Expression of the Alzheimer's Disease Mutations A beta PP695sw and PSEN1M146I in Double-Transgenic Gottingen Minipigs

Mutations in the amyloid-beta protein precursor gene (A beta PP), the presenilin 1 gene (PSEN1) or the presenilin 2 gene (PSEN2) that increase production of the A beta PP-derived peptide A beta(42) cause early-onset Alzheimer's disease. Rodent models of the disease show that further increase in A beta(42) production and earlier brain pathology can be obtained by coexpressing A beta PP and PSEN1 mutations. To generate such elevated A beta(42) 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 A beta PP695 cDNA with the Lys670Asn/Met671Leu (A beta PPsw) double-mutation. Both transgenes were expressed in fibroblasts and in the brain, and their respective proteins were processed normally. Immunohistochemical staining with A beta(42)-specific antibodies detected intraneuronal accumulation of A beta(42) 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.