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

• Published in: Science Advances
• Main Authors: Watamura, Naoto, Sato, Kaori, Shiihashi, Gen, Iwasaki, Ayami, Kamano, Naoko, Takahashi, Mika, Sekiguchi, Misaki, Mihira, Naomi, Fujioka, Ryo, Nagata, Kenichi, Hashimoto, Shoko, Saito, Takashi, Ohshima, Toshio, Saido, Takaomi C., Sasaguri, Hiroki
• Format: Article in Journal/Newspaper
• Language: English
• Published: American Association for the Advancement of Science (AAAS) 2022
• Subjects: Arctic
• Online Access: http://dx.doi.org/10.1126/sciadv.abm6155; https://www.science.org/doi/pdf/10.1126/sciadv.abm6155

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 ( App NL-G-F and App NL-F mice). We have now generated App knock-in mice devoid of the Swedish mutations ( App G-F mice) and evaluated its characteristics. Amyloid β peptide (Aβ) pathology was exhibited by App G-F mice from 6 to 8 months of age and was accompanied by neuroinflammation. Aβ-secretase inhibitor, verubecestat, attenuated Aβ production in App G-F mice, but not in App NL-G-F mice, indicating that the App G-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.