A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency
| Autor: | 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 |
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| Přispěvatelé: | Clinical chemistry, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Neuroinfection & -inflammation |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Alzheimer Disease/genetics
Haploinsufficiency/genetics Amyloid beta-Peptides Swine SORLA Membrane Transport Proteins large animal model Haploinsufficiency Alzheimer's disease General Biochemistry Genetics and Molecular Biology Swine Miniature/metabolism Alzheimer Disease retromer-dependent endosomal recycling SORL1 Amyloid beta-Peptides/genetics Swine Miniature genome editing Humans Animals Membrane Transport Proteins/genetics LDL-Receptor Related Proteins/genetics CRISPR-Cas9 LDL-Receptor Related Proteins Biomarkers |
| Zdroj: | Andersen, O M, Bøgh, N, Landau, A M, Pløen, G G, Jensen, A M G, Monti, G, Ulhøi, B P, Nyengaard, J R, Jacobsen, K R, Jørgensen, M M, Holm, I E, Kristensen, M L, Alstrup, A K O, Hansen, E S S, Teunissen, C E, Breidenbach, L, Droescher, M, Liu, Y, Pedersen, H S, Callesen, H, Luo, Y, Bolund, L, Brooks, D J, Laustsen, C, Small, S A, Mikkelsen, L F & Sørensen, C B 2022, ' A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency ', Cell reports. Medicine, vol. 3, no. 9, 100740 . https://doi.org/10.1016/j.xcrm.2022.100740 Andersen, O M, Bøgh, N, Landau, A M, Pløen, G G, Jensen, A M G, Monti, G, Ulhøi, B P, Nyengaard, J R, Jacobsen, K R, Jørgensen, M M, Holm, I E, Kristensen, M L, Alstrup, A K O, Hansen, E S S, Teunissen, C E, Breidenbach, L, Droescher, M, Liu, Y, Pedersen, H S, Callesen, H, Luo, Y, Bolund, L, Brooks, D J, Laustsen, C, Small, S A, Mikkelsen, L F & Sørensen, C B 2022, ' A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency ', Cell Reports Medicine, vol. 3, no. 9, 100740 . https://doi.org/10.1016/j.xcrm.2022.100740 Cell Reports Medicine, 3(9):100740. Cell Press |
| ISSN: | 2666-3791 |
| DOI: | 10.1016/j.xcrm.2022.100740 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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