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J Alzheimers Dis. 2016 Jul 14;53(4):1617-30. doi: 10.3233/JAD-160408.

Expression of the Alzheimer's Disease Mutations AβPP695sw and PSEN1M146I in Double-Transgenic Göttingen Minipigs.

Author information

1
Department of Biomedicine (East), Aarhus University, Aarhus C, Denmark.
2
Department of Large Animal Sciences/Reproduction, University of Copenhagen, Frederiksberg C, Denmark.
3
Department of Animal Science, Aarhus University, Tjele, Denmark.
4
Department of Pathology, Randers Hospital, Randers, Denmark.
5
Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medicine Göttingen, Georg-August-University Göttingen, Göttingen, Germany.
6
Tanz Centre for Research in Neurodegenerative Diseases, Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
7
Department of Clinical Medicine, Aarhus University, Aarhus C, Denmark.

Abstract

Mutations in the amyloid-β protein precursor gene (AβPP), the presenilin 1 gene (PSEN1) or the presenilin 2 gene (PSEN2) that increase production of the AβPP-derived peptide Aβ42 cause early-onset Alzheimer's disease. Rodent models of the disease show that further increase in Aβ42 production and earlier brain pathology can be obtained by coexpressing AβPP and PSEN1 mutations. To generate such elevated Aβ42 level in a large animal model, we produced Göttingen minipigs carrying in their genome one copy of a human PSEN1 cDNA with the Met146Ile (PSEN1M146I) mutation and three copies of a human AβPP695 cDNA with the Lys670Asn/Met671Leu (AβPPsw) double-mutation. Both transgenes were expressed in fibroblasts and in the brain, and their respective proteins were processed normally. Immunohistochemical staining with Aβ42-specific antibodies detected intraneuronal accumulation of Aβ42 in brains from a 10- and an 18-month-old pig. Such accumulation may represent an early event in the pathogenesis of Alzheimer's disease.

KEYWORDS:

Alzheimer’s disease; amyloid; porcine model; presenilin; transgenic

PMID:
27540966
DOI:
10.3233/JAD-160408
[Indexed for MEDLINE]

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