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

被引：25

作者：

Andersen, Olav M. ^{[1
]}

Bogh, Nikolaj ^{[2
]}

Landau, Anne M. ^{[2
]}

Ploen, Gro G. ^{[2
]}

Jensen, Anne Mette G. ^{[1
]}

Monti, Giulia ^{[1
]}

Ulhoi, Benedicte P. ^{[3
]}

Nyengaard, Jens R. ^{[2
,4
]}

Jacobsen, Kirsten R. ^{[5
]}

Jorgensen, Margarita M. ^{[6
]}

Holm, Ida E. ^{[7
]}

Kristensen, Marianne L. ^{[1
]}

Alstrup, Aage Kristian O. ^{[2
,8
,9
]}

Hansen, Esben S. S. ^{[2
]}

Teunissen, Charlotte E. ^{[10
]}

Breidenbach, Laura ^{[11
]}

Droescher, Mathias ^{[11
]}

Liu, Ying ^{[12
]}

Pedersen, Hanne S. ^{[12
]}

Callesen, Henrik ^{[12
]}

Luo, Yonglun ^{[1
,13
]}

Bolund, Lars ^{[1
,13
]}

Brooks, David J. ^{[2
,14
]}

Laustsen, Christoffer ^{[2
]}

Small, Scott A. ^{[1
,15
,16
]}

Mikkelsen, Lars F. ^{[5
]}

Sorensen, Charlotte B. ^{[2
]}

机构：

[1] Aarhus Univ, Dept Biomed, Aarhus, Denmark

[2] Aarhus Univ, Dept Clin Med, Aarhus, Denmark

[3] Aarhus Univ Hosp, Dept Pathol, Aarhus, Denmark

[4] Aarhus Univ, Sect Stereol & Microscopy, Core Ctr Mol Morphol, Aarhus, Denmark

[5] Ellegaard Gottingen Minipigs AS, Dalmose, Denmark

[6] Randers Reg Hosp, Dept Pathol, Randers, Denmark

[7] Aalborg Univ Hosp, Dept Pathol, Aalborg, Denmark

[8] Aarhus Univ Hosp, Dept Nucl Med, Aarhus, Denmark

[9] Aarhus Univ Hosp, PET Ctr, Aarhus, Denmark

[10] Univ Amsterdam, Dept Clin Chem, Med Ctr, Amsterdam, Netherlands

[11] AbbVie Deutschland GmbH & Co KG, Neurosci Res, Ludwigshafen, Germany

[12] Aarhus Univ, Dept Anim Sci, Tjele, Denmark

[13] BGI Shenzhen, Qingdao Europe Adv Inst Life Sci, Lars Bolund Inst Regenerat Med, Qingdao, Peoples R China

[14] Newcastle Univ, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England

[15] Columbia Univ, Dept Neurol, New York, NY USA

[16] Columbia Univ, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA

来源：

CELL REPORTS MEDICINE | 2022年 / 3卷 / 09期

关键词：

AMYLOID PRECURSOR PROTEIN; SORTILIN-RELATED RECEPTOR; RETROMER COMPLEX; BETA; DYSFUNCTION; ASSOCIATION; NEURODEGENERATION; DEPOSITION; SECRETASE; PATHOLOGY;

D O I：

10.1016/j.xcrm.2022.100740

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

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 Gottingen 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 beta-amyloid (A beta) 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.

引用

页数：27

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