Elucidating the combined effects of amyloid and tau in a novel bigenic rat model with human alzheimer’s disease‐like pathology

Abstract Background Both amyloid beta (Aβ) and tau pathologies co‐exist in Alzheimer’s disease. While studies have shown that Aβ and tau interaction results in elevated AD pathology, it is not clearly understood how they might affect one another during early pathology stages leading to Aβ plaque formation. This study aimed at determining how and to which extent a combination of gradually developing amyloid and tau pathologies exacerbate each other in the context of Alzheimer’s disease‐like pathology in a novel transgenic rat model. Methods Heterozygous McGill‐R‐Thy1‐APP and R955‐hTau single transgenic rats were crossed, producing a novel bigenic rat model with both human amyloid and tau pathologies, named McGill‐R‐APPxhTau955. Bigenic rats express human APP with the Swedish and Indiana mutations (KM670/671NL, V717F) as well as the longest isoform of human tau (2N4R) with the P301S mutation causative of frontotemporal dementia. Transgenic rats (n = 10‐12) were raised to cohorts at 12, 20 and 24 months of age and were subject to a battery of behavioural testing for cognition. Examination of amyloid and tau pathology, as well as inflammatory and neurodegenerative processes, was performed primarily using immunohistochemistry (IHC) and Western blot (WB). Levels of amyloid, tau and p‐tau were measured in CSF, brain and blood serum by electrochemiluminescence immunoassays. Bigenic animals were compared to single transgenics and wild‐type littermate controls. Results APPxR955‐hTau bigenic rats produced a gradual accumulation of human amyloid and tau, resulting in progressive cognitive deficits and Alzheimer‐like pathology. We discovered that tau accumulation produced a compensatory effect on cognition and long‐term potentiation at 20 months, rescuing amyloid‐induced cognitive effects. However, at 24 months of age, bigenic rats displayed worsened cognition compared to single transgenics in spatial learning and memory. Reflective of these findings, bigenic rats developed an increased phosphorylaton of tau at 24 months and increased Aβ plaque pathology. Status of biomarker levels, neuroinflammation and neurodegeneration are actively under investigation and are expected to trend similarly. Conclusions The McGill‐R‐APPxhTau novel bigenic rat, developing slow progressing amyloid and tau pathologies, is an attractive model for the further investigation of mechanisms by which both proteins effect one another, the observation of biomarker changes and elucidation of early disease stages.