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

• 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
• 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' 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

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（由适用提供）：阿尔茨海默氏病（AD）遭受了全球约2500万人的折磨，是最古老的痴呆症最常见的原因。迫切需要新的治疗目标发现和相应的新复合开发。假设一种沉积在AD大脑中的蛋白质（a。）在AD发病机理中起关键作用。 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会引起神经元损伤。最近发现，电压门控钾通道KV1.3（KCNA3）在小胶质细胞激活中起重要作用。因此，我们打算研究KV1.3是否在AD中的小胶质细胞激活，神经毒性和淀粉样蛋白沉积中起作用。我们在我们的体外和原位实验中发现，选择性KV1.3阻滞剂PAP -1阻断了A a a活化的小胶质细胞诱导的神经毒性，但并未阻止小胶质细胞对吞噬诱导的有益作用。我们还发现，在两个AD小鼠模型中，与淀粉样蛋白斑相关的小胶质细胞中有强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。在这项赠款的帮助下，我们现在希望获得体内原理证明KV1.3可能是治疗靶标，其特定抑制剂可能具有AD的治疗潜力。我们将确定：1。小胶质细胞激活和相关的神经元损伤，响应体内促炎性刺激需要小胶质细胞KV1.3通道活性吗？为了回答这个问题，我们将确定KV1.3活性的封锁是否会减少用脂多糖或AB低聚物治疗后小鼠小鼠的小胶质激活和树突变性。我们还将检查小胶质细胞KV1.3活性及其对这些促炎性刺激的影响。 2。选择性KV1.3称为PAP-1的阻滞剂可以在体内抑制小胶质细胞激活并改善称为3xtg-AD小鼠的AD小鼠模型的认知功能？为了解决这个问题，我们将通过使用PAP-1处理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，淀粉样蛋白沉积，TAU病理学和认知性能的影响。 Lay：小胶质细胞是大脑中发现的一种白细胞，已被证明会导致阿尔茨海默氏病的发病机理。我们建议的目的是测试称为KV1.3的钾通道是否对小胶质细胞引起的损害很重要。我们将进一步测试KV1.3的抑制剂是否会降低阿尔茨海默氏病动物模型中的小胶质细胞活性。 公共卫生相关性：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在与阿尔茨海默氏病有关的小鼠模型中的作用，以建立KV1.3作为阿尔茨海默氏病的治疗靶点。