Beta Amyloid and Hyperexcitability

β淀粉样蛋白和过度兴奋

• 批准号: 8665842
• 负责人: SUSAN L TSUNODA
• 金额: $ 7.44万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8665842
• 关键词: Abeta synthesis; Action Potentials; Affect; Alzheimer disease prevention; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Animal Behavior; Applications Grants; Attenuated; Behavioral; Biological Models; Brain; Cell Death; Cognitive; Dementia; Deposition; Disease; Disease Progression; Down-Regulation; Drosophila genus; Elderly; Epilepsy; Event; Exhibits; Functional disorder; Future; Genetic; Genetic Identity; Goals; Hippocampus (Brain); Human; Image; Investigation; Ion Channel; Lead; Learning; Memory; Memory impairment; Modeling; Motor; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Patients; Peptides; Phenotype; Population; Production; Reporting; Research; Risk; Seizures; Signal Transduction; Symptoms; System; Testing; Tissues; Transgenic Organisms; age related; electrical property; insight; locomotor deficit; mouse model; mutant; neuronal excitability; peptide A; progressive neurodegeneration; public health relevance; voltage

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population. Most AD research has focused on understanding how beta-amyloid (Abeta) peptide accumulation, and neurofibrillary tangles (NFT), contribute to the cause of AD. There is, however, less known about how these events lead to the later manifestations of AD, such as progressive neurodegeneration and a decline in cognitive and motor function. With no current cure for AD (prevention of the primary events), understanding the subsequent cellular events that underlie disease progression may give important insight into potential treatments that could halt or slow the devastating effects of the disease. Recently, over-production of Abeta has been shown to result in hyperexcitability and Ca2+ "overload" in hippocampal and cortical neurons. Increased excitability is also consistent with behavioral studies which have shown enhanced seizure activity in mouse models with increased Abeta expression, and increased risk of epilepsy in AD patients. The goal of this proposal is to determine whether a transgenic Drosophila model that expresses the secreted human Abeta42, which exhibits many of the hallmarks of AD (e.g. Abeta deposits, age-dependent learning/memory and locomotor deficits, neurodegeneration), also displays neuronal hyperexcitability. We will identify how intrinsic electrical properties of neurons are altered, and how these changes affect neuronal excitability. These studies are essential for establishing the Abeta42-Drosophila transgenic line as an effective model for investigations into how Abeta42-induced intrinsic changes, and hyperexcitability, contribute to downstream cellular and behavioral deficits seen AD. Since ion channels are so highly conserved, cellular strategies are likely to be shared across species and findings are expected to be significant for mammalian systems.

描述（由申请人提供）：阿尔茨海默氏病（AD）是老年人口中最普遍的痴呆形式。大多数AD研究都集中在理解β-淀粉样蛋白（ABETA）肽积累和神经原纤维缠结（NFT）中如何有助于AD的原因。但是，关于这些事件如何导致AD的后期表现，例如进行性神经退行性变化以及认知和运动功能下降，鲜为人知。由于目前无法治愈AD（预防主要事件），因此了解疾病进展的后续细胞事件可能会使潜在的治疗方法有重要的见解，从而可能停止或减缓疾病的毁灭性作用。最近，ABETA的过量产生可导致海马和皮质神经元中的过度兴奋性和Ca2+“过载”。提高的兴奋性也与行为研究一致，行为研究表明，ABETA表达增加的小鼠模型中的癫痫发作活性增强，并且AD患者的癫痫风险增加。该提案的目的是确定表达分泌的人Abeta42的转基因果蝇模型，该模型是否表现出AD的许多标志（例如Abeta沉积物，年龄依赖性学习/记忆和运动型，神经变性，NeuroDegeneration）也表现出神经元素降低性降低性。我们将确定神经元的内在电性能如何改变，以及 这些变化如何影响神经元兴奋性。这些研究对于建立Abeta42-嗜醇转基因线是必不可少的，作为研究ABETA42诱导的内在变化以及过度兴奋性的有效模型，这有助于看到下游细胞和行为缺陷AD。由于离子通道是如此高度保守，因此可能会在各种物种之间共享细胞策略，并且预计发现对哺乳动物系统有意义。