. 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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Comments

  1. 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.

  2. 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.

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