Synaptic damage in models of beta-amyloid associated pathology

β-淀粉样蛋白相关病理模型中的突触损伤

• 批准号: 7674558
• 负责人: EDWARD H. KOO
• 金额: $ 33.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674558
• 关键词: Acute; Age; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Animal Model; Animals; Attenuated; Axon; Behavioral; Brain; Cognitive deficits; Defect; Disease; Excision; Functional disorder; Hippocampus (Brain); In Vitro; Individual; Injection of therapeutic agent; Injury; Laboratories; Lesion; Long-Term Potentiation; Mediating; Modeling; Mutant Strains Mice; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neuropathy; Pathogenesis; Pathology; Phenotype; Process; Proteins; Research; Senile Plaques; Staging; Subfamily lentivirinae; Synapses; Synaptic Transmission; Testing; Time; Toxic effect; Transgenic Mice; Wallerian Degeneration; Work; beta amyloid pathology; beta-site APP cleaving enzyme 1; depression; in vivo; mutant; neuron loss; postsynaptic; presynaptic; programs; receptor recycling; secretase; selective expression; synaptic function

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.

该提议的目的是了解阿尔茨海默氏症中存在的突触损害的原因 疾病（AD）。越来越多的证据表明，突触损失是最早的改变之一，也是最好的变化之一 AD认知缺陷的相关性。因此，了解什么是导致突触伤害的是至关重要的 在广告中，尤其是在最早甚至疾病前的阶段。淀粉样β-蛋白质，主要成分 大脑中的老年斑块已被证明会在体外和体内损害突触功能。但是， Abeta诱导突触功能障碍和突触丧失的机制尚不清楚。在这个项目中，我们 将在几种与广告相关的动物模型中检验几种Abeta诱导的突触损伤的假设 与其他三个项目共同共享概念和技术方法的病理学 程序。在第一个目的中，我们将确定Abeta是从突触前或后神经元中释放的 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 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。第二个目标将研究年龄的影响Abeta引起的影响 海马神经元中的突触功能障碍。尽管大多数研究都集中在Abeta的影响上 减少大脑，我们的方法测试相反的情况：Abeta暴露必须多长时间 在突触传播之前，在大脑中持续存在，并且是否相关。最后，如果 突触扰动确实是早期的，是神经变性的关键因素，然后轴突很可能 同时退化。在这方面，在AD个体和动物的大脑中可以看到轴突病理 型号。第三个目的将检查APP转基因小鼠的表型（慢速） Wallerian变性）突变小鼠。后一种突变动物中的轴突受到伤害和免受 各种有毒药物和神经变性。因此，我们可以测试保存轴突是否可以 衰减APP转基因小鼠的突触损伤。