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

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<jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>App</jats:italic>) gene in mice. We use an <jats:italic>App</jats:italic> knock-in mouse model carrying a humanized Aβ sequence and three AD mutations in the endogenous <jats:italic>App</jats:italic> gene. Genome editing of the model zygotes using multiple combinations of CRISPR/Cas9 tools produces genetically mosaic animals with various <jats:italic>App</jats:italic> 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 <jats:italic>App</jats:italic> 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.</jats:p>

Journal

  • Nature Communications

    Nature Communications 9 (1), 1800-, 2018-05-04

    Springer Science and Business Media LLC

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