Are mechanisms leading to FAD, SAD and age-associated cognitive decline similar?

摘要 阿尔茨海默病（AD）是老年痴呆症的最常见原因， 与脑淀粉样斑块有关，主要由Aβ肽组成。这些 肽是通过淀粉样前体蛋白（APP）的双切割产生的。BACE1 裂解产生C-β末端片段β-CTGF，然后加工成几个Aβ 通过γ-β分泌酶的同种型。遗传数据表明，APP加工的调节有助于 AD.此外，APP的多晶型减少了BACE 1对APP的加工， 散发性AD和来自正常老化的依赖性认知衰退。因此，人类基因 有证据表明APP和APP加工对于正常的认知功能是重要的。 为了深入了解AD的致病机制以及AD的发病机制， 保护性突变保护人类免受AD和正常衰老--阿尔茨海默病依赖性认知衰退， 我们引入了一种家族性APP突变（瑞典K670 N/M671 L突变，Apps大鼠）， 保护性APP突变（Appp大鼠）和家族性PSEN 1突变（L435 F，Psen 1 LF大鼠）， 基因组App和Psen 1大鼠基因座。大鼠和人APP相差3个氨基酸 在Aβ区域：鉴于大多数主要研究者认为Aβ的聚集形式 AD中的致病因子，并且考虑到人Aβ可能比啮齿动物Aβ具有更高的倾向 形成尚未确定的Aβ毒性形式，与瑞典突变一起，我们 引入突变以“人源化”大鼠Aβ序列。作为对照组， 仅携带人源化Aβ序列（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模型使 没有关于致病机制的先入为主的假设，除了无偏见的遗传。 相反，转基因模型产生高水平的Aβ，并且容易存款， 淀粉样蛋白斑块，是基于这样的假设，即斑块和/或其他形式的有毒Abβ具有 一个重要的致病作用。我们建议剖析由罕见的 保护性APP变体使用这些KI大鼠模型。我们将研究Appp对 由Apps和Psen 1 LF FAD突变触发的病理过程和正常衰老- 依赖性认知衰退我们将分析APP处理，大脑病理学，神经学 炎症和神经变性，突触传递/可塑性，学习和记忆。 解剖由Appp变异体引发的保护性通路可能为治疗铺平道路。 这种方法可以预防痴呆症以及模仿老年痴呆症的“正常”认知能力下降。 由保护性APP变体触发的机制。

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 polymorfism 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 and the mechanisms by which the protective mutation protects humans from AD and normal aging-­dependent cognitive decline, we introduced a familial APP mutation (the Swedish K670N/M671L mutation, Apps rats), the protective APP mutation (Appp 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 Abβ have a central pathogenic role. We propose to dissect protective mechanisms triggered by the rare protective APP variant using these KI rat models. We will study the impact of Appp on the pathological processes triggered by the Apps and Psen1LF FAD mutations and on normal aging-­ dependent cognitive decline. We will analyze APP processing, brain pathology, neuro-­ inflammation and neurodegeneration, synaptic transmission/plasticity, learning & memory. Dissecting protective pathways set off by the Appp variant may pave the way to therapeutic approaches that can prevent dementia as well as “normal” cognitive decline mimicking the mechanisms triggered by the protective APP variant.