Janice Malcolm, Canada
McGill University Cell Anatomy and Cell BiologyAuthor Of 1 Presentation
ALTERATIONS TO MYELIN, VASCULATURE AND NEURONAL LOSS ASSOCIATED WITH MODEST ACCUMULATION OF HUMAN P301S TAU IN A NOVEL TRANSGENIC RAT MODEL FOR HUMAN TAUOPATHY.
Abstract
Aims
This study aimed to determine whether a gradual and relatively modest accumulation of mutated human tau in the forebrain of a novel transgenic rat model was sufficient to trigger early-stage pathological processes leading to end-stage tau pathology.
Methods
R955-hTau transgenic rats expressing the longest isoform of human tau (2N4R) with the P301S mutation for frontotemporal dementia were used. Transgenic rats were bred and raised to 10, 18-20 and 24-26 months of age and were subject to behavioral testing of cognition. At these time points, examination of tau pathology in the brain was also performed using immunohistochemistry, immunofluorescence and electron microscopy.
Results
R955-hTau rats developed an age-associated accumulation of human tau in the brain resulting in tau hyperphosphorylation and tau pathology at 24-26 months of age. Cognitive deficits in learning and memory were present at late life stages, coinciding with neurodegeneration. Coincidentally with advanced tau pathology we also observed microglial and astrocytic activation as well as myelin abnormalities and vascular alterations.
Conclusions
R955-hTau, a novel transgenic rat model with a gradual pathological accumulation of human P301S tau, represents an attractive model for the identification of novel indicators of early tau pathology. Since extensive neurodegeneration, neuroinflammation, and vascular and myelin alterations are present only at late life stages, this model presents a more sensitive time frame to identify early tau-mediated pathological changes in the brain. As such it should be a suitable model for examining mechanisms involved in tauopathy as well factors exacerbating tau pathology in a species with a greater degree of translation to humans.