{"entity": "publication", "iuid": "73f79f2fc206426caa16aafb578b1761", "timestamp": "2026-07-22T14:22:40.255Z", "links": {"self": {"href": "https://publications.scilifelab.se/publication/73f79f2fc206426caa16aafb578b1761.json"}, "display": {"href": "https://publications.scilifelab.se/publication/73f79f2fc206426caa16aafb578b1761"}}, "title": "CRISPR-Cas9 treatment partially restores amyloid-\u03b2 42/40 in human fibroblasts with the Alzheimer's disease PSEN 1 M146L mutation.", "authors": [{"family": "Konstantinidis", "given": "Evangelos", "initials": "E"}, {"family": "Molisak", "given": "Agnieszka", "initials": "A"}, {"family": "Perrin", "given": "Florian", "initials": "F"}, {"family": "Streubel-Gallasch", "given": "Linn", "initials": "L"}, {"family": "Fayad", "given": "Sarah", "initials": "S"}, {"family": "Kim", "given": "Daniel Y", "initials": "DY"}, {"family": "Petri", "given": "Karl", "initials": "K"}, {"family": "Aryee", "given": "Martin J", "initials": "MJ"}, {"family": "Aguilar", "given": "Ximena", "initials": "X"}, {"family": "Gy\u00f6rgy", "given": "Bence", "initials": "B"}, {"family": "Giedraitis", "given": "Vilmantas", "initials": "V"}, {"family": "Joung", "given": "J Keith", "initials": "JK"}, {"family": "Pattanayak", "given": "Vikram", "initials": "V"}, {"family": "Essand", "given": "Magnus", "initials": "M"}, {"family": "Erlandsson", "given": "Anna", "initials": "A"}, {"family": "Berezovska", "given": "Oksana", "initials": "O"}, {"family": "Ingelsson", "given": "Martin", "initials": "M"}], "type": "journal article", "published": "2022-06-14", "journal": {"title": "Mol Ther Nucleic Acids", "issn": "2162-2531", "volume": "28", "pages": "450-461", "issn-l": "2162-2531"}, "abstract": "Presenilin 1 (PS1) is a central component of \u03b3-secretase, an enzymatic complex involved in the generation of the amyloid-\u03b2 (A\u03b2) peptide that deposits as plaques in the Alzheimer's disease (AD) brain. The M146L mutation in the PS1 gene (PSEN1) leads to an autosomal dominant form of early-onset AD by promoting a relative increase in the generation of the more aggregation-prone A\u03b242. This change is evident not only in the brain but also in peripheral cells of mutation carriers. In this study we used the CRISPR-Cas9 system from Streptococcus pyogenes to selectively disrupt the PSEN1 allele in human fibroblasts. A disruption of more than 50% of mutant alleles was observed in all CRISPR-Cas9-treated samples, resulting in reduced extracellular A\u03b242/40 ratios. Fluorescence resonance energy transfer-based conformation and western blot analyses indicated that CRISPR-Cas9 treatment also affects the overall PS1 conformation and reduces PS1 levels. Moreover, our guide RNA did not lead to any detectable editing at the highest-ranking candidate off-target sites identified by ONE-seq and CIRCLE-seq. Overall, our data support the effectiveness of CRISPR-Cas9 in selectively targeting the M146LPSEN1 allele and counteracting the AD-associated phenotype. We believe that this system could be developed into a therapeutic strategy for patients with this and other dominant mutations leading to early-onset AD.M146L", "doi": "10.1016/j.omtn.2022.03.022", "pmid": "35505961", "labels": {"NGI Uppsala (Uppsala Genome Center)": "Service", "NGI Short read": "Service", "National Genomics Infrastructure": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC9043867"}, {"db": "pii", "key": "S2162-2531(22)00071-3"}], "notes": [], "created": "2022-11-28T10:49:45.806Z", "modified": "2022-11-28T10:49:45.810Z"}