Novel Prionic Mechanism Underlying Alzheimer?s Disease

阿尔茨海默病的新朊病毒机制

• 批准号: 8299528
• 负责人: Dale E. Bredesen
• 金额: $ 36.92万
• 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/8299528
• 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; Signal Pathway; Signal Transduction; Synapses; Testing; Transgenic Mice; abeta accumulation; abstracting; alpha secretase; amyloid precursor protein ligand; amyloid precursor protein processing; base; effective therapy; human NTN1 protein; insight; netrin-1; novel; response; theories

Project Summary/Abstract 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.

项目摘要/摘要 越来越清楚的是，当前对阿尔茨海默氏病的看法是不正确的：超过50,000 现在已经在淀粉样β肽（S）（ABETA）上发表了论文，该论文被认为是介导的 阿尔茨海默氏病通过化学和物理机制，例如金属结合，活性氧 生产和直接溶酶体膜损伤。但是，这种观点不能解释为什么Abeta是 由正常细胞组成产生，也不是其生理功能是什么。此外，这些理论是 与我们最近的发现不兼容，即淀粉样蛋白的胞质内域中的点突变 前体蛋白（APP）对ABETA的积累没有影响，但完全完全 抑制转基因小鼠中的AD表型（Galvan等，2006; Saganich等，2006; Galvan等，， 2008）。我们的结果表明，对阿尔茨海默氏病的全新观点是生理失衡 信号通路可介导可塑性。 App与竞争配体互动，介导两者 神经突收缩和神经突扩展：当App与Netrin-1相互作用时（Press） 介导神经突的延伸和细胞存活；但是，Abeta与Netrin-1竞争，Abeta绑定时 应用程序介导神经突收缩，突触重组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。 为了进一步生产Abeta，通过一种新型机制产生“ prionic”效应：抑制α-分泌酶， 否则将切割应用程序和排除Abeta组。这一发现也意味着Netrin-1是 “内源性抗腐蚀性”和增强该过程的分子P75NTR是“ prionogenitic”。 我们建议使用四个特定目的来测试该模型的分析和这些初步数据： （1）通过提出的新型蛋白酶抑制机理评估Abeta的“祖先”性质。 （2）确定观察到的sappalpha的减少是否与Abeta相比，并用Netrin-1的SAPP增加， 代表这些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介导的下游信号传导效应， Abeta和Netrin-1。 这些提出的研究旨在测试基于 新兴数据表示AD中应用信号的关键作用。由于仍然没有真正有效的疗法 广告，至关重要的是要探索诸如此类的替代模型及其宗旨和含义确认或 被驳斥。此外，该领域的研究最终可能导致对其他神经退行性的新见解 帕金森氏症和肌萎缩性侧索硬化症等疾病。

项目成果

AβPP-selective BACE inhibitors (ASBI): novel class of therapeutic agents for alzheimer's disease.

• DOI: 10.3233/jad-130578
• 发表时间: 2013
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Descamps O;Spilman P;Zhang Q;Libeu CP;Poksay K;Gorostiza O;Campagna J;Jagodzinska B;Bredesen DE;John V
• 通讯作者: John V

Structural and functional alterations in amyloid-β precursor protein induced by amyloid-β peptides.

淀粉样β 肽诱导的淀粉样β 前体蛋白的结构和功能改变。

• DOI: 10.3233/jad-2011-101938
• 发表时间: 2011
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Libeu,ClarePeters;Poksay,KarenS;John,Varghese;Bredesen,DaleE
• 通讯作者: Bredesen,DaleE

Altering APP proteolysis: increasing sAPPalpha production by targeting dimerization of the APP ectodomain.

• DOI: 10.1371/journal.pone.0040027
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Libeu CA;Descamps O;Zhang Q;John V;Bredesen DE
• 通讯作者: Bredesen DE

Paradoxical effect of TrkA inhibition in Alzheimer's disease models.

• DOI: 10.3233/jad-130017
• 发表时间: 2014
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Zhang Q;Descamps O;Hart MJ;Poksay KS;Spilman P;Kane DJ;Gorostiza O;John V;Bredesen DE
• 通讯作者: Bredesen DE