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.

Tsunoda，苏珊 项目摘要 年龄可能是导致多种神经系统疾病的最重要因素，包括 阿尔茨海默氏病（AD）。我们的总体假设是，正常衰老期间受影响的蛋白质靶标可能 在与年龄相关的疾病状况中尤其受到影响。在此提案中，我们专注于依赖电压 K+通道KV4，如这样的目标。多项研究发现，Aβ42诱导KV4通道的下降 有助于下游认知和运动病理。在这里，我们将检查是否有所下降 KV4通道的正常衰老，无论是正常衰老和 Aβ42积累导致KV4的逐渐丧失，以及KV4的损失是否导致早衰的迹象 寿命缩短。果蝇提供了理想的模型，可将其强大的分子遗传工具包与 寿命短以研究衰老/Aβ42积累如何影响神经元信号传导。我们建议：1）测试 假设KV4通道通过检查KV4 mRNA，蛋白质水平和 定位以及电流2）测试了ROS的年龄/Aβ42依赖性积累的假设 影响KV4通道，以及3）测试运动活动和寿命是否正常时，是否会改善 KV4的水平在基因上恢复，并在不存在KV4时加剧。