A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide.
A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide.
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阿尔茨海默氏病的第三代小鼠模型表明，由野生型人淀粉样蛋白β肽组成的早期和增加的核斑块病理学。
DOI：
10.1016/j.jbc.2021.101004
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Sasaguri H
中科院分区：
文献类型：
--
作者：
Sato K;Watamura N;Fujioka R;Mihira N;Sekiguchi M;Nagata K;Ohshima T;Saito T;Saido TC;Sasaguri H
我们先前开发了阿尔茨海默病（AD）的单个App敲入小鼠模型，其具有瑞典和拜罗伊特/伊比利亚突变，具有或不具有北极突变（分别为AppNL-G-F和AppNL-F小鼠）。这些模型以年龄依赖性方式显示Aβ病理学、神经炎症和认知障碍。前一种模型早在6个月时就表现出广泛的病理学，但不适合研究Aβ代谢和清除，因为Arctic突变使Aβ对蛋白水解降解具有抗性并易于聚集。特别是，由于其对抗A β抗体的离散亲和力，其不适用于临床前免疫治疗研究。后一种模型可能需要长达18个月的时间才能使病理学变得突出，这使得对阿尔茨海默病动物模型的需求尚未得到满足，该动物模型既能迅速显示病理学又可用于抗体治疗。因此，我们利用已引入致病性突变（P117 L）的突变型Psen 1基因敲入小鼠，通过将AppNL-F系与Psen 1 P117 L/WT系杂交，产生一种新模型，该模型显示野生型人Aβ的早期沉积。我们表明，在App和Psen 1基因的致病性突变的影响是加性或协同作用。这种新的第三代小鼠模型显示出比AppNL-G-F小鼠更多的核心斑块病理学和神经炎症，并将有助于加速疾病修饰疗法的开发，以治疗临床前AD。
We previously developed single App knock-in mouse models of Alzheimer's disease (AD) harboring the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL-G-F and AppNL-F mice, respectively). These models showed Aβ pathology, neuroinflammation, and cognitive impairment in an age-dependent manner. The former model exhibits extensive pathology as early as 6 months, but is unsuitable for investigating Aβ metabolism and clearance because the Arctic mutation renders Aβ resistant to proteolytic degradation and prone to aggregation. In particular, it is inapplicable to preclinical immunotherapy studies due to its discrete affinity for anti-Aβ antibodies. The latter model may take as long as 18 months for the pathology to become prominent, which leaves an unfulfilled need for an Alzheimer's disease animal model that is both swift to show pathology and useful for antibody therapy. We thus utilized mutant Psen1 knock-in mice into which a pathogenic mutation (P117L) had been introduced to generate a new model that exhibits early deposition of wild-type human Aβ by crossbreeding the AppNL-F line with the Psen1P117L/WT line. We show that the effects of the pathogenic mutations in the App and Psen1 genes are additive or synergistic. This new third-generation mouse model showed more cored plaque pathology and neuroinflammation than AppNL-G-F mice and will help accelerate the development of disease-modifying therapies to treat preclinical AD.
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