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

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)...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9177067/
https://www.ncbi.nlm.nih.gov/pubmed/35675411
http://dx.doi.org/10.1126/sciadv.abm6155
Descripción
Sumario: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.