Expression of the Alzheimer's Disease Mutations AbPP695sw and PSEN1M146I in Double Transgenic Gottingen Minipigs.
Mutations in the amyloid b protein precursor gene (AbPP) the presenilin 1 gene (PSEN1) or the presenilin 2 gene (PSEN2) that increase production of the AbPP derived peptide Ab42 cause early onset Alzheimer's disease. Rodent models of the disease show that further increase in Ab42 production and earlier brain pathology can be obtained by coexpressing AbPP and PSEN1 mutations. To generate such elevated Ab42 level in a large animal model, we produced Gottingen minipigs carrying in their genome one copy of a human PSEN1 cDNA with the Met146Ile (PSEN1M146I) mutation and three copies of a human AbPP695 cDNA with the Lys670Asn/Met671Leu (AbPPsw) double mutation. Both transgenes were expressed in fibroblasts and in the brain, and their respective proteins were processed normally. Immunohistochemical staining with Ab42 specific antibodies detected intraneuronal accumulation of Ab42 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.
Journal of Alzheimer's disease JAD