Novel Prionic Mechanism Underlying Alzheimer?s Disease

描述（由申请人提供）：越来越清楚的是，目前对阿尔茨海默病的看法是不正确的：现已发表了超过50，000篇关于淀粉样β肽（Abeta）的论文，认为淀粉样β肽通过化学和物理机制介导阿尔茨海默病，如金属结合、活性氧物质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是由正常细胞组成性产生的，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一致，即淀粉样前体蛋白（APP）的胞质内结构域中的点突变对A β的积累没有影响，但却完全抑制了转基因小鼠中的AD表型（Galvan et al.，2006; Saganich等人，2006; Galvan等人，2008年）。我们的研究结果提出了一个全新的观点，即阿尔茨海默病是一种生理信号通路的不平衡，这种通路有助于介导可塑性。APP与竞争配体相互作用，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，在出版中），其介导神经突延伸和细胞存活;然而，Abeta与netrin-1竞争，并且当Abeta结合APP时，其介导神经突收缩、突触重组和最终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，通过一种新的机制产生“朊病毒”效应：抑制α-分泌酶，否则它会切割APP并阻止Abeta形成。这一发现也意味着netrin-1是一种“内源性抗朊病毒”，而增强这一过程的分子p75 NTR是“朊病毒原性的”。 我们建议使用四个具体目标来测试这个模型和这些初步数据的结果：（1）通过所提出的蛋白酶抑制的新机制来评估Abeta的“朊病毒”性质。(2)确定观察到的sAPP α与Abeta的减少以及sAPP与netrin-1的增加是否代表APP的这些配体的直接或间接效应。（3）评估Abeta与APP相互作用的结构效应。（4）评估APP响应于两种拮抗配体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兴数据开发的模型，这些数据表明APP信号在AD中的关键作用。由于AD仍然没有真正有效的治疗方法，因此探索诸如此类的替代模型，并确认或反驳其原则和含义至关重要。此外，这一领域的研究可能最终导致对其他神经退行性疾病的新见解，如帕金森氏症和肌萎缩侧索硬化症。 公共卫生相关性：阿尔茨海默病是美国最重要的医疗保健问题之一，通过了解其潜在的机制将有助于开发有效的治疗方法。我们已经提供了证据表明，阿尔茨海默病的流行观点是不正确的，并开发了一种新的模型，提供了深入了解这种重要和常见疾病的机制和潜在治疗方法。

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.