Beta Amyloid and Hyperexcitability

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形式。大多数阿尔茨海默病的研究都集中在了解β -淀粉样蛋白（Abeta）肽积累和神经原纤维缠结（NFT）是如何导致阿尔茨海默病的。然而，对于这些事件如何导致阿尔茨海默病的后期表现，如进行性神经变性和认知和运动功能下降，人们知之甚少。由于目前还没有治愈阿尔茨海默病（预防原发事件）的方法，了解疾病进展背后的后续细胞事件可能会对潜在的治疗方法提供重要的见解，这些治疗方法可能会阻止或减缓这种疾病的破坏性影响。最近，Abeta的过度产生已被证明会导致海马和皮质神经元的高兴奋性和Ca2+“过载”。兴奋性增加也与行为学研究一致，行为学研究显示，在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。本研究的目的是确定表达人类分泌的Abeta42的转基因果蝇模型是否也表现出神经元的高兴奋性，而Abeta42表现出阿尔茨海默病的许多特征（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内在电特性是如何被改变的

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.