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An isogenic panel of single App knock-in mouse models of Alzheimer’s disease confers differential profiles of β-secretase inhibition and endosomal abnormalities

Authors :
Naoko Kamano
Takashi Saito
Gen Shiihashi
Naomi Yamazaki
Ayami Iwasaki
Mika Takahashi
Shoko Hashimoto
Ryo Fujioka
Toshio Ohshima
Kenichi Nagata
Misaki Sekiguchi
Takaomi C. Saido
Hiroki Sasaguri
Kaori Sato
Naoto Watamura
Publication Year :
2021
Publisher :
Cold Spring Harbor Laboratory, 2021.

Abstract

SUMMARYWe 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 (AppNL- G-F and AppNL-F mice). These models showed the development of amyloid β peptide (Aβ) pathology, neuroinflammation and cognitive impairment with aging. We have now generated App knock-in mice devoid of the Swedish mutations (AppG-F mice) and some additional mutants to address the following two questions: [1] Do the Swedish mutations influence the mode of β-secretase inhibitor action in vivo? [2] Does the quantity of C-terminal fragment of amyloid precursor protein (APP) generated by β-secretase (CTF-β) affect endosomal properties as previously reported as well as other pathological events? Aβ pathology was exhibited by AppG-F mice from 6 to 8 months of age, and was accompanied by microglial and astrocyte activation. We found that a β-secretase inhibitor, verubecestat, inhibited Aβ production in AppG-F mice, but not in AppNL-G-F mice, indicating that the AppG-F mice are more suitable for preclinical studies of β-secretase inhibition given that most AD patients do not carry Swedish mutations. We also found that the quantity of CTF-β generated by various App knock-in mutants failed to correlate with endosomal alterations or enlargement, implying that CTF-β, endosomal abnormalities, or both are unlikely to play a major role in AD pathogenesis. This is the first AD mouse model ever described that recapitulates amyloid pathology in the brain without the presence of Swedish mutations and without relying on the overexpression paradigm. Thus, experimental comparisons between different App knock-in mouse lines will potentially provide new insights into our understanding of the etiology of AD.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........f43e26f67c71a03140aaf1edbf7d18c0
Full Text :
https://doi.org/10.1101/2021.08.22.457278