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

描述（由申请人提供）：缺乏对机制的了解阻碍了我们对阿尔茨海默病（AD）的可靠治疗靶点的探索，阿尔茨海默病是老年人最常见的痴呆症，也是所有年龄段的主要原因之一。目前基于β淀粉样蛋白 (A�) 假说的疾病缓解策略，例如 A� 抗体免疫疗法，取得的成功有限。与此同时，A� 的下游信号通路以及 A� 独立机制正在被积极探索作为 AD 治疗的潜在靶点。其中一个潜在机制是通过对 AMP 激活蛋白激酶 (AMPK) 的调节，AMPK 是一种中央细胞能量传感器和信号转导器，整合了与突触可塑性、学习和记忆相关的许多信号通路。此外，AMPK 活性在氧化应激过程中受到刺激，已知氧化应激在 AD 发病机制中发挥作用。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 失调造成的损伤的治疗方法。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 模型小鼠病理生理学的多个方面。制定了四个具体目标来检验这一假设，如下所述。前两个目标将在指导阶段 (K99) 进行：目标 1 是确定 AMPK 信号在 AD 模型小鼠中如何调节，以及是否可以通过恢复 AMPK 活性来挽救异常的 AD 相关自噬；目标 2 是确定 AMPK 活性的药理学抑制是否可以逆转 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 (R00) 期间实现另外两个目标：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；目标 4 是确定在 APP/PS1/AMPK�2( /-) 双突变小鼠中纠正的 AD 相关细胞和分子异常。该项目的研究结果可能为识别 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/R00 申请的研究项目和职业发展部分将为申请人提供关键的培训，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来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 (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.