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 Callesen; Yonglun Luo; Lars Bolund; David J Brooks; Christoffer Laustsen; Scott A Small; Lars F Mikkelsen; Charlotte B Sørensen

doi:10.1016/j.xcrm.2022.100740

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 journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

23 Citations (Scopus)

Abstract

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 language	English
Article number	100740
Journal	Cell Reports Medicine
Volume	3
Issue	9
DOIs	https://doi.org/10.1016/j.xcrm.2022.100740
Publication status	Published - Sept 2022

Keywords

Alzheimer's disease
CRISPR-Cas9
SORL1
SORLA
genome editing
large animal model
retromer-dependent endosomal recycling

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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., ... Sørensen, C. B. (2022). A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency. Cell Reports Medicine, 3(9), Article 100740. https://doi.org/10.1016/j.xcrm.2022.100740

@article{bcea839f92974f8097151c874198a115,

title = "A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency",

abstract = "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 G{\"o}ttingen 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.",

keywords = "Alzheimer's disease, CRISPR-Cas9, SORL1, SORLA, genome editing, large animal model, retromer-dependent endosomal recycling",

author = "Andersen, {Olav M} and Nikolaj B{\o}gh and Landau, {Anne M} and Pl{\o}en, {Gro G} and Jensen, {Anne Mette G} and Giulia Monti and Ulh{\o}i, {Benedicte P} and Nyengaard, {Jens R} and Jacobsen, {Kirsten R} and J{\o}rgensen, {Margarita M} and Holm, {Ida E} and Kristensen, {Marianne L} and Alstrup, {Aage Kristian O} and Hansen, {Esben S S} and Teunissen, {Charlotte E} and Laura Breidenbach and Mathias Droescher and Ying Liu and Pedersen, {Hanne S} and Henrik Callesen and Yonglun Luo and Lars Bolund and Brooks, {David J} and Christoffer Laustsen and Small, {Scott A} and Mikkelsen, {Lars F} and S{\o}rensen, {Charlotte B}",

year = "2022",

month = sep,

doi = "10.1016/j.xcrm.2022.100740",

language = "English",

volume = "3",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

number = "9",

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Andersen, OM , Bøgh, N , Landau, AM , Pløen, GG , Jensen, AMG, Monti, G, Ulhøi, BP, Nyengaard, JR, Jacobsen, KR, Jørgensen, MM, Holm, IE, Kristensen, ML, Alstrup, AKO , Hansen, ESS, Teunissen, CE, Breidenbach, L, Droescher, M, Liu, Y, Pedersen, HS, Callesen, H , Luo, Y, Bolund, L, Brooks, DJ , Laustsen, C, Small, SA, Mikkelsen, LF & Sørensen, CB 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

TY - JOUR

T1 - A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency

AU - Andersen, Olav M

AU - Bøgh, Nikolaj

AU - Landau, Anne M

AU - Pløen, Gro G

AU - Jensen, Anne Mette G

AU - Monti, Giulia

AU - Ulhøi, Benedicte P

AU - Nyengaard, Jens R

AU - Jacobsen, Kirsten R

AU - Jørgensen, Margarita M

AU - Holm, Ida E

AU - Kristensen, Marianne L

AU - Alstrup, Aage Kristian O

AU - Hansen, Esben S S

AU - Teunissen, Charlotte E

AU - Breidenbach, Laura

AU - Droescher, Mathias

AU - Liu, Ying

AU - Pedersen, Hanne S

AU - Callesen, Henrik

AU - Luo, Yonglun

AU - Bolund, Lars

AU - Brooks, David J

AU - Laustsen, Christoffer

AU - Small, Scott A

AU - Mikkelsen, Lars F

AU - Sørensen, Charlotte B

PY - 2022/9

Y1 - 2022/9

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - CRISPR-Cas9

KW - SORL1

KW - SORLA

KW - genome editing

KW - large animal model

KW - retromer-dependent endosomal recycling

U2 - 10.1016/j.xcrm.2022.100740

DO - 10.1016/j.xcrm.2022.100740

M3 - Journal article

C2 - 36099918

SN - 2666-3791

VL - 3

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 9

M1 - 100740

ER -

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

Abstract

Keywords

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