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

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 Commun

journal_title

Nature communications

authors

Nagata K,Takahashi M,Matsuba Y,Okuyama-Uchimura F,Sato K,Hashimoto S,Saito T,Saido TC

doi

10.1038/s41467-018-04238-0

subject

Has Abstract

pub_date

2018-05-04 00:00:00

pages

1800

issue

1

issn

2041-1723

pii

10.1038/s41467-018-04238-0

journal_volume

9

pub_type

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