AMPK in Alzheimer's Disease-Associated Synaptic Failure and Memory Deficits

AMPK 在阿尔茨海默病相关的突触衰竭和记忆缺陷中的作用

• 批准号: 9134581
• 负责人: Tao Ma
• 金额: $ 24.63万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9134581
• 关键词: 5' -AMP-activated protein kinase; Address; Age; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antibodies; Autophagocytosis; Basic Science; Behavioral; Brain; Cause of Death; Cognition Disorders; Data; Defect; Dementia; Disease; Elderly; Etiology; Failure; Functional disorder; Gene Deletion; Genes; Genetic; Genetic Translation; Goals; Hand; Health; Homeostasis; Immunotherapy; Impairment; Knowledge; Learning; Lobe; Memory; Memory impairment; Mentors; Molecular; Molecular Abnormality; Mus; Mutant Strains Mice; Neurodegenerative Disorders; Oxidative Stress; Pathogenesis; Peptides; Phase; Play; Protein Kinase Inhibitors; Regulation; Research; Research Personnel; Research Project Grants; Role; Signal Pathway; Signal Transduction; Solid; Synapses; Synaptic plasticity; Techniques; Testing; Therapeutic; Training; Transducers; Translating; Work; base; career development; effective therapy; improved; insight; meetings; new therapeutic target; prevent; protein kinase inhibitor; sensor; success; synaptic failure; theories; therapeutic target

DESCRIPTION (provided by applicant): Lack of mechanistic understanding hampers our search for solid therapeutic targets on Alzheimer's disease (AD), the most common form of dementia in the elderly and one of the leading causes of death across all ages. Current disease modifying strategies based on the Amyloid beta (A�) hypothesis, such as A� antibody immunotherapy, have met with limited success. Meanwhile, the downstream signaling pathways of A� as well as A�-independent mechanisms are being actively pursued as potential targets for AD therapy. One such potential mechanism is via regulation on the AMP-activated protein kinase (AMPK), a central cellular energy sensor and signaling transducer integrating a number of signaling pathways implicated in synaptic plasticity, learning and memory. Moreover, AMPK activity is stimulated during oxidative stress which is known to play a role in AD pathogenesis. The goal of this project is to understand the role of AMPK in AD pathophysiology and to develop therapeutics that can reverse impairments due to AMPK dysregulation. Driven by the preliminary data, the central hypothesis is that restoring normal AMPK activity will improve multiple aspects of pathophysiology in APP/PS1 AD model mice. Four specific aims are formulated to test this hypothesis as described in the following. The first two aims are to be performed during the mentored phase (K99): Aim 1 is to determine how AMPK signaling is regulated in AD model mice and whether aberrant AD-related autophagy can be rescued by restoring AMPK activity; Aim 2 is to determine whether pharmacologically inhibition of AMPK activity reverse synaptic plasticity impairments and memory deficits displayed by AD model mice. And with this information in hand, I will then move on to the other two aims to be achieved during the independent phase (R00): Aim 3 is to determine whether genetic reduction of AMPK activity prevents synaptic and behavioral defects in AD model mice; and Aim 4 is to determine the AD-related cellular and molecular abnormalities that are corrected in APP/PS1/AMPK�2(+/-) double mutant mice. Findings derived from this project will potentially provide important insights into identification of novel therapeutic targets for AD and other related cognitive syndromes such as frontotemporal lobe dementia. Furthermore, the research project and career development components of this K99/R00 application will provide critical training for the applicant to become a successful independent investigator who can integrate these knowledge and techniques to improve our understanding of neurodegenerative diseases.

描述（由适用提供）：缺乏机械理解阻碍了我们对阿尔茨海默氏病（AD）的固体治疗靶标的搜索，这是古老的痴呆症的最常见形式，也是所有年龄段的主要死亡原因之一。当前基于淀粉样蛋白β（A）假设（例如抗体免疫疗法）的疾病修改策略已取得了有限的成功。同时，正在积极追求A纽的下游信号通路以及独立机制的潜在靶标。一种潜在的机制是通过对AMP激活蛋白激酶（AMPK）的调节，该蛋白激酶（AMPK）是一种中央细胞能传感器和信号传导传感器，该蛋白质传感器整合了在突触可塑性，学习和记忆中实施的许多信号传导途径。此外，在氧化应激期间刺激了AMPK活性，该活性在AD发病机理中起作用。该项目的目的是了解AMPK在AD病理生理学中的作用，并开发可以由于AMPK失调引起的损害的理论。在初步数据的驱动下，中心假设是恢复正常AMPK活性将改善APP/PS1 AD模型小鼠中病理生理的多个方面。如下所述，制定了四个具体目标以检验该假设。前两个目的是在修补阶段（K99）进行：AIM 1是确定在AD模型小鼠中如何调节AMPK信号传导，以及是否可以通过恢复AMPK活性来挽救与异常的AD相关自噬；目的2是确定药物对AMPK活性的抑制反向合成可塑性障碍和记忆定义了AD模型小鼠所显示的。借助这些信息，我将继续前进在独立阶段（R00）中实现的其他两个目标：AIM 3是确定AMPK活性的遗传减少是否可以防止AD模型小鼠中的合成和行为缺陷； AIM 4是确定App/PS1/AMPK≠2（+/-）双突变小鼠中与AD相关的细胞和分子异常。从该项目中得出的结果将有可能提供重要的见解，以识别AD和其他相关认知综合征（例如额颞叶痴呆症）的新型治疗靶标。此外，该K99/R00应用程序的研究项目和职业发展组成部分将为该应用程序提供关键的培训，以成为成功的独立研究者，他们可以将这些知识和技术整合起来，以提高我们对神经退行性疾病的理解。