The Microglial Kv1.3 Channel in Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）困扰着全球约2500万人，是老年痴呆症的最常见原因。因此，迫切需要发现新的治疗靶点并开发相应的新化合物。一种沉积在AD大脑中的蛋白质称为淀粉样蛋白（A），已被假设在AD发病机制中起关键作用。抗体可以激活小胶质细胞清除A，但同时释放细胞毒性物质，造成神经元损伤。最近发现电压门控钾通道Kv1.3（KCNA 3）在小胶质细胞激活中起重要作用。因此，我们打算研究Kv1.3是否在AD的小胶质细胞活化、神经毒性和淀粉样蛋白沉积中起作用。我们在体外和原位实验中发现，选择性Kv1.3阻断剂PAP-1阻断了A <$激活的小胶质细胞诱导的神经毒性，但没有阻断小胶质细胞吞噬A <$的有益作用。我们还发现在两种AD小鼠模型中与淀粉样斑块相关的小胶质细胞中存在强烈的Kv1.3免疫反应性。我们的研究结果表明，Kv1.3参与小胶质细胞活化和神经毒性在AD。在这项资助的帮助下，我们现在希望获得Kv1.3可能是治疗靶点的体内原理证明，其特异性抑制剂可能对AD具有治疗潜力。我们将确定：1。小胶质细胞激活和相关的神经元损伤在体内对促炎刺激的反应需要小胶质细胞Kv1.3通道活性吗？为了回答这个问题，我们将确定在用脂多糖或Ab寡聚物治疗后，Kv1.3活性的阻断是否减少小鼠中的小胶质细胞活化和树突状变性。我们还将研究小胶质细胞Kv1.3活性及其对小胶质细胞活化状态的影响，以响应这些促炎刺激。2.一种名为PAP-1的选择性Kv1.3阻断剂能否抑制体内小胶质细胞活化并改善名为3xTg-AD小鼠的AD小鼠模型的认知功能？为了解决这个问题，我们将通过用PAP-1治疗3xTg-AD小鼠进行治疗试验，并确定PAP-1对小胶质细胞活化状态、淀粉样蛋白沉积、tau病理学和认知表现的影响。雷：小胶质细胞，一种在大脑中发现的白色血细胞，已被证明有助于阿尔茨海默病的发病机制。我们的建议的目的是测试钾通道Kv1.3是否在小胶质细胞引起的损伤中很重要。我们将进一步测试Kv1.3抑制剂是否会降低阿尔茨海默病动物模型中小胶质细胞的活性。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) afflicts approximately 25 million people worldwide and is the most common cause of dementia in the elderly. There is an urgent need for new therapeutic target discovery and corresponding new compound development. A protein deposited in AD brains called amyloid-¿ (A¿) has been hypothesized to play a critical role in AD pathogenesis. Ab can activate microglia to clear A¿ but at the same time releasing cytotoxic substances to cause neuronal damage. Recently it was found that the voltage-gated potassium channel Kv1.3 (KCNA3) plays an important role in microglia activation. Therefore we intend to study if Kv1.3 plays a role in microglia activation, neurotoxicity, and amyloid deposition in AD. We found in our in vitro and in situ experiments that the selective Kv1.3 blocker PAP-1 blocked the neurotoxicity induced by A¿- activated microglia, but did not block the beneficial effect of microglia to phagocytose A¿. We also found strong Kv1.3 immunoreactivities in microglia associated with amyloid plaques in two AD mouse models. Our results suggest the involvement of Kv1.3 in microglia activation and neurotoxicity in AD. With the help of this grant we now wish to obtain in vivo proof of principle that Kv1.3 could be a therapeutic target and its specific inhibitors may have a therapeutic potential for AD. We will determine: 1. Do microglia activation and associated neuronal damage in response to pro-inflammatory stimuli in vivo require microglial Kv1.3 channel activity? To answer this question we will determine if blockade of Kv1.3 activity reduces microglial activation and dendritic degeneration in mice after treatment with lipopolysscharides or Ab oligomers. We will also examine the microglial Kv1.3 activity and its influence on the microglial activation state in response to these pro-inflammatory stimuli. 2. Can a selective Kv1.3 blocker called PAP-1 inhibit microglia activation in vivo and improve cognitive function of an AD mouse model called 3xTg-AD mice? To address this question, we will perform a therapeutic trial by treating 3xTg-AD mice with PAP-1 and determine the effect of PAP-1 on microglia activation state, amyloid deposition, tau pathology, and cognitive performance. Lay: Microglia, a type of white blood cells found in the brain, have been shown to contribute to the pathogenesis of Alzheimer's disease. The aims of our proposal are to test whether a potassium channel called Kv1.3 is important in microglia-caused damage. We will further test whether an inhibitor for Kv1.3 reduces microglia activity in an animal model of Alzheimer's disease.