CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30604771.
- Also identified by DOI 10.1038/s41467-018-07971-8 and PMC identifier 6318289.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
CRISPR/Cas9 guided gene-editing is a potential therapeutic tool, however application to neurodegenerative disease models has been limited. Moreover, conventional mutation correction by gene-editing would only be relevant for the small fraction of neurodegenerative cases that are inherited. Here we introduce a CRISPR/Cas9-based strategy in cell and animal models to edit endogenous amyloid precursor protein (APP) at the extreme C-terminus and reciprocally manipulate the amyloid pathway, attenuating APP-β-cleavage and Aβ production, while up-regulating neuroprotective APP-α-cleavage. APP N-terminus and compensatory APP-homologues remain intact, with no apparent effects on neurophysiology in vitro. Robust APP-editing is seen in human iPSC-derived neurons and mouse brains with no detectable off-target effects. Our strategy likely works by limiting APP and BACE-1 approximation, and we also delineate mechanistic events that abrogates APP/BACE-1 convergence in this setting. Our work offers conceptual proof for a selective APP silencing strategy.
Medical subject headings
- Amyloid Precursor Protein Secretases
- Amyloid beta-Peptides
- Amyloid beta-Protein Precursor
- Gene Editing
- Genetic Therapy
- Neurodegenerative Diseases