Watamura N, Sato K, Shiihashi G, Iwasaki A, Kamano N, Takahashi M, Sekiguchi M, Mihira N, Fujioka R, Nagata K, Hashimoto S, Saito T, Ohshima T, Saido TC, Sasaguri H. An isogenic panel of App knock-in mouse models: Profiling β-secretase inhibition and endosomal abnormalities. Sci Adv. 2022 Jun 10;8(23):eabm6155. Epub 2022 Jun 8 PubMed.
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Northwestern University Feinberg School of Medicine
This is a useful model to add to the armamentarium of mice to investigate amyloid pathology. It will be particularly useful for testing dose-response relationships of BACE1 inhibitors in vivo. The Swedish mutation makes APP such a strong substrate for BACE1 that it really skews the doses of BACE inhibitor toward unnecessarily high levels that could mislead translation to humans. I am happy to see this new model and hope the authors will make it available to the AD research community, as they have done with their previous models.
University of Connecticut Health
Previous in vitro and in vivo studies have demonstrated that BACE1 cleaves Swedish mutant APP more effectively, and removal of Swedish mutations in APP is a necessary step for a better model. I agree that this G-F mouse model is more useful for evaluating the BACE1 inhibition compared to mouse models currently available for testing amyloid hypothesis. However, the presence of two mutated residues still makes APP different from that in patients with sporadic AD.
German Center for Neurodegenerative Diseases (DZNE)
The new GF knock-in mouse line is a very welcome addition to the toolbox of AD mouse models. Similar to previously generated models from the same group or by Denali, it expresses APP at endogenous levels but avoids the widely used Swedish mutation, which has a major effect on APP shedding by rerouting APP shedding from α- to β-secretase. Thus, the new mouse line will not only be a great tool for studying the natural cleavage of APP by the β-secretase BACE1, but also by the α-secretase ADAM10, which is much less investigated as an AD drug target compared to BACE1.
The authors provide an elegant experiment to demonstrate the advantage of the natural BACE1 cleavage sequence. They show that the established BACE inhibitor verubecestat blocked BACE1-mediated cleavage of wild-type APP in the new mouse line, but not of the Swedish mutant APP (SweAPP) in the previously generated mouse line. From this, the authors conclude that SweAPP is not useful to study BACE inhibition in mice.
However, this is overselling the advantage of the mouse a bit, because previous studies, such as Neumann et al., 2018, revealed that BACE inhibitors can indeed block cleavage of SweAPP in mouse models. To my knowledge, this is also true for verubecestat, although it blocks SweAPP cleavage less potently than cleavage of the wild-type APP sequence.
The reason for reduced efficacy on SweAPP presumably involves protein trafficking. Compared to wild-type APP, SweAPP is so efficiently cleaved by BACE1 that the cleavage already happens in the secretory pathway and not predominantly in the endosomal compartment. Thus, the Swedish mutation does not only alter the extent of cleavage by BACE1, but also the cellular localization where the cleavage happens.
Several BACE inhibitors accumulate in endosomes, where they efficiently block BACE1 cleavage of substrates, but may obviously do this less well if the substrate (such as SweAPP) is preferentially cleaved in the secretory pathway. This may explain the preferential effect of verubecestat on wild-type versus SweAPP.
Nevertheless, the verubecestat experiment demonstrates a clear advantage of the new mouse model.
Neumann U, Ufer M, Jacobson LH, Rouzade-Dominguez ML, Huledal G, Kolly C, Lüönd RM, Machauer R, Veenstra SJ, Hurth K, Rueeger H, Tintelnot-Blomley M, Staufenbiel M, Shimshek DR, Perrot L, Frieauff W, Dubost V, Schiller H, Vogg B, Beltz K, Avrameas A, Kretz S, Pezous N, Rondeau JM, Beckmann N, Hartmann A, Vormfelde S, David OJ, Galli B, Ramos R, Graf A, Lopez Lopez C. The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer's disease. EMBO Mol Med. 2018 Nov;10(11) PubMed.
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