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

描述（由申请人提供）：缺乏对机制的理解阻碍了我们寻找阿尔茨海默病（AD）的可靠治疗靶点，AD是老年人最常见的痴呆症形式，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（Abeta）假说的疾病修改策略，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与Abeta无关的机制正被积极寻求作为AD治疗的潜在靶点。其中一种潜在的机制是通过调节amp活化蛋白激酶（AMPK）， AMPK是一种中枢细胞能量传感器和信号转导器，整合了涉及突触可塑性、学习和记忆的许多信号通路。此外，AMPK活性在氧化应激过程中受到刺激，这在AD的发病机制中起作用。该项目的目标是了解AMPK在AD病理生理中的作用，并开发可以逆转AMPK失调导致的损伤的治疗方法。在初步数据的推动下，中心假设是恢复正常的AMPK活性将改善APP/PS1 AD模型小鼠的多个病理生理方面。如下所述，我们制定了四个具体目标来检验这一假设。前两个目标将在指导阶段（K99）完成：目标1是确定AMPK信号如何在AD模型小鼠中被调节，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活性的药理学抑制是否能逆转AD模型小鼠的突触可塑性损伤和记忆缺陷。有了这些信息，我将继续讨论独立阶段（R00）要实现的另外两个目标：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；目的4是确定APP/PS1/AMPK¿2（+/-）双突变小鼠ad相关的细胞和分子异常是否得到纠正。该项目的研究结果将为识别阿尔茨海默病和其他相关认知综合征（如额颞叶痴呆）的新治疗靶点提供潜在的重要见解。此外，该K99/R00申请的研究项目和职业发展部分将为申请人提供重要的培训，使其成为一名成功的独立研究者，能够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.