The Microglial Kv1.3 Channel in Alzheimer's Disease

阿尔茨海默病中的小胶质细胞 Kv1.3 通道

基本信息

批准号：
8191960
负责人：
LEE-WAY JIN
金额：
$ 18.71万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8191960
关键词：
Address Affect Aftercare Alzheimer&apos s Disease Amyloid Amyloid deposition Animal Model Attention Brain Calcium Channel Cells Cognitive Data Dementia Deposition Development Elderly Genetic Goals Grant Health Human In Situ In Vitro Inflammatory Investigation Knock-out Kv1.3 potassium channel Lead Lesion Leukocytes Ligands Lipopolysaccharides MAP Kinase Gene MAPK14 gene Mediating Membrane Potentials Microglia Modeling Molecular Molecular Conformation Mus Names Neurons Pathogenesis Pathology Pathway interactions Patients Pattern Performance Phagocytosis Pharmaceutical Preparations Play Potassium Channel Prevention Process Protein Precursors Proteins Proteolytic Processing Role Senile Plaques Signal Pathway Signal Transduction Slice Solutions Stimulus Stroke Synapses Testing Therapeutic Therapy Clinical Trials Time Voltage-Gated Potassium Channel Wild Type Mouse base cognitive function cytokine cytotoxic driving force immunoreactivity improved in vivo inhibitor/antagonist killings mouse model neuroinflammation neurotoxic neurotoxicity new therapeutic target patch clamp research study response small molecule synaptic function tau Proteins therapeutic target

项目摘要

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. PUBLIC HEALTH RELEVANCE: Recent evidence suggests that the potassium channel Kv1.3 is involved in microglia activation. We will investigate the role of microglial Kv1.3 in mouse models relevant to Alzheimer's disease, in order to establish Kv1.3 as a therapeutic target for Alzheimer's disease.

描述（由申请人提供）：阿尔茨海默病（AD）困扰着全世界约2500万人，是老年人痴呆的最常见原因，迫切需要发现新的治疗靶点和开发相应的新化合物。 AD大脑称为淀粉样蛋白-¿ (A¿) 已被开发在 AD 发病机制中发挥关键作用，Ab 可以激活小胶质细胞以清除 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（KCNA3）在小胶质细胞激活中发挥重要作用，因此我们打算研究Kv1.3是否发挥作用。我们在体外和原位实验中发现，选择性 Kv1.3 阻断剂 PAP-1 可以阻断 A¿ 诱导的神经毒性。 - 激活小胶质细胞，但不会阻止小胶质细胞吞噬 A 的有益作用我们还在两个 AD 小鼠模型中发现与淀粉样斑块相关的小胶质细胞具有很强的 Kv1.3 免疫反应性，我们的结果表明 Kv1.3 参与了 AD 中的小胶质细胞激活和神经毒性。原理证明 Kv1.3 可能是一个治疗靶点，其特异性抑制剂可能具有治疗 AD 的潜力。我们将确定： 1. 小胶质细胞激活和相关神经元损伤是否响应促炎刺激。体内需要小胶质细胞 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抗体寡聚物治疗后，阻断 Kv1.3 活性是否会减少小胶质细胞活化和树突变性。 2. 称为 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称为 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 对小胶质细胞激活状态、淀粉样蛋白的影响Lay：小胶质细胞是大脑中发现的一种白细胞，已被证明与阿尔茨海默氏病的发病机制有关。我们提议的目的是测试钾通道是否存在。 Kv1.3 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的小胶质细胞活性。公共健康相关性：最近的证据表明钾通道 Kv1.3 参与小胶质细胞激活我们将研究小胶质细胞 Kv1.3 在与阿尔茨海默病相关的小鼠模型中的作用，以便将 Kv1.3 确立为治疗靶点。阿尔茨海默病。