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

<jats:p> 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 ( <jats:italic> App <jats:sup>NL-G-F</jats:sup> </jats:italic> and <jats:italic> App <jats:sup>NL-F</jats:sup> </jats:italic> mice). We have now generated <jats:italic>App</jats:italic> knock-in mice devoid of the Swedish mutations ( <jats:italic> App <jats:sup>G-F</jats:sup> </jats:italic> mice) and evaluated its characteristics. Amyloid β peptide (Aβ) pathology was exhibited by <jats:italic> App <jats:sup>G-F</jats:sup> </jats:italic> mice from 6 to 8 months of age and was accompanied by neuroinflammation. Aβ-secretase inhibitor, verubecestat, attenuated Aβ production in <jats:italic> App <jats:sup>G-F</jats:sup> </jats:italic> mice, but not in <jats:italic> App <jats:sup>NL-G-F</jats:sup> </jats:italic> mice, indicating that the <jats:italic> App <jats:sup>G-F</jats:sup> </jats:italic> 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 <jats:italic>App</jats:italic> 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 <jats:italic>App</jats:italic> , knock-in mouse lines will provide previously unidentified insights into our understanding of the etiology of AD. </jats:p>