CRISPR-Cas9 treatment partially restores amyloid-β 42/40 in human fibroblasts with the Alzheimer's disease PSEN1 M146L mutation

Presenilin 1 (PS1) is a central component of γ-secretase, an enzymatic complex involved in the generation of the amyloid-β (Aβ) 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 A...

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Hoofdauteurs: Evangelos Konstantinidis (Auteur), Agnieszka Molisak (Auteur), Florian Perrin (Auteur), Linn Streubel-Gallasch (Auteur), Sarah Fayad (Auteur), Daniel Y. Kim (Auteur), Karl Petri (Auteur), Martin J. Aryee (Auteur), Ximena Aguilar (Auteur), Bence György (Auteur), Vilmantas Giedraitis (Auteur), J. Keith Joung (Auteur), Vikram Pattanayak (Auteur), Magnus Essand (Auteur), Anna Erlandsson (Auteur), Oksana Berezovska (Auteur), Martin Ingelsson (Auteur)
Formaat: Boek
Gepubliceerd in: Elsevier, 2022-06-01T00:00:00Z.
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Samenvatting:Presenilin 1 (PS1) is a central component of γ-secretase, an enzymatic complex involved in the generation of the amyloid-β (Aβ) 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 Aβ42. 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 PSEN1M146L 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 Aβ42/40 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 PSEN1M146L 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.
Beschrijving item:2162-2531
10.1016/j.omtn.2022.03.022