Characterization of an APP/tau rat model of Alzheimer's disease by positron emission tomography and immunofluorescent labeling.

Background: To better understand the etiology and pathomechanisms of Alzheimer's disease, several transgenic animal models that overexpress human tau or human amyloid-beta (Aβ) have been developed. In the present study, we generated a novel transgenic rat model by cross-breeding amyloid precursor protein (APP) rats with tau rats. We characterized this model by performing positron emission tomography scans combined with immunofluorescent labeling and cerebrospinal fluid analyses.

Methods: APP/Tau rats were generated by cross-breeding male McGill-R-Thy1-APP transgenic rats with female hTau-40/P301L transgenic rats. APP/Tau double transgenic rats and non-transgenic (ntg) littermates aged 7, 13, and 21 months were subjected to dynamic [C] PiB scan and dynamic [F]THK-5317 scans. For regional brain analysis, a template was generated from anatomical MR images of selected animals, which was co-registered with the PET images. Regional analysis was performed by application of the simplified reference tissue model ([C]PiB data), whereas [F]THK-5317 data were analyzed using a 2-tissue compartment model and Logan graphical analysis. In addition, immunofluorescent labeling (tau, amyloid) and cerebrospinal fluid analyses were performed.

Results: [C]PiB binding potential (BP) and [F]THK-5317 volume of distribution (V) showed an increase with age in several brain regions in the APP/Tau group but not in the ntg control group. Immunohistochemical analysis of brain slices of PET-scanned animals revealed a positive correlation between Aβ labeling and [C]PiB regional BP. Tau staining yielded a trend towards higher levels in the cortex and hippocampus of APP/Tau rats compared with ntg littermates, but without reaching statistical significance. No correlation was found between tau immunofluorescence labeling results and the respective [F]THK-5317 V values.

Conclusions: We thoroughly characterized a novel APP/Tau rat model using combined PET imaging and immunofluorescence analysis. We observed an age-related increase in [C]PiB and [F]THK-5317 binding in several brain regions in the APP/Tau group but not in the ntg group. Although we were able to reveal a positive correlation between amyloid labeling and [C]PiB regional brain uptake, we observed relatively low human tau and amyloid fibril expression levels and a somewhat unstable brain pathology which questions the utility of this animal model for further studies.