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

描述（由申请人提供）：缺乏对机理的理解阻碍了我们对阿尔茨海默病（AD）的可靠治疗靶点的研究，阿尔茨海默病是老年痴呆症中最常见的形式，也是所有年龄段死亡的主要原因之一。目前基于淀粉样蛋白β（Abeta）假说的疾病修饰策略，如Abeta抗体免疫疗法，取得了有限的成功。与此同时，Abeta的下游信号通路以及Abeta非依赖性机制正被积极寻求作为AD治疗的潜在靶点。其中一个潜在的机制是通过对AMP活化蛋白激酶（AMPK）的调节，AMPK是一种中央细胞能量传感器和信号转导器，整合了许多涉及突触可塑性、学习和记忆的信号传导途径。此外，AMPK活性在氧化应激期间被刺激，这是已知的在AD发病机制中起作用。该项目的目标是了解AMPK在AD病理生理学中的作用，并开发可以逆转AMPK失调所致损伤的治疗方法。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学的多个方面。如下所述，制定了四个具体目标来检验这一假设。前两个目的将在指导阶段（K99）进行：目的1是确定AD模型小鼠中AMPK信号传导如何调节，以及是否可以通过恢复AMPK活性来挽救异常AD相关的自噬;目的2是确定AMPK活性的抑制是否逆转AD模型小鼠表现出的突触可塑性损伤和记忆缺陷。有了这些信息，我将继续在独立阶段（R 00）实现其他两个目标：目标3是确定AMPK活性的遗传降低是否可以预防AD模型小鼠的突触和行为缺陷;目标4是确定APP/PS1/AMPK <$2（+/-）双突变小鼠中纠正的AD相关细胞和分子异常。来自该项目的发现将可能为识别AD和其他相关认知综合征（如额颞叶痴呆）的新治疗靶点提供重要见解。此外，该K99/R 00申请的研究项目和职业发展部分将为申请人提供关键培训，使其成为一名成功的独立研究者，他们可以整合这些知识和技术，以提高我们对神经退行性疾病的理解。

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 (Abeta) hypothesis, such as Abeta antibody immunotherapy, have met with limited success. Meanwhile, the downstream signaling pathways of Abeta as well as Abeta-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.