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CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage
- Source :
- Nature Communications, Nature Communications, Vol 10, Iss 1, Pp 1-11 (2019)
- Publication Year :
- 2018
-
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.<br />Gene editing strategies are typically designed to correct mutant genes, but most neurodegenerative diseases are sporadic. Here the authors describe a strategy to selectively edit the C-terminus of APP and attenuate amyloid-β production, while upregulating neuroprotective α-cleavage.
- Subjects :
- 0301 basic medicine
Male
General Physics and Astronomy
02 engineering and technology
Stereotaxic Techniques
Amyloid beta-Protein Precursor
Mice
Amyloid precursor protein
CRISPR
lcsh:Science
Gene Editing
Neurons
Multidisciplinary
biology
Chemistry
Brain
Neurodegenerative Diseases
Dependovirus
021001 nanoscience & nanotechnology
Cell biology
Treatment Outcome
Female
0210 nano-technology
Science
Transgene
Genetic Vectors
Induced Pluripotent Stem Cells
Mice, Transgenic
Transfection
Neuroprotection
General Biochemistry, Genetics and Molecular Biology
Article
03 medical and health sciences
mental disorders
Gene silencing
Animals
Humans
Injections, Intraventricular
Amyloid beta-Peptides
Cas9
HEK 293 cells
General Chemistry
Genetic Therapy
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
HEK293 Cells
Stereotaxic technique
biology.protein
lcsh:Q
Amyloid Precursor Protein Secretases
CRISPR-Cas Systems
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 10
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature communications
- Accession number :
- edsair.doi.dedup.....e3ace6c9faac8fabf1f60cd30767e0f4