Kv4 Channels as a Target of Aging and Beta-Amyloid

Kv4 通道作为衰老和 β-淀粉样蛋白的靶点

• 批准号: 10179642
• 负责人: SUSAN L TSUNODA
• 金额: $ 13.82万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10179642
• 关键词: Action Potentials; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Brain; Brain region; Cognitive; Disease; Drosophila genus; Event; Genome; Investigation; Kv4 channel; Lead; Longevity; Messenger RNA; Modeling; Molecular; Molecular Genetics; Motor; Motor Activity; Mus; Nerve Degeneration; Neurons; Oxidative Stress; Pathology; Peptides; Play; Potassium Channel; Proteins; Reactive Oxygen Species; Role; Synaptic plasticity; Testing; age effect; age related; aging brain; cognitive function; density; fly; improved; motor disorder; negative affect; nervous system disorder; neurotransmission; normal aging; overexpression; postsynaptic; voltage

Tsunoda, Susan Project Summary Age is perhaps the most significant contributing factor to multiple neurological diseases, including Alzheimer’s Disease (AD). Our overarching hypothesis is that protein targets affected during normal aging may be especially affected in age-related disease conditions. In this proposal, we focus on the voltage-dependent K+ channel, Kv4, as such a target. Multiple studies have found that Aβ42 induces a decline in Kv4 channels that contributes to downstream cognitive and motor pathologies. Here, we will examine whether there is a decline in Kv4 channels with normal aging, whether reactive oxygen species (ROS) that arise with both normal aging and Aβ42 accumulation lead to this progressive loss of Kv4, and whether loss of Kv4 leads to signs of early aging and a shortened lifespan. Drosophila offers an ideal model for combining its powerful molecular-genetic toolkit with a short lifespan to study how aging/Aβ42 accumulation affects neuronal signaling. We propose: 1) to test the hypothesis that Kv4 channels are progressively lost with age by examining Kv4 mRNA, protein level and localization, as well as current, 2) to test the hypothesis that the age/Aβ42-dependent accumulation of ROS affects Kv4 channels, and 3) to test if normal age-related decline in motor activity and lifespan are improved when levels of Kv4 are genetically restored, and exacerbated when Kv4 is absent.

角田，苏珊 项目概要 年龄可能是多种神经系统疾病最重要的影响因素，包括 阿尔茨海默病（AD）。我们的总体假设是，正常衰老过程中受影响的蛋白质靶标可能 尤其受到与年龄相关的疾病的影响。在本提案中，我们重点关注电压相关的 K+通道，Kv4，就是这样一个目标。多项研究发现 Aβ42 会导致 Kv4 通道下降，从而 导致下游认知和运动病理。在这里，我们将检查是否有下降 Kv4 通道与正常衰老有关，无论是正常衰老还是在正常衰老过程中产生的活性氧 (ROS) Aβ42 积累导致 Kv4 逐渐丧失，Kv4 丧失是否会导致早衰迹象和 寿命缩短。果蝇提供了一个理想的模型，将其强大的分子遗传工具包与 寿命较短，以研究衰老/Aβ42 积累如何影响神经元信号传导。我们建议：1）测试 通过检查 Kv4 mRNA、蛋白质水平和 本地化以及电流，2) 检验年龄/Aβ42 依赖性 ROS 积累的假设 影响 Kv4 通道，以及 3) 测试与年龄相关的运动活动和寿命的正常下降是否在以下情况下得到改善： Kv4 水平会通过基因恢复，而当 Kv4 缺失时，Kv4 水平会加剧。