Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Waseda University, Shinjuku, Tokyo 162-8480, Japan.
Sci Adv. 2022 Jun 10;8(23):eabm6155. doi: 10.1126/sciadv.abm6155. Epub 2022 Jun 8.
We previously developed single App knock-in mouse models of Alzheimer's disease (AD) that harbor the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation ( and mice). We have now generated knock-in mice devoid of the Swedish mutations ( mice) and evaluated its characteristics. Amyloid β peptide (Aβ) pathology was exhibited by mice from 6 to 8 months of age and was accompanied by neuroinflammation. Aβ-secretase inhibitor, verubecestat, attenuated Aβ production in mice, but not in mice, indicating that the mice are more suitable for preclinical studies of β-secretase inhibition given that most patients with AD do not carry the Swedish mutations. Comparison of isogenic knock-in lines revealed that multiple factors, including elevated C-terminal fragment β (CTF-β) and humanization of Aβ might influence endosomal alterations in vivo. Thus, experimental comparisons between different isogenic , knock-in mouse lines will provide previously unidentified insights into our understanding of the etiology of AD.
我们之前开发了具有瑞典和 Beyreuther/Iberian 突变的阿尔茨海默病（AD）的单一 App 敲入小鼠模型，或带有或不带有北极突变（ 和 小鼠）。我们现在已经生成了缺乏瑞典突变的 敲入小鼠（ 小鼠），并评估了其特征。淀粉样β肽（Aβ）病理学在 6 至 8 个月大的 小鼠中表现出来，伴有神经炎症。Aβ-分泌酶抑制剂 verubecestat 可减少 小鼠的 Aβ产生，但不能减少 小鼠的 Aβ产生，这表明由于大多数 AD 患者不携带瑞典突变，因此 小鼠更适合β-分泌酶抑制的临床前研究。对同基因 敲入系的比较表明，多种因素，包括 C 端片段 β（CTF-β）升高和 Aβ的人源化，可能会影响体内内体的改变。因此，不同同基因 敲入小鼠系之间的实验比较将为我们对 AD 病因的理解提供以前未发现的见解。
