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

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 CallesenYonglun Luo, Lars Bolund, David J. Brooks, Christoffer Laustsen, Scott A. Small, Lars F. Mikkelsen, Charlotte B. Sørensen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

14 Citations (Scopus)
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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.

Original languageEnglish
Article number100740
JournalCell reports. Medicine
Issue number9
Publication statusPublished - 20 Sept 2022

Bibliographical note

Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.


  • Alzheimer's disease
  • CRISPR-Cas9
  • SORL1
  • genome editing
  • large animal model
  • retromer-dependent endosomal recycling
  • Amyloid beta-Peptides/genetics
  • Alzheimer Disease/genetics
  • Humans
  • Swine, Miniature/metabolism
  • Haploinsufficiency/genetics
  • Membrane Transport Proteins/genetics
  • Animals
  • Swine
  • Biomarkers
  • LDL-Receptor Related Proteins/genetics


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