Modified intrinsic excitability in transgenic mouse models of progressive beta-amyloidopathy

进行性β-淀粉样蛋白病转基因小鼠模型中内在兴奋性的改变

• 批准号: G1100623/1
• 负责人: Andrew Randall
• 金额: $ 69.03万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1100623%2F1
• 关键词: Modified; intrinsic; excitability; transgenic; mouse

Alzheimer?s disease (AD) is devastating and frightening for both sufferers and their families. In its early stages, Alzheimer?s leads to memory loss and confusion; at its peak, it leads to a complete breakdown of mental ability as brain tissue degenerates and the electrical activity underlying brain function breaks down. We are living to ever greater ages and therefore are more likely to fall victim to AD. Research into what goes wrong with the brain in AD is therefore increasingly important. We can recreate some of the conditions that occur in the AD patient?s brain by genetically modifying mice. For example, we can produce mice that accumulate the toxic peptide beta-amyloid in their brain as they age. High levels of these peptides are a key feature of AD and are thought by most researchers to be key causative factor. Information in the brain is largely encoded by brief electrical signals (spikes) generated when individual nerve cells (neurones) become stimulated. These neurones are connected together in large networks, and it is these neuronal networks which are thought to process and store memories. Disturbances in such neuronal networks are thought to underlie many disorders of memory, including those in AD. We have recently been trying to understand the causes of these electrical disturbances in AD by studying mouse models that overproduce beta-amyloid. To do this we record the electrical activity of individual neurones in the hippocampus, an area of the brain crucial for memory. This recently allowed us to identifying striking changes to the shape, size and patterns of spikes in mouse models of AD. These changes result from a reduced flow of sodium ions across the cell membrane via specialised proteins called sodium channels. We believe that if such changes are paralleled in man they will contribute substantially to the cognitive deficits that are a hallmark of AD. Using AD model mice we propose to further investigate the relationship between the changes to electrical properties of the brain and the age-dependent over-production of beta-amyloid. This will allow us to compare our findings with other studies of disease progression in these mice We will also investigate how the changes to sodium channels and spikes are produced and will also use secretase inhibitor drugs, similar to those in clinical trails, to attempt to reverse the alterations to electrical activity that develop as our mice age.

老年痴呆症？阿尔茨海默病（AD）对患者和他们的家庭来说是毁灭性的和可怕的。在早期阶段，老年痴呆症？它会导致记忆丧失和混乱;在高峰期，它会导致精神能力的完全崩溃，因为脑组织退化，大脑功能的电活动中断。我们的年龄越来越大，因此更有可能成为AD的受害者。因此，研究AD患者的大脑出了什么问题变得越来越重要。我们可以重现AD病人的症状？通过基因改造老鼠的大脑。例如，我们可以制造出随着年龄增长而在大脑中积累有毒肽β-淀粉样蛋白的小鼠。高水平的这些肽是AD的一个关键特征，并且被大多数研究人员认为是关键的致病因素。大脑中的信息主要由单个神经细胞（神经元）受到刺激时产生的短暂电信号（尖峰）编码。这些神经元在大的网络中连接在一起，正是这些神经元网络被认为是处理和存储记忆的。这种神经元网络的紊乱被认为是许多记忆障碍的基础，包括AD中的记忆障碍。我们最近一直试图通过研究过度产生β-淀粉样蛋白的小鼠模型来了解AD中这些电干扰的原因。为了做到这一点，我们记录了海马体中单个神经元的电活动，海马体是大脑中对记忆至关重要的区域。最近，这使我们能够识别AD小鼠模型中尖峰的形状，大小和模式的显着变化。这些变化是由于钠离子通过称为钠通道的专门蛋白质穿过细胞膜的流量减少所致。我们相信，如果这些变化在人类中得到证实，它们将大大有助于认知缺陷，这是AD的标志。使用AD模型小鼠，我们建议进一步研究脑电特性的变化与年龄依赖性β-淀粉样蛋白过度产生之间的关系。这将使我们能够将我们的发现与这些小鼠疾病进展的其他研究进行比较。我们还将研究钠通道和尖峰的变化是如何产生的，并将使用分泌酶抑制剂药物，类似于临床试验中的药物，试图逆转随着小鼠年龄的增长而发生的电活动的变化。