Beta Amyloid and Presynaptic Nicotinic Receptors

β 淀粉样蛋白和突触前烟碱受体

• 批准号: 6881568
• 负责人: Robert Alan Nichols
• 金额: $ 22.61万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6881568
• 关键词: amyloid proteins; calcium metabolism; cellular polarity; confocal scanning microscopy; corpus striatum; frontal lobe /cortex; genetically modified animals; hippocampus; laboratory mouse; microdialysis; mitochondria; neural degeneration; neuroprotectants; nicotinic receptors; phosphorylation; presenilin; receptor expression

DESCRIPTION (provided by applicant): A prominent characteristic of Alzheimer's disease is the loss of brain nerve cells that employ the neurotransmitter acetylcholine. Cholinergic neurons may be lost as a consequence of the formation of toxic deposits, known as neuritic plaques, which contain beta amyloid peptides as a major component. However, the correlation between amyloid deposition and cognitive impairment appears to be poor. On the other hand, target receptors for acetylcholine may be affected, indicating an action of soluble beta amyloid. Indeed, beta amyloid has recently been shown to interact directly with nicotinic receptors on neuronal cell bodies. In brain, a substantial portion of the nicotinic receptors are localized to presynaptic nerve endings. Preliminarily, it was found that beta amyloid first activates and then occludes presynaptic nicotinic receptor-induced functional responses in isolated hippocampal nerve endings, but does not affect responses mediated by the closely related 5-HT3 serotonin receptors co-localized with the nicotinic receptors on the same nerve endings. Thus, it is hypothesized that soluble beta amyloid selectively alters neuronal signaling via disruption of postsynaptic and presynaptic nicotinic receptors in the brain. The specific aims of this proposal are to characterize the effects of beta amyloid peptides on 1) nicotine-induced calcium responses and neurosecretion in individual nerve endings using confocal microscopy; 2) neurotransmitter release in vivo using microdialysis; and 3) initiation of nerve terminal degenerative responses to prolonged beta amyloid treatment, including mitochondria depolarization and calcium dysregulation, and the possible role of protein phosphorylation in these events. In each case, mouse hippocampus, cortex, and, on a limited basis as a control, striatum will be examined. The use of inbred mice will allow studies with transgenic mouse models, including the APP mutant APPswe/PS1 and nicotinic receptor null mutants, allowing definite determination of which particular presynaptic nicotinic receptor subunits are targets for beta amyloid and what effect chronic beta amyloid has on presynaptic nicotinic receptor function. Nicotinic receptors have been strongly implicated in memory mechanisms in the brain. Their disruption by elevated soluble beta amyloid may cause alterations in neuronal signaling in early Alzheimer's disease leading to reduced cognitive function. The role of presynaptic nicotinic receptors may be key, as these receptors are prominently localized to nerve endings in the brain. Characterizing the functional effects of beta amyloid on presynaptic nicotinic receptors may thus yield important information related to early events in Alzheimer's disease.

描述(申请人提供)：阿尔茨海默病的一个显著特征是使用神经递质乙酰胆碱的脑神经细胞丢失。胆碱能神经元可能会由于形成有毒沉积物而丢失，这种沉积物被称为神经性斑块，其中含有作为主要成分的β淀粉样肽。然而，淀粉样蛋白沉积和认知障碍之间的相关性似乎很差。另一方面，乙酰胆碱的目标受体可能会受到影响，这表明可溶性β淀粉样蛋白的作用。事实上，β淀粉样蛋白最近被证明与神经元细胞体上的尼古丁受体直接相互作用。在大脑中，很大一部分尼古丁受体定位于突触前神经末梢。初步发现，在分离的海马神经末梢，β-淀粉样蛋白首先激活并阻断突触前烟碱受体诱导的功能反应，但不影响与烟碱受体共同定位的密切相关的5-HT3 5-羟色胺受体所介导的反应。因此，假设可溶性β淀粉样蛋白通过破坏脑中突触后和突触前的尼古丁受体选择性地改变神经元信号。这项建议的具体目的是描述β淀粉样多肽对1)尼古丁诱导的钙反应和单个神经末梢的神经分泌的影响，使用共聚焦显微镜；2)使用微透析在体内释放神经递质；以及3)启动对长期β淀粉样蛋白治疗的神经末梢退行性反应，包括线粒体去极化和钙调节失调，以及蛋白质磷酸化在这些事件中的可能作用。在每种情况下，将检查小鼠的海马体、皮质，以及作为对照的有限基础上的纹状体。近交系小鼠的使用将允许对转基因小鼠模型进行研究，包括APP突变体APPswe/PS1和尼古丁受体缺失突变体，从而能够明确确定哪些特定的突触前尼古丁受体亚单位是β淀粉样蛋白的靶标，以及慢性β淀粉样蛋白对突触前尼古丁受体功能有什么影响。 尼古丁受体与大脑的记忆机制密切相关。它们被升高的可溶性β淀粉样蛋白破坏可能会导致早期阿尔茨海默病患者神经元信号的改变，从而导致认知功能下降。突触前尼古丁受体的作用可能是关键，因为这些受体主要定位于大脑的神经末梢。因此，表征β淀粉样蛋白对突触前烟碱受体的功能影响可能会产生与阿尔茨海默病早期事件相关的重要信息。