Generation of App knock-in mice reveals deletion mutations protective against Alzheimer’s disease-like pathology

Kenichi Nagata (), Mika Takahashi, Yukio Matsuba, Fumi Okuyama-Uchimura, Kaori Sato, Shoko Hashimoto, Takashi Saito and Takaomi C. Saido ()
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Kenichi Nagata: RIKEN Center for Brain Science
Mika Takahashi: RIKEN Center for Brain Science
Yukio Matsuba: RIKEN Center for Brain Science
Fumi Okuyama-Uchimura: RIKEN Center for Brain Science
Kaori Sato: RIKEN Center for Brain Science
Shoko Hashimoto: RIKEN Center for Brain Science
Takashi Saito: RIKEN Center for Brain Science
Takaomi C. Saido: RIKEN Center for Brain Science

Nature Communications, 2018, vol. 9, issue 1, 1-7

Abstract: Abstract Although, a number of pathogenic mutations have been found for Alzheimer’s disease (AD), only one protective mutation has been identified so far in humans. Here we identify possible protective deletion mutations in the 3′-UTR of the amyloid precursor protein (App) gene in mice. We use an App knock-in mouse model carrying a humanized Aβ sequence and three AD mutations in the endogenous App gene. Genome editing of the model zygotes using multiple combinations of CRISPR/Cas9 tools produces genetically mosaic animals with various App 3′-UTR deletions. Depending on the editing efficiency, the 3′-UTR disruption mitigates the Aβ pathology development through transcriptional and translational regulation of APP expression. Notably, an App knock-in mouse with a 34-bp deletion in a 52-bp regulatory element adjacent to the stop codon shows a substantial reduction in Aβ pathology. Further functional characterization of the identified element should provide deeper understanding of the pathogenic mechanisms of AD.

Date: 2018
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DOI: 10.1038/s41467-018-04238-0

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