform-specific inhibition on cognitive impairments in AD model mice. Aim 3 is to identify molecular mechanisms associated with GSK3 isoform-specific roles in AD. The project includes in-depth analyses using multiple experimental approaches, including synaptic electrophysiology, pharmacology, imaging, mouse genetics, proteomics/phosphoproteomics, and behavioral tests. Data derived from the proposed studies could uncover previously unrecognized isoform-specific roles of GSK3 signaling dysregulation in AD etiology. The multidisciplinary approach shall enable us to identify detailed mechanisms associated with aberrant GSK3 isoform signaling in AD pathogenesis, thus providing insights into effective therapeutic targets and diagnostic biomarkers for AD and other aging-related cognitive syndromes.