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中突触损伤的原因 疾病（AD）。越来越多的证据表明，突触丢失是最早的改变之一， 与AD中的认知缺陷相关。因此，了解突触损伤的原因至关重要 在AD中，尤其是在早期甚至疾病前阶段。淀粉样β蛋白， 脑中的老年斑已经显示在体外和体内都损害突触功能。但 Abeta诱导突触功能障碍和突触丧失的机制尚不清楚。本课题 将在几种AD相关的动物模型中测试A β诱导的突触损伤的几种假设。 病理学与本项目的其他三个项目共享概念和技术方法。 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是否是 在Abeta诱导的突触功能障碍中更重要。这将通过选择性表达淀粉样蛋白来测试 前体蛋白（APP）分别在CA1或CAS神经元，并评估突触的功能 在这两组神经元之间。第二个目标将研究年龄如何影响Abeta诱导 海马神经元突触功能障碍。虽然大多数研究都集中在Abeta的影响上， 我们的方法测试了相反的情况：Abeta暴露多长时间 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 突触扰动确实是神经变性的早期和关键因素，那么轴突很可能 同时退化。在这方面，在AD个体和动物模型中的脑中观察到轴突病理学。 模型第三个目标将检查APP转基因小鼠与WLD杂交的表型（慢转基因小鼠）。 沃勒变性）突变小鼠。后者突变动物的轴突受到保护，免受损伤， 各种有毒物质和神经变性。因此，我们可以测试保留轴突是否可以 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.