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：目前已经发表了5万多篇关于淀粉样β肽（Abeta）的论文，它被认为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正常细胞会产生β，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）胞浆内区域的点突变对β的积累没有影响，但却完全抑制了转基因小鼠的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，认为阿尔茨海默病是一种调节可塑性的生理信号通路失衡。APP与竞争配体相互作用，介导神经突收缩和神经突延伸：APP与netrin-1相互作用时（Calheiros et al., in press），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，它介导神经突收缩、突触重组，最终导致神经元程序性细胞死亡。有趣的是，Abeta的作用呈现正反馈：当Abeta结合APP时，APP的加工导致Abeta的进一步产生，通过抑制α分泌酶的新机制产生“朊”效应，否则该机制将分裂APP并阻止Abeta的形成。这一发现还表明netrin-1是一种“内源性抗朊病毒”，而一种增强这一过程的分子p75NTR是“朊病毒源性的”。我们建议测试该模型和这些初步数据的后果，使用四个具体目标：(1)通过提出的蛋白酶抑制新机制评估Abeta的“朊酸”性质。(2)确定观察到的sAPPalpha与Abeta减少，sAPP与netrin-1增加是否代表了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对两种拮抗配体Abeta和netrin-1的下游信号效应。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中起关键作用。由于目前还没有真正有效的阿尔茨海默病治疗方法，因此探索诸如此类的替代模型，并证实或驳斥它们的原理和含义是至关重要的。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。

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.