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

糖原合酶激酶 3 α 亚型在阿尔茨海默病病理生理学中的作用

• 批准号: 10672556
• 负责人: Tao Ma
• 金额: $ 162.55万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672556
• 关键词: Acute; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amyloid beta-Protein; Biochemistry; Brain; Brain Pathology; Cell physiology; Cognition Disorders; Cognitive deficits; Data; Defect; Dendritic Spines; Development; Diagnostic; Disease; Electrophysiology (science); Etiology; Functional disorder; Future; Genetic Suppression; Glycogen (Starch) Synthase; Glycogen Synthase Kinase 3; Goals; Hippocampus; Image; Impaired cognition; Impairment; Investigation; Link; Long-Term Depression; Long-Term Potentiation; Metabolic Pathway; Methods; Molecular; Morphology; Mus; Mutant Strains Mice; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Pathogenesis; Pathology; Performance; Pharmacology; Phosphorylation; Phosphotransferases; Prognostic Marker; Protein Biosynthesis; Protein Isoforms; Proteomics; Regulation; Repression; Role; Sequence Homology; Series; Signal Pathway; Signal Transduction; Slice; Synapses; Synaptic plasticity; Syndrome; Testing; Therapeutic; Toxic effect; Transgenic Model; Work; antagonist; behavior test; cognitive function; diagnostic biomarker; diagnostic strategy; experimental study; genetic approach; glycogen synthase kinase 3 beta; improved; inhibitor; innovation; insight; interdisciplinary approach; interest; knock-down; mouse genetics; mouse model; new therapeutic target; normal aging; novel; phosphoproteomics; prevent; synaptic failure; synaptic function; targeted biomarker; tau Proteins; therapeutically effective; therapy development

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.

项目概要/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。阐明 AD 中出错的分子信号通路 可以为这种破坏性神经退行性疾病的病因学和潜在治疗策略提供见解 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种疾病有关。 AD 病理生理学的各个方面。与此同时，基于GSK3抑制的疗法的开发也已取得进展。 由于缺乏对异构体特异性神经元效应的了解，特别是 GSK3α，它已 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 由于抑制 α 和 β 亚型可能导致显着的毒性，因此存在另一层困难。 该项目旨在研究 GSK3 在 AD 发病机制中的异构体特异性作用。我们有选择性地 使用遗传方法抑制 AD 模型小鼠大脑中的 GSK3α 或 β 同工型。此外，我们将测试 AD 模型中 GSK3 的同类首创选择性拮抗剂。根据前期工作和前期工作 研究中，要测试的中心假设是 GSK3 亚型的破坏，特别是 GSK3α，代表 AD 相关认知障碍的关键分子信号传导机制。有三个 具体目标。目标 1 试图阐明 GSK3α 同工型在 AD 相关突触可塑性损伤中的作用。 目标 2 是确定 GSK3 同工型特异性抑制对 AD 模型小鼠认知障碍的影响。 目标 3 是确定与 AD 中 GSK3 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进行深入分析，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。数据推导 拟议研究中的结果可能会揭示之前未被识别的 GSK3 信号传导的异构体特异性作用 AD 病因学失调。多学科方法将使我们能够确定详细的机制 与 AD 发病机制中异常的 GSK3 同工型信号传导相关，从而提供有效的见解 AD 和其他与衰老相关的认知综合征的治疗靶点和诊断生物标志物。