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(申请人提供)：阿尔茨海默病(AD)是老年人群中最常见的痴呆症形式。大多数AD研究都集中在了解β-淀粉样蛋白(Abeta)多肽堆积和神经原纤维缠结(NFT)是如何导致AD的。然而，关于这些事件如何导致AD的后期表现，如进行性神经变性和认知和运动功能下降，人们知之甚少。由于目前还没有治疗AD的方法(预防主要事件)，了解疾病进展背后的后续细胞事件可能会为阻止或减缓疾病的破坏性影响的潜在治疗方法提供重要的见解。最近，Abeta的过度产生被证明会导致海马神经元和皮质神经元的过度兴奋和钙超载。兴奋性的增加也与行为学研究一致，这些研究表明，随着Abeta表达的增加，小鼠模型的癫痫活动增强，AD患者癫痫的风险增加。这项建议的目的是确定表达分泌的人类Abeta42的转基因果蝇模型是否也表现出神经元的过度兴奋性。人类Abeta42表现出AD的许多特征(如Abeta沉积、年龄依赖性学习/记忆和运动障碍、神经变性)。我们将确定神经元的内在电属性是如何改变的，以及 这些变化是如何影响神经元兴奋性的。这些研究对于建立Abeta42-果蝇转基因系作为研究Abeta42诱导的内在变化和过度兴奋如何导致AD下游细胞和行为缺陷的有效模型至关重要。由于离子通道是如此高度保守，细胞策略可能会在不同物种之间共享，这些发现有望对哺乳动物系统具有重要意义。