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.

项目总结/文摘