An isogenic panel of App knock-in mouse models: Profiling β-secretase inhibition and endosomal abnormalities

Naoto Watamura, Kaori Sato, Gen Shiihashi, Ayami Iwasaki, Naoko Kamano, Mika Takahashi, Misaki Sekiguchi, Naomi Mihira, Ryo Fujioka, Kenichi Nagata, Shoko Hashimoto, Takashi Saito, Toshio Ohshima, Takaomi C. Saido*, Hiroki Sasaguri

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 (AppNL-G-F and AppNL-F mice). We have now generated App knock-in mice devoid of the Swedish mutations (AppG-F mice) and evaluated its characteristics. Amyloid β peptide (Aβ) pathology was exhibited by AppG-F mice from 6 to 8 months of age and was accompanied by neuroinflammation. Aβ-secretase inhibitor, verubecestat, attenuated Aβ production in AppG-F mice, but not in AppNL-G-F mice, indicating that the AppG-F 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 App 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 App, knock-in mouse lines will provide previously unidentified insights into our understanding of the etiology of AD.

Original languageEnglish
Article numbereabm6155
JournalScience Advances
Volume8
Issue number23
DOIs
Publication statusPublished - 2022 Jun

ASJC Scopus subject areas

  • General

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