Isoform-specific roles of AMPK in synaptic failure and memory deficit in Alzheimer's Disease

AMPK 在阿尔茨海默病突触衰竭和记忆缺陷中的异构体特异性作用

• 批准号: 9925166
• 负责人: Tao Ma
• 金额: $ 52.63万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925166
• 关键词: 5' -AMP-activated protein kinase; Acute; Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer’s disease biomarker; Amino Acids; Amyloid beta-Protein; Behavioral; Biochemical; Biological Assay; Biological Markers; Brain; Catalytic Domain; Cell model; Cognition Disorders; Complex; Data; Defect; Dementia; Development; Diagnosis; Diagnostic; Disease; Electrophysiology (science); Excision; Exhibits; Future; Gap Junctions; Genes; Genetic; Genetic Translation; Hippocampus (Brain); Homeostasis; Human; Image; Impairment; Knockout Mice; Knowledge; Learning; Long-Term Potentiation; Mammals; Mass Spectrum Analysis; Measures; Memory; Memory Loss; Memory impairment; Methods; Molecular; Mus; Mutant Strains Mice; Neurodegenerative Disorders; Neurons; Neurosciences; Pathogenesis; Pathology; Performance; Phenotype; Phosphotransferases; Play; Prognostic Marker; Protein Biosynthesis; Protein Isoforms; Protein Kinase; Proteins; Proteomics; Regulation; Reporting; Repression; Role; Short-Term Memory; Signal Pathway; Signal Transduction; Slice; Surface; Synapses; Synaptic plasticity; Syndrome; Testing; Transgenic Mice; Transgenic Model; Translations; Treatment Efficacy; Work; base; behavior test; brain tissue; conditional knockout; confocal imaging; design; diagnostic biomarker; effective therapy; experimental study; improved; insight; interdisciplinary approach; knock-down; mouse genetics; mouse model; new therapeutic target; novel; prevent; protein kinase inhibitor; sensor; spatial memory; synaptic failure; targeted biomarker; therapeutic target

Project Summary/Abstract The basic molecular mechanisms associated with Alzheimer’s disease (AD) remain a critical knowledge gap that prevents identification of effective therapeutic targets and diagnostic/prognostic biomarkers. The current proposal will address this gap by studying the role of signaling pathways associated with AMP-activated protein kinase (AMPK) isoforms in AD. AMPK functions as a central cellular energy sensor to maintain energy homeostasis. Moreover, AMPK is a nexus to incorporate multiple signaling pathways for de novo protein synthesis (mRNA translation). Importantly, both disruptions in energy homeostasis and impairments in de novo protein synthesis are implicated in cognitive syndromes associated with neurodegenerative diseases, including AD. The kinase catalytic subunit of AMPK exists in two isoforms in brain: α1 and α2, and their roles in synaptic plasticity and memory are unknown. We generated brain- and isoform-specific conditional AMPKα1 and α2 knockout mice (AMPKα1 cKO and AMPKα2 cKO), and performed behavioral, electrophysiology, imaging, and biochemical tests to characterize isoform-specific phenotypes. Driven by our preliminary data, our central hypothesis is that disruption of AMPK isoform homeostasis represents a key molecular mechanism underlying AD-associated impairments of synaptic plasticity and memory defects. Three specific aims are formulated to test the hypothesis. Aim 1 seeks to identify isoform-specific roles of AMPK in hippocampal synaptic plasticity and memory formation. Aim 2 is designed to determine AMPK isoform-specific regulation of synaptic failure and memory impairment in Tg19959 AD mouse model. Aim 3 is designed to elucidate AMPK isoform-specific effects on de novo protein synthesis and brain Aβ pathology in Tg19959 AD mouse model. The project proposes in-depth analyses using multiple state-of-art methods in neuroscience and AD, including mouse genetics, synaptic electrophysiology, confocal imaging, and behavioral tests. Moreover, novel methods to measure de novo protein synthesis combined with mass spectrometry/proteomics approach will be applied to reveal identities of proteins in AD brains whose synthesis is dysregulated because of abnormal signaling due to disruption of AMPK isoform homeostasis. This multidisciplinary approach will enable us to identify detailed cellular/molecular mechanisms associated with aberrant AMPK signaling in AD pathogenesis, providing insights into novel therapeutic targets and diagnostic biomarkers for AD and other dementia syndromes.

项目摘要/摘要 与阿尔茨海默氏病有关的基本分子机制（AD）仍然是一个关键的知识差距 这样可以识别有效的治疗靶标和诊断/预后生物标志物。电流 提案将通过研究与AMP激活相关的信号通路的作用来解决这一差距 AD中的蛋白激酶（AMPK）同工型。 AMPK充当中央细胞能量传感器以维持能量 稳态。此外，AMPK是合并从头蛋白的多个信号通路的联系 合成（mRNA翻译）。重要的是，能量稳态的破坏和从头损害的损害 蛋白质合成在与神经退行性疾病相关的认知综合征中隐含 广告。 AMPK的激酶催化亚基存在于大脑中的两个同工型中：α1和α2，它们在突触中的作用 可塑性和记忆未知。我们产生了脑和同工型特异性条件AMPKα1和α2 敲除小鼠（AMPKα1CKO和AMPKα2CKO），并进行了行为，电生理学，成像和 生化测试以表征同工型特异性表型。在我们的初步数据的驱动下，我们的中央 假设是AMPK同工型稳态的破坏代表了一种关键的分子机制 突触可塑性和记忆缺陷的广告相关障碍。提出三个具体目标 检验假设。 AIM 1试图识别AMPK在海马突触可塑性中的同工型特异性作用 和内存形成。 AIM 2旨在确定突触衰竭的AMPK同工型特异性调节 和TG19959 AD鼠标模型中的内存障碍。 AIM 3旨在阐明AMPK亚型特异性 TG19959 AD小鼠模型中对新蛋白合成和脑Aβ病理的影响。项目 使用神经科学和AD的多种最新方法进行深入分析的建议，包括小鼠 遗传学，突触电生理学，共聚焦成像和行为测试。而且，新颖的方法 从头蛋白质合成结合质谱/蛋白质组学方法将应用于 揭示蛋白质在AD大脑中的身份，其合成因应有的信号异常而失调 破坏AMPK同工稳态。这种多学科的方法将使我们能够确定详细的 在AD发病机理中与异常AMPK信号相关的细胞/分子机制，提供 对AD和其他痴呆综合症的新型热靶标和诊断生物标志物的见解。