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Lookup NU author(s): Professor David BrooksORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
The established causal genes in Alzheimer’s disease (AD), APP, PSEN1, and PSEN2, are functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease’s initial preclinical phase. Mutations in SORL1, encoding the endosome recycling receptor SORLA, are found in 2-3% of all early-onset AD cases, and SORL1 haploinsufficiency appears causal of AD. To test whether SORL1 can function as an AD causal gene, we use CRISPR-Cas9-based gene editing to develop a model of SORL1 haploinsufficiency in Göttingen Minipigs taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young adult minipigs is found to phenocopy the preclinical in vivo profile of AD observed with APP, PSEN1, and PSEN2 resulting in elevated levels of A and tau preceding amyloid plaque formation and neurodegeneration as observed in humans. Our study provides functional support that SORL1 haploinsufficiency leads to endosome cytopathology with biofluid hallmarks of autosomal dominant AD.
Author(s): Andersen OM, Bøgh N, Landau AM, Pløen GG, Jensen AMG, Monti G, Ulhøi BP, Nyengaard JR, Jacobsen K, Jørgensen M, Holm I, Kristensen ML, Hansen ESS, Teunessen C, Breidenbach L, Droescher M, Liu Y, Pedersen HS, Alstrup AKO, Callesen H, Luo Y, Bolund L, Brooks DJ, Laustsen C, Small S, Mikkelsen LF, Sørensen CB
Publication type: Article
Publication status: Published
Journal: Cell Reports Medicine
Year: 2022
Volume: 3
Print publication date: 20/09/2022
Online publication date: 12/09/2022
Acceptance date: 19/08/2022
Date deposited: 20/08/2022
ISSN (electronic): 2666-3791
Publisher: Cell Press
URL: https://doi.org/10.1016/j.xcrm.2022.100740
DOI: 10.1016/j.xcrm.2022.100740
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