Therapeutic Use of Autophagy Enhancer Drugs for Alzheimer's Disease

描述（由申请人提供）：自噬似乎在易聚集蛋白的处理中起关键作用。例如，我们发现自噬负责处理突变型抗胰蛋白酶（AT）的不溶性聚合物，AT缺乏导致肝脏疾病。在我们最近的工作中，我们发现卡马西平（carbamazepine， CBZ），一种多年来作为抗惊厥药使用的药物，具有广泛的安全余地，在AT缺乏的细胞系模型中增强突变AT （ATZ）的自噬处理。此外，在小鼠模型中，CBZ显著降低了ATZ的肝脏负荷，逆转了ATZ引起的肝纤维化。我们最近还开发了一个高含量筛选（HCS）平台，以确定依赖于新型秀丽隐杆线虫AT缺乏症模型的治疗药物。低复杂性药物库的初步筛选已经确定了6种潜在的候选药物，每种药物都以剂量和时间依赖的方式显着减少了蠕虫细胞内ATZ的积累。有趣的是，这些候选药物中有4种已被证明可以增强自噬活性，特别是增强亨廷顿蛋白的自噬处理，亨廷顿蛋白是另一种导致人类疾病的易聚集蛋白。总之，这些数据为我们的HCS平台和至少2种不同类型的聚集蛋白的自噬增强剂策略提供了强有力的验证。因此，这些结果也为检测自噬增强剂在其他由聚集蛋白引起的疾病中的作用提供了基础。最后，一项小型试点研究表明，CBZ治疗可减少阿尔茨海默病（AD） PS1/APP小鼠模型中的斑块负荷。在本应用中，我们建议在小鼠AD模型中广泛测试这些自噬增强药物对神经病理和行为后遗症的影响。前提是增强的自噬将防止神经毒性中间体在大脑中的积累。我们将研究CBZ及其相关的奥卡西平（OBZ）以及在秀丽隐杆线虫AT缺陷模型/ HCS平台中鉴定出的具有自噬增强活性的候选物对PS1/APP小鼠Ab水平、斑块负荷、学习和记忆的影响。这些小鼠将在GFP-LC3背景下繁殖，以便容易地监测大脑中的自噬，作为药物疗效的终点测量。我们知道CBZ， OBZ和其他自噬增强药物目前已被fda批准，在人体中安全使用，并能穿透血脑屏障。我们的目标是尽快将其中一种或多种药物用于临床试验。

DESCRIPTION (provided by applicant): Autophagy appears to play a critical role in disposal of aggregation-prone proteins. For example, we have found that autophagy is responsible for disposal of insoluble polymers of mutant a1antitrypsin (AT) that cause liver disease in AT deficiency. In our recent work we have discovered that carbamazepine (CBZ), a drug that has been used for years as an anticonvulsant with a wide margin of safety, enhanced the autophagic disposal of mutant AT (ATZ) in cell line models of AT deficiency. Furthermore, in mouse models, CBZ markedly reduced the hepatic load of ATZ and reversed hepatic fibrosis, the tissue damage caused by ATZ. We have also recently developed a high-content screening (HCS) platform to identify therapeutic drugs that depends on a novel C.elegans model of AT deficiency. An initial screen of a low complexity drug library has identified 6 potential candidates, each of which markedly reduced intracellular accumulation of ATZ in the worm in a dose- and time-dependent manner. Interestingly, 4 of these candidates have been shown to enhance autophagic activity in general and to specifically enhance autophagic disposal of huntingtin, another aggregation-prone protein that causes human disease. Together, these data provide powerful validation of our HCS platform and of the autophagy enhancer strategy for at least 2 different types of aggregated proteins. So these results also provide a basis for testing autophagy enhancers on other diseases caused by aggregated proteins. Finally, a small pilot study shows that CBZ treatment reduces plaque load in the PS1/APP mouse model of Alzheimer's disease (AD). In this application we propose extensive testing of these autophagy enhancer drugs on neuropathologic and behavioral sequellae in the mouse AD model. The premise is that enhanced autophagy will prevent accumulation of neurotoxic intermediates in the brain. We will examine the effect of CBZ and its relative oxcarbazepine (OBZ) as well as candidates with autophagy enhancer activity that are identified in the C. elegans AT deficiency model/ HCS platform on Ab levels, plaque load, learning and memory in PS1/APP mice. These mice will be bred onto the GFP-LC3 background to permit easy monitoring of autophagy in the brain as an end-point measure of drug efficacy. We know that CBZ, OBZ and the other autophagy enhancer drugs identified so far are FDA-approved, have been used safely in humans and permeate the blood-brain barrier. The goal will be to position one or more of these drugs for clinical trials as soon as possible. PUBLIC HEALTH RELEVANCE: The proposed studies are designed to identify new pharmacologically strategies for ameliorating the neurodegenerative sequellae of Alzheimer's disease.