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) 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.