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

阿尔茨海默病？S病(AD)对患者和他们的家人来说都是毁灭性的和可怕的。在阿尔茨海默病的早期阶段，S会导致记忆力丧失和精神错乱；在鼎盛时期，它会导致脑组织退化，大脑功能背后的电活动崩溃，导致智力完全崩溃。我们的年龄越来越大，因此更有可能成为AD的受害者。因此，研究阿尔茨海默病患者大脑的问题变得越来越重要。我们可以通过对老鼠进行基因改造来重现AD患者S的大脑中的一些情况。例如，我们可以培育出随着年龄增长而在大脑中积累有毒多肽β-淀粉样蛋白的小鼠。高水平的这些多肽是AD的一个关键特征，被大多数研究人员认为是关键致病因素。大脑中的信息在很大程度上是由单个神经细胞(神经元)受到刺激时产生的短暂电信号(棘波)编码的。这些神经元在大型网络中连接在一起，而正是这些神经元网络被认为处理和存储记忆。这种神经元网络的紊乱被认为是许多记忆障碍的基础，包括阿尔茨海默病。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理解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，这是大脑中对记忆至关重要的区域。这使得我们最近能够在AD小鼠模型中识别出棘波的形状、大小和模式的显著变化。这些变化是由于钠离子通过称为钠通道的特殊蛋白质穿过细胞膜的流量减少所致。我们认为，如果这些变化在人类身上是平行的，它们将极大地促进认知缺陷，这是AD的一个标志。利用AD模型小鼠，我们建议进一步研究大脑电特性的变化与年龄相关的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。我们还将调查钠通道和尖峰信号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增长而发展的电活动的变化。

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.