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）：阿尔茨海默病（AD）是老年人群中最常见的痴呆症。大多数 AD 研究的重点是了解 β-淀粉样蛋白 (Abeta) 肽的积累和神经原纤维缠结 (NFT) 如何导致 AD。然而，人们对这些事件如何导致 AD 的后期表现（例如进行性神经变性以及认知和运动功能下降）知之甚少。由于目前还没有治疗 AD 的方法（预防主要事件），了解疾病进展的后续细胞事件可能会为潜在的治疗方法提供重要的见解，从而阻止或减缓疾病的破坏性影响。最近，Abeta 的过量产生已被证明会导致海马和皮质神经元过度兴奋和 Ca2+“超载”。兴奋性的增加也与行为研究相一致，行为研究表明，Abeta 表达增加的小鼠模型中癫痫活动增强，AD 患者癫痫风险增加。该提案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过度兴奋，该模型表现出 AD 的许多特征（例如 Abeta 沉积、年龄依赖性学习/记忆和运动缺陷、神经变性） 。我们将确定神经元的固有电特性是如何改变的，并且 这些变化如何影响神经元的兴奋性。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。由于离子通道如此高度保守，细胞策略可能在物种之间共享，并且这些发现预计对哺乳动物系统具有重要意义。