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.

项目概要/摘要 越来越明显的是，目前对阿尔茨海默病的看法是错误的：超过 50,000 现已发表有关淀粉样β肽（Abeta）的论文，该肽被认为可以介导 阿尔茨海默病的化学和物理机制，例如金属结合、活性氧 产生，并直接损害溶酶体膜。然而，这种观点并不能解释为什么阿贝塔是 由正常细胞组成型产生，也不知道其生理功能是什么。此外，这些理论是 与我们最近的发现不相容，即淀粉样蛋白胞质内结构域的点突变 前体蛋白（APP），对 Abeta 的积累没有影响，但完全 抑制转基因小鼠的 AD 表型（Galvan 等人，2006；Saganich 等人，2006；Galvan 等人， 2008）。我们的研究结果提出了一种全新的观点，即阿尔茨海默氏病是一种生理失衡。 介导可塑性的信号通路。 APP 与竞争性配体相互作用，介导两者 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）， 介导神经突延伸和细胞存活；然而，Abeta 与 netrin-1 竞争，当 Abeta 结合时 APP 它介导神经突回缩、突触重组，并最终介导神经元程序性细胞死亡。 有趣的是，Abeta 的效果呈现正反馈：当 Abeta 绑定 APP 时，APP 的处理导致 进一步产生 Abeta，通过抑制 α 分泌酶的新机制产生“朊病毒”效应， 否则会裂解 APP 并阻止 Abeta 形成。这一发现还表明 netrin-1 是一种 “内源性抗朊病毒”和增强这一过程的分子，p75NTR，是“朊病毒”。 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影响： (1) 通过所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 是否会减少 sAPPalpha，而 netrin-1 是否会增加 sAPP， 代表 APP 这些配体的直接或间接作用。 (3)评估Abeta与APP相互作用的结构效应。 (4) 评估 APP 响应两种拮抗配体介导的下游信号传导效应， Abeta 和 netrin-1。 这些拟议的研究旨在测试基于以下内容开发的模型： 新出现的数据表明 APP 信号在 AD 中发挥着关键作用。由于目前还没有真正有效的治疗方法 AD，至关重要的是探索诸如此类的替代模型，并确认或确认它们的原则和含义 反驳道。此外，该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 疾病，如帕金森病和肌萎缩侧索硬化症等。

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