Understanding the Neuroprotective Activities of Posiphen

描述（由申请人提供）：唐氏综合征（DS）患者在生命早期表现出阿尔茨海默病（AD）神经病理学，并在他们的第四或第五十年发展为进行性认知障碍。表达淀粉样蛋白（A¿）前体（APP）的转基因小鼠沉积淀粉样蛋白，但不呈现变性表型。DS小鼠模型Ts65Dn小鼠遭受许多神经元亚型的退化，包括在AD中丢失的基底前脑胆碱能神经元。这似乎需要APP复制，尽管高APP并不足以诱导转基因小鼠的神经变性。我们之前发现了一种新的化合物Posiphen，它通过调节APP的5'-非翻译区来抑制APP的翻译。我们计划通过Posiphen治疗动物模型来降低APP的表达，以确定长期治疗是否可以预防AD样病理，以及这种治疗是否可以预防DS的神经退行性变。TS65Dn小鼠的神经变性似乎依赖于APP，这使其成为评估抗APP治疗对神经保护作用的有用模型。这个R21项目将测试APP合成的减少将恢复这种高表达蛋白的稳态，从而防止DS小鼠的神经元损失和行为的假设。第二个假设是Posiphen治疗会减少淀粉样蛋白以斑块的形式积累。在未来的研究中，我们计划继续与Nigel Greig博士合作进行药物的临床开发。该项目的两个具体目的是：1)评估Posiphen对TS65Dn小鼠的影响，TS65Dn小鼠的APP自然表达水平提高1.5倍，并随着年龄的增长积累分泌的APP衍生物；2)确定Posiphen对转基因小鼠淀粉样蛋白沉积的影响。我们假设治疗将成功地减少DS小鼠模型中的神经退行性变，并为我们提供工具来确定可能针对干预的晚期和窗口期。

DESCRIPTION (provided by applicant): Individuals with Down syndrome (DS) exhibit Alzheimer's disease (AD) neuropathology early in life, and develop progressive cognitive impairment in their fourth or fifth decade. Transgenic mice expressing Amyloid beta protein (A¿) precursor (APP) deposit amyloid but do not present degeneration phenotypes. A mouse model of DS, the Ts65Dn mice, suffers degeneration of a number of neuronal subtypes, including the basal forebrain cholinergic neurons that are lost in AD. This appears to require APP duplication although high APP is not sufficient to induce neurodegeneration in transgenic mice. We previously identified a novel compound - Posiphen - that inhibits APP translation by regulating the 5'-untranslated region of APP. We are planning to reduce APP expression by treating animal models with Posiphen to determine whether long-term treatment could arrent AD like pathology and if neurodegeneration in DS can be prevented by this treatment. The neurodegeneration in the TS65Dn mice appears to depend on APP making it a useful model to evaluate neuroprotection by anti-APP therapies. This R21 project will test the hypothesis that reduction of APP synthesis will restore homeostasis of this highly expressed protein and therefore prevent neuronal loss and behavior in DS mice. The second hypothesis is that Posiphen treatment will reduce amyloid accumulation as plaques. In future studies, we plan to continue collaborating with Dr. Nigel Greig for clinical development of the drug. The two specific aims of the project are: 1) Evaluate the effects of Posiphen treatment in the TS65Dn mice, which naturally express 1.5 times higher levels of APP and accumulate secreted APP derivatives with age; 2) Determine the effect of Posiphen on amyloid deposition in transgenic mouse models. We hypothesize that the treatment will successfully reduce neurodegeneration in the DS mouse model and provide us with the tools to identify the late and windows that may be targeted for intervention.