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

项目总结/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，其特征在于 认知障碍和突触失效。阐明AD中出错的分子信号通路 可以为这种毁灭性的神经退行性疾病的病因学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（GSK 3）的异常过度活性与多种 AD病理生理学方面。同时，基于GSK 3抑制的疗法的发展已经被证实。 由于缺乏对同种型特异性神经元效应的了解，特别是对GSK 3 α的了解， 与GSK 3 β相比，它在很大程度上被忽视了。开发GSK 3亚型选择性抑制剂的挑战 由于α和β同种型的抑制可能导致显著的毒性，因此存在另一层困难。 本研究旨在探讨GSK 3在AD发病机制中的作用。我们有选择地 用遗传学方法抑制AD模型小鼠脑中的GSK 3 α或β亚型。此外，我们将测试 在AD模型中的GSK 3的第一类亚型选择性拮抗剂。根据以前的工作和初步的 在这些研究中，需要检验的中心假设是，GSK 3亚型，特别是GSK 3 α的破坏， 一种支持AD相关认知障碍的关键分子信号机制。有三 明确的目标。目的1探讨GSK 3 α亚型在AD相关突触可塑性损伤中的作用。 目的二是研究特异性抑制GSK 3亚型对AD模型小鼠认知功能的影响。 目的3是确定与AD中GSK 3亚型特异性作用相关的分子机制。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/磷酸蛋白质组学和行为测试。导出的数据 从拟议的研究中可以发现以前未被认识到的GSK 3信号传导的亚型特异性作用 AD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AD发病机制中的异常GSK 3亚型信号传导相关，从而提供了对AD有效治疗的见解。 AD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.