Novel Prionic Mechanism Underlying Alzheimer?s Disease

阿尔茨海默病的新朊病毒机制

• 批准号: 7886554
• 负责人: Dale E. Bredesen
• 金额: $ 38.41万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7886554
• 关键词: Abeta synthesis; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyotrophic Lateral Sclerosis; Apoptosis; Area; Binding; Cell Survival; Chemicals; Cleaved cell; Data; Development; Disease; Feedback; Healthcare; Lead; Ligands; Mediating; Membrane; Metals; Modeling; NGFR Protein; Nature; Neurites; Neurodegenerative Disorders; Neurons; Normal Cell; Paper; Parkinson Disease; Peptide Hydrolases; Phenotype; Physiological; Point Mutation; Prions; Process; Production; Publishing; Reactive Oxygen Species; Research; Research Design; Role; Signal Pathway; Signal Transduction; Synapses; Testing; Transgenic Mice; abeta accumulation; alpha secretase; amyloid precursor protein ligand; amyloid precursor protein processing; base; effective therapy; human NTN1 protein; insight; netrin-1; novel; public health relevance; response; theories

DESCRIPTION (provided by applicant): It is becoming increasingly clear that the current view of Alzheimer's disease is incorrect: over 50,000 papers have now been published on the amyloid beta peptide(s) (Abeta), which is thought to mediate Alzheimer's disease by chemical and physical mechanisms, such as metal binding, reactive oxygen species production, and direct lysosomal membrane damage. However, this view does not explain why Abeta is produced constitutively by normal cells, nor what its physiological function is. Furthermore, these theories are incompatible with our recent finding that a point mutation in the intracytoplasmic domain of the amyloid precursor protein (APP), which has no effect on the accumulation of Abeta, nevertheless completely suppresses the AD phenotype in transgenic mice (Galvan et al., 2006; Saganich et al., 2006; Galvan et al., 2008). Our results suggest a completely new view of Alzheimer's disease as an imbalance in physiological signaling pathways that serve to mediate plasticity. APP interacts with competing ligands, mediating both neurite retraction and neurite extension: when APP interacts with netrin-1 (Calheiros et al., in press), it mediates neurite extension and cell survival; however, Abeta competes with netrin-1, and when Abeta binds APP it mediates neurite retraction, synaptic re-organization, and ultimately neuronal programmed cell death. Interestingly, the effect of Abeta shows positive feedback: when Abeta binds APP, the processing of APP leads to further production of Abeta, creating a "prionic" effect by a novel mechanism: inhibition of alpha-secretase, which would otherwise cleave APP and preclude Abeta formation. This finding also implies that netrin-1 is an "endogenous anti-prion" and a molecule that enhances this process, p75NTR, is "prionogenic". We propose to test the ramifications of this model and these preliminary data, using four specific aims: (1) Evaluate the "prionic" nature of Abeta via the proposed novel mechanism of protease inhibition. (2) Determine whether the observed reduction in sAPPalpha with Abeta, and increase in sAPP with netrin-1, represent direct or indirect effects of these ligands of APP. (3) Evaluate the structural effects of Abeta interaction with APP. (4) Evaluate the downstream signaling effects mediated by APP in response to the two antagonistic ligands, Abeta and netrin-1. These proposed studies are designed to test the model that has been developed based on the emerging data indicating a key role for APP signaling in AD. Since there is still no truly effective therapy for AD, it is critical that alternative models such as this be explored, and their tenets and implications confirmed or refuted. Furthermore, research in this area may ultimately lead to new insights into other neurodegenerative diseases, such as Parkinson's and amyotrophic lateral sclerosis, as well. PUBLIC HEALTH RELEVANCE: Alzheimer's disease represents one of the most significant healthcare problems in the U.S., and development of effective therapy will be facilitated by understanding its underlying mechanism. We have provided evidence that the prevailing view of Alzheimer's disease is incorrect, and have developed a new model that offers insight into the mechanism and potential treatment of this important and common disease.

描述（由申请人提供）：越来越明显的是，目前对阿尔茨海默病的看法是不正确的：现已发表超过 50,000 篇关于淀粉样β肽（Abeta）的论文，人们认为它通过化学物质介导阿尔茨海默病以及物理机制，例如金属结合、活性氧的产生和直接溶酶体膜损伤。然而，这种观点并没有解释为什么Abeta是由正常细胞组成型产生的，也没有解释它的生理功能是什么。此外，这些理论与我们最近的发现不相容，即淀粉样前体蛋白（APP）胞质内结构域的点突变对Abeta的积累没有影响，但完全抑制了转基因小鼠的AD表型（Galvan等人） .，2006；Saganich 等，2006；Galvan 等，2008）。我们的研究结果提出了一种全新的观点，即阿尔茨海默病是调节可塑性的生理信号通路的不平衡。 APP 与竞争性配体相互作用，介导神经突收缩和神经突延伸：当 APP 与 netrin-1 相互作用时（Calheiros 等人，正在出版），它介导神经突延伸和细胞存活；然而，Abeta 与 netrin-1 竞争，当 Abeta 结合 APP 时，它会介导神经突收缩、突触重组，并最终导致神经元程序性细胞死亡。有趣的是，Abeta 的作用显示出正反馈：当 Abeta 结合 APP 时，APP 的加工导致 Abeta 的进一步产生，通过一种新机制产生“朊病毒”效应：抑制 α 分泌酶，否则会裂解 APP 并阻止阿贝塔形成。这一发现还意味着 netrin-1 是一种“内源性抗朊病毒”，而增强这一过程的分子 p75NTR 是“产生朊病毒的”。 我们建议使用四个具体目标来测试该模型和这些初步数据的后果：（1）通过提出的蛋白酶抑制新机制评估 Abeta 的“朊病毒”性质。 (2) 确定观察到的 Abeta 使 sAPPalpha 减少，以及 netrin-1 使 sAPP 增加，是否代表这些 APP 配体的直接或间接影响。 (3)评估Abeta与APP相互作用的结构效应。 (4) 评估 APP 响应两种拮抗配体 Abeta 和 netrin-1 介导的下游信号传导效应。 这些拟议的研究旨在测试基于新出现的数据开发的模型，这些数据表明 APP 信号传导在 AD 中发挥着关键作用。由于目前还没有真正有效的 AD 治疗方法，因此探索此类替代模型并确认或反驳其原理和含义至关重要。此外，这一领域的研究最终可能会给其他神经退行性疾病带来新的见解，例如帕金森病和肌萎缩侧索硬化症。 公共健康相关性：阿尔茨海默病是美国最重要的医疗保健问题之一，了解其潜在机制将有助于开发有效的治疗方法。我们提供的证据表明，人们对阿尔茨海默病的普遍看法是不正确的，并且开发了一种新模型，可以深入了解这种重要且常见疾病的机制和潜在治疗方法。