Expression of the Alzheimer’s Disease Mutations AβPP695sw and PSEN1M146I in Double-Transgenic Göttingen Minipigs
- 8 August 2016
- journal article
- Published by IOS Press in Journal of Alzheimer's Disease
- Vol. 53 (4), 1617-1630
- https://doi.org/10.3233/jad-160408
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
This publication has 50 references indexed in Scilit:
- N-truncated amyloid β (Aβ) 4-42 forms stable aggregates and induces acute and long-lasting behavioral deficitsActa Neuropathologica, 2013
- Generation of minipigs with targeted transgene insertion by recombinase-mediated cassette exchange (RMCE) and somatic cell nuclear transfer (SCNT)Transgenic Research, 2012
- Presenilins and -Secretase: Structure, Function, and Role in Alzheimer DiseaseCold Spring Harbor Perspectives in Medicine, 2011
- The Δ F508 Mutation Causes CFTR Misprocessing and Cystic Fibrosis–Like Disease in PigsScience Translational Medicine, 2011
- Pregnancies and piglets from large white sow recipients after two transfer methods of cloned and transgenic embryos of different pig breedsTheriogenology, 2010
- Cystic Fibrosis Pigs Develop Lung Disease and Exhibit Defective Bacterial Eradication at BirthScience Translational Medicine, 2010
- Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s diseaseActa Neuropathologica, 2010
- Pyroglutamate Abeta pathology in APP/PS1KI mice, sporadic and familial Alzheimer’s disease casesJournal of Neural Transmission, 2009
- Disruption of the CFTR Gene Produces a Model of Cystic Fibrosis in Newborn PigsScience, 2008
- Intraneuronal Aβ immunoreactivity is not a predictor of brain amyloidosis-β or neurofibrillary degenerationActa Neuropathologica, 2007