Studies of dementia pathogenesis in genetically faithful rat models of Familal Alzheimer disease

项目总结/摘要 阿尔茨海默病（AD）是世界上年龄依赖性痴呆的最常见原因， 与脑淀粉样斑块相关，主要由Aβ肽组成。这些肽是由 淀粉样前体蛋白（APP）的双重裂解。BACE 1裂解产生C-末端 片段，β-CTF，然后被γ-分泌酶加工成几种Aβ亚型。基因数据表明， APP加工的调节有助于AD。此外，APP的多态性减少了处理 APP的BACE 1保护散发性AD和正常的年龄依赖性认知功能下降。因此 人类遗传学证据表明APP和APP加工对于正常认知功能是重要的。 为了深入了解AD的致病机制，我们引入了一种家族性APP突变（瑞典人）。 K670 N/M671 L突变，AppS大鼠）和家族性PSEN 1突变（L435 F，Psen 1 LF大鼠）插入基因组App 和Psen 1大鼠基因座。大鼠和人APP在Aβ区有3个氨基酸的差异： 大多数人认为Aβ的聚集形式是AD的主要致病因素， 可能比啮齿类动物Aβ更容易形成尚未鉴定的Aβ毒性形式， 瑞典突变我们引入突变来“人源化”大鼠Aβ序列。作为对照，我们生产了 仅携带人源化Aβ序列的大鼠（Apph大鼠）。我们选择敲入（KI）方法，而不是 更常见的转基因过表达方法，因为KI模型没有预先考虑 关于致病机制的假设，除了无偏见的遗传。相反，转基因模型， 产生高水平的Aβ，并容易存款淀粉样斑块，是基于这样的假设， 斑块和/或其他形式的毒性Aβ具有中心致病作用。我们建议解剖病原体 使用这些KI大鼠FAD模型研究神经变性的机制。我们将研究应用程序的影响， Psen 1 FAD突变对APP加工、脑病理学、神经炎症和神经变性的影响， 突触传递/可塑性，学习和记忆。此外，我们还将评估不同APP衍生的 在由突变APP和PSEN 1触发的神经退行性过程中的代谢物。这些研究将测试 主流假说，但也考虑替代的致病机制，包括可能性， FAD的发病机制可能依赖于APP和PSEN 1在脑内正常功能的改变。

Project Summary/Abstract Alzheimer's Disease (AD) is the most common cause of ageing-dependent dementia in the world and is associated with cerebral amyloid plaques, mostly composed of Aβ peptides. These peptides are produced by a double cleavage of the amyloid precursor protein (APP). BACE1 cleavage produces the C-terminal fragment, β-CTF, which is then processed into several Aβ isoforms by γ-secretase. Genetic data suggest that regulation of APP processing contributes to AD. In addition, a polymorphism of APP that reduces processing of APP by BACE1 protects from sporadic AD and from normal aging-dependent cognitive decline. Thus, the human genetic evidence indicates that APP and APP processing are important for normal cognitive functions. To gain insights into the pathogenic mechanisms of AD we introduced a familial APP mutation (the Swedish K670N/M671L mutation, AppS rats) and a familial PSEN1 mutation (L435F, Psen1LF rats) into the genomic App and Psen1 rat loci, respectively. Rat and human APP differ by 3 amino-acids in the Aβ region: given that aggregated forms of Aβ are considered by most the main pathogenic factor in AD, and given that human Aβ may have higher propensity than rodent Aβ to form yet-to-be-identified toxic forms of Aβ, together with the Swedish mutations we introduced mutations to “humanize” the rat Aβ sequence. As controls, we produced rats carrying only the humanized Aβ sequence (Apph rats). We choose a knock in (KI) approach rather than the more common transgenic overexpression approach because KI models make no preconceived assumption about pathogenic mechanisms, except the unbiased genetic one. In contrast, transgenic models, which produce high levels of Aβ and can readily deposit amyloid plaques, are based on the hypothesis that plaques and/or other forms of toxic Aβ have a central pathogenic role. We propose to dissect pathogenic mechanisms of neurodegeneration using these KI rat models of FAD. We will study the impact of App and Psen1 FAD mutations on APP processing, brain pathology, neuro-inflammation and neurodegeneration, synaptic transmission/plasticity, learning & memory. In addition, we will assess the role of distinct APP-derived metabolites in neurodegenerative processes triggered by mutant APP and PSEN1. These studies will test the mainstream hypotheses but also consider alterative pathogenic mechanisms, including the possibility that FAD pathogenesis may depend on the alteration of the normal function of APP and PSEN1 in the brain.