Presenilin 1 transgene addition to amyloid precursor protein overexpressing transgenic rats increases amyloid beta 42 levels and results in loss of memory retention

Background: We previously reported the production of transgenic rats (APP21 line) that over-express human amyloid precursor protein (APP) containing Swedish and Indiana mutations. In order to generate a better model for Alzheimer's disease (AD), the APP21 rat line was used to generate double transgenic line that over-expressed Presenilin 1 (PS1) with L166P mutation in addition to APP transgene (APP + PS1 line). Results: Thirty-two double transgenic founders were generated and the ultimate transgenic founder was selected based on PS1 transgene copy number and level of amyloid-beta (A beta)(42) peptide. The APP + PS1 double transgenic rats had 38 times more PS1 in brains compared to APP rats. Behavioral assessment using Barnes maze showed that APP + PS1 rats exhibited a larger learning and memory deficit than APP21 rats. Double transgenic rats also produced more A beta(42). Histological examination of the brains showed that the APP21 rat line displayed neurofibrillary tangles and in contrast, the APP + PS1 line showed chromatolysis in hippocampal neurons and neuronal loss in CA3 region of hippocampus. Conclusions: Due to the separate segregation of APP and PS1 transgenes in APP + PS1 double transgenic rats, this transgenic line may be a valuable model for studying the effects of various levels of APP and PS1 transgenes on various aspects of brain pathologies associated with the AD phenotype.