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  • A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency.

A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency.

Cell reports. Medicine (2022-09-14)
Olav M Andersen, Nikolaj Bøgh, Anne M Landau, Gro G Pløen, Anne Mette G Jensen, Giulia Monti, Benedicte P Ulhøi, Jens R Nyengaard, Kirsten R Jacobsen, Margarita M Jørgensen, Ida E Holm, Marianne L Kristensen, Aage Kristian O Alstrup, Esben S S Hansen, Charlotte E Teunissen, Laura Breidenbach, Mathias Droescher, Ying Liu, Hanne S Pedersen, Henrik Callesen, Yonglun Luo, Lars Bolund, David J Brooks, Christoffer Laustsen, Scott A Small, Lars F Mikkelsen, Charlotte B Sørensen
摘要

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 individuals with early-onset AD, and SORL1 haploinsufficiency appears to be causal for 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 β-amyloid (Aβ) and tau preceding amyloid plaque formation and neurodegeneration, as observed in humans. Our study provides functional support for the theory that SORL1 haploinsufficiency leads to endosome cytopathology with biofluid hallmarks of autosomal dominant AD.

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