Progressive human-like tauopathy with downstream neurodegeneration and neurovascular compromise in a transgenic rat model

Abstract

Tauopathies, including frontotemporal dementia (FTD) and Alzheimer's disease (AD), clinically present with progressive cognitive decline and the deposition of neurofibrillary tangles (NFTs) in the brain. Neurovascular compromise is also prevalent in AD and FTD however the relationship between tau and the neurovascular unit is less understood relative to other degenerative phenotypes. Current animal models confer the ability to recapitulate aspects of the CNS tauopathies, however, existing models either display overaggressive phenotypes, or do not develop neuronal loss or genuine neurofibrillary lesions. In this report, we communicate the longitudinal characterization of brain tauopathy in a novel transgenic rat model, coded McGill-R955-hTau. The model expresses the longest isoform of human P301S tau. Homozygous R955-hTau rats displayed a robust, progressive accumulation of mutated human tau leading to the detection of tau hyperphosphorylation and cognitive deficits accelerating from 14 months of age. This model features extensive tau hyperphosphorylation with endogenous tau recruitment, authentic neurofibrillary lesions, and tau-associated neuronal loss, ventricular dilation, decreased brain volume, and gliosis in aged rats. Further, we demonstrate how neurovascular integrity becomes compromised at aged life stages using a combination of electron microscopy, injection of the tracer horseradish peroxidase and immunohistochemical approaches.

Keywords: human tauopathy; neurofibrillary tangles; neurovascular compromise; transgenic rat model.