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.