TY - JOUR
T1 - An isogenic panel of App knock-in mouse models
T2 - Profiling β-secretase inhibition and endosomal abnormalities
AU - Watamura, Naoto
AU - Sato, Kaori
AU - Shiihashi, Gen
AU - Iwasaki, Ayami
AU - Kamano, Naoko
AU - Takahashi, Mika
AU - Sekiguchi, Misaki
AU - Mihira, Naomi
AU - Fujioka, Ryo
AU - Nagata, Kenichi
AU - Hashimoto, Shoko
AU - Saito, Takashi
AU - Ohshima, Toshio
AU - Saido, Takaomi C.
AU - Sasaguri, Hiroki
N1 - Funding Information:
We thank N. Iwata (Nagasaki University) and A. Hoshino and T. Hino (Kyoto Prefectural University of Medicine) for valuable discussions. We also thank Y. Nagai-Watanabe for secretarial work. This work was supported by AMED under grant number JP20dm0207001 [Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/ MINDS)] (T.C.S.), JSPS KAKENHI grant number JP18K07402 (H.S.), and the Takeda Science Foundation (H.S.).
Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved
PY - 2022/6
Y1 - 2022/6
N2 - 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.
AB - 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.
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U2 - 10.1126/sciadv.abm6155
DO - 10.1126/sciadv.abm6155
M3 - Article
C2 - 35675411
AN - SCOPUS:85131772080
SN - 2375-2548
VL - 8
JO - Science Advances
JF - Science Advances
IS - 23
M1 - eabm6155
ER -