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; 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）：越来越清楚的是，阿尔茨海默氏病的当前观点是不正确的：现在已经在淀粉样蛋白β肽（S）（ABETA）上发表了超过50,000篇论文（ABETA），这被认为可以通过化学和物理机制来介导阿尔茨海默氏病，例如金属结合型金属生产，并损害了反应性氧化型物质，并导致元素的生产。但是，这种观点并不能解释为什么Abeta由正常细胞组成性产生，也不解释其生理功能是什么。此外，这些理论与我们最近的发现不相容，即淀粉样蛋白前体蛋白（APP）中囊肿内的点突变对ABETA的积累没有影响，但仍完全抑制了Transgenic小鼠的AD AD型（Galvan等，2006; Saganich et and; Saganich et and; galvan al。我们的结果表明，对阿尔茨海默氏病的全新观点是用于介导可塑性的生理信号通路的不平衡。 APP与竞争的配体相互作用，介导神经突收缩和神经突扩展：当App与Netrin-1相互作用时（印刷中的Calheiros等人），它会介导神经突的延伸和细胞存活；但是，Abeta与Netrin-1竞争，当Abeta结合应用时，它会介导神经突收缩，突触重新组织和最终神经元程序的细胞死亡。有趣的是，Abeta的效果显示出积极的反馈：当Abeta绑定应用程序时，应用程序的处理会导致Abeta的进一步生产，从而通过一种新型机制产生了“ prionic”效应：抑制α-分泌酶，否则将切断App并排除Abeta的形成。这一发现还意味着Netrin-1是一种“内源性抗prion”，并且可以增强该过程的分子P75NTR是“ prionogenitic”。 我们建议使用四个特定目的来测试该模型的后果和这些初步数据：（1）通过拟议的蛋白酶抑制作用的新型机制评估Abeta的“ Prionic”性质。 （2）确定观察到的sappalpha的降低是用ABETA降低的，并用Netrin-1增加了SAPP，代表APP的这些配体的直接或间接效应。 （3）评估Abeta相互作用与应用程序的结构效应。 （4）评估APP介导的两个拮抗配体Abeta和Netrin-1介导的下游信号传导效应。 这些提出的研究旨在测试基于新兴数据开发的模型，该数据表明AD中的应用信号具有关键作用。由于仍然没有真正有效的AD疗法，因此必须探索诸如此类的替代模型及其宗旨和含义得到证实或驳斥至关重要。此外，该领域的研究最终可能导致对其他神经退行性疾病的新见解，例如帕金森氏症和肌萎缩性侧面硬化症。 公共卫生相关性：阿尔茨海默氏病是美国最重要的医疗保健问题之一，通过了解其潜在机制，将促进有效疗法的发展。我们提供了证据表明，对阿尔茨海默氏病的普遍观点是不正确的，并且开发了一种新模型，该模型可深入了解这种重要和常见疾病的机制和潜在治疗方法。