Therapeutic Use of Autophagy Enhancer Drugs for Alzheimer's Disease

描述（由申请人提供）：自噬似乎在处理易聚集蛋白质中起关键作用。例如，我们已经发现自噬是负责处理突变的α 1抗胰蛋白酶（AT）的不溶性聚合物，导致AT缺乏的肝脏疾病。在我们最近的工作中，我们已经发现，卡马西平（CBZ），一种药物，已被用作抗惊厥药物多年，具有广泛的安全范围，增强自噬处置的突变AT（ATZ）在细胞系模型的AT缺陷。在小鼠模型中，CBZ可显著降低ATZ的肝负荷，逆转ATZ引起的肝纤维化。我们最近还开发了一个高内容筛选（HCS）平台，以识别依赖于AT缺陷的新型秀丽隐杆线虫模型的治疗药物。一个低复杂性的药物库的初步筛选已确定6个潜在的候选人，其中每一个显着减少ATZ在蠕虫的细胞内积累的剂量和时间依赖性的方式。有趣的是，这些候选物中的4种已被证明可以增强自噬活性，并特异性地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有力的验证。因此，这些结果也为测试自噬增强剂对由聚集蛋白引起的其他疾病的作用提供了基础。最后，一项小型初步研究表明，CBZ治疗减少了阿尔茨海默病（AD）PS1/APP小鼠模型中的斑块负荷。在本申请中，我们提出了这些自噬增强剂药物在小鼠AD模型中对神经病理和行为后遗症的广泛测试。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和它的相对奥卡西平（OBZ）以及在C. elegans AT缺陷模型/ HCS平台对PS 1/APP小鼠的Ab水平、斑块负荷、学习和记忆的影响。这些小鼠将在GFP-LC 3背景下繁殖，以允许容易地监测脑中的自噬作为药物功效的终点测量。我们知道，CBZ、OBZ和其他迄今为止发现的自噬增强剂药物都是FDA批准的，已经安全地用于人类，并渗透到血脑屏障中。我们的目标是尽快将一种或多种这些药物用于临床试验。 公共卫生相关性：拟议的研究旨在确定新的治疗策略，以改善阿尔茨海默病的神经退行性后遗症。

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.