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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Nagata K,Takahashi M,Matsuba Y,Okuyama-Uchimura F,Sato K,Hashimoto S,Saito T,Saido TCdoi
10.1038/s41467-018-04238-0subject
Has Abstractpub_date
2018-05-04 00:00:00pages
1800issue
1issn
2041-1723pii
10.1038/s41467-018-04238-0journal_volume
9pub_type
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