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

项目摘要/摘要 阿尔茨海默病(AD)是世界上最常见的老年依赖痴呆的原因， 与脑淀粉样斑块相关，主要由Aβ多肽组成。这些多肽是由 淀粉样前体蛋白(APP)的双裂解。BACE1裂解产生C-末端 β-CTF片段，用β-分泌酶将其加工成不同的A-γ亚型。基因数据表明 对APP处理的监管导致了AD。此外，应用程序的多态可以减少处理 BACE1的APP保护了散发性AD和正常衰老依赖的认知能力下降。因此， 人类遗传证据表明，APP和APP处理对正常认知功能非常重要。 为了深入了解AD的发病机制，我们引入了一种家族性APP突变(瑞典人 K670N/M671L突变，APPS大鼠)和家族性PSEN1突变(L435F，Psen1LF大鼠)进入基因组App 和PSEN1大鼠基因座。大鼠和人类APP在Aβ区有3个氨基酸不同：鉴于 聚集形式的A-β被大多数人认为是AD的主要致病因素，并且考虑到人类A-β 可能比啮齿动物Aβ有更高的倾向形成尚未被识别的Aβ中毒形式，连同 瑞典突变我们引入突变是为了使大鼠的Aβ序列人性化。作为对照，我们制作了 只携带人源化Aβ序列的大鼠(APPH大鼠)。我们选择敲门(KI)方法，而不是 更常见的转基因过表达方法，因为KI模型没有先入为主的 关于致病机制的假设，除了无偏见的遗传机制。相比之下，转基因模型， 它们会产生高水平的A，并容易沉积淀粉样斑块，是基于这样的假设 斑块和/或其他形式的有毒A具有中心致病作用。我们建议解剖病原体 用这些KI大鼠FAD模型研究神经退行性变的机制。我们将研究App和 PSEN1 FAD突变对APP处理、脑病理、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，我们还将评估不同的应用程序派生的角色 突变型APP和PSEN1引发的神经退行性变过程中的代谢物。这些研究将测试 主流假说，但也考虑了替代致病机制，包括 FAD的发病机制可能与脑内APP和PSEN1的正常功能改变有关。

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 A and can readily deposit amyloid plaques, are based on the hypothesis that plaques and/or other forms of toxic A 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.