Synaptic damage in models of beta-amyloid associated pathology

这项建议的目的是了解阿尔茨海默氏症患者突触损伤的原因 疾病(AD)。越来越多的证据表明，突触丢失是最早也是最好的改变之一 阿尔茨海默病患者认知功能障碍的相关性研究因此，了解是什么导致突触损伤是至关重要的。 在阿尔茨海默病中，尤其是在疾病的早期甚至疾病前期。淀粉样β蛋白，其主要成分 大脑中的老年斑，在体外和体内都被证明会损害突触功能。然而， Abeta导致突触功能障碍和突触丢失的机制尚不清楚。在这个项目中，我们 将在几个AD相关动物模型中测试Abeta诱导的突触损伤的几个假说 与本项目的其他三个项目共享概念和技术方法的病理学 程序。在第一个目标中，我们将确定从突触前或突触后神经元释放的Abeta是 更重要的是Abeta诱导的突触功能障碍。这将通过选择性表达淀粉样蛋白来测试 CA1或CAS神经元中的前体蛋白(APP)，并评估突触的功能 在这两组神经元之间。第二个目标是研究年龄如何影响Abeta诱导的 海马神经元的突触功能障碍。虽然大多数研究都集中在Abeta的影响上 对于大脑的减少，我们的方法测试了相反的情景：Abeta暴露必须持续多久 在突触传递受到干扰之前在大脑中持续存在，以及这是否与年龄有关。最后，如果 突触的扰动确实是神经变性的早期和关键因素，然后轴突很可能 伴随着堕落。在这一点上，轴突病理可见于AD患者和动物的大脑。 模特们。第三个目标是检测APP转基因小鼠与WLDs杂交的表型(Slow 沃勒氏变性)突变小鼠。后一种突变动物的轴突在损伤中受到保护，并在 各种毒物和神经退行性变。因此，我们可以测试保存轴突是否可以 减轻APP转基因小鼠的突触损伤。

The objective of this proposal is to understand the causes of synaptic damage that is present in Alzheimer's disease (AD). Increasing evidence indicate that synapse loss is one of the earliest alterations and the best correlate of the cognitive deficits in AD. Consequently, it is crucial to understand what causes synaptic injury in AD, especially in the earliest or even pre-disease stages. Amyloid beta-protein, the major constituent of senile plaques in brain, has been shown to impair synaptic function both in vitro and in vivo. However, the mechanisms by which Abeta induce synaptic dysfunction and synapse loss are not clear. In this project, we will test several hypotheses of Abeta-induced synaptic damage in several animal models of AD-related pathology that share conceptual and technical approaches in common with the other three Projects of this Program. In the first Aim, we will determine whether Abeta released from the pre- or postsynaptic neuron is more important in Abeta induced synaptic dysfunction. This will be tested by selectively expressing amyloid precursor protein (APP) in CA1 or CAS neurons, respectively, and assessing the function of the synapses between these two sets of neurons. The second Aim will examine how age influences Abeta induced synaptic dysfunction in hippocampal neurons. While most studies have concentrated on the effects of Abeta reduction in brain, our approach tests the opposite scenario: how long does Abeta exposure have to be sustained in brain before synaptic transmission is perturbed and whether this is related .toage. Lastly, if synaptic perturbations are indeed early and key contributors to neurodegeneration, then axons are likely to degenerate concomitantly. In this regard, axonal pathology is seen in brains of AD individuals and in animal models. The third Aim will examine the phenotype of APP transgenic mice crossed to the WLDs (slow Wallerian degeneration) mutant mice. Axons in the latter mutant animals are protected in injury and from various toxic agents and neurodegeneration. Consequently, we can test whether preserving axons can attenuate synaptic damage in APP transgenic mice.