Neuronal loss and inflammation preceding fibrillary tau pathology in a rat model with early human-like tauopathy

In tauopathies such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), the microtubule associated protein tau undergoes conformational and posttranslational modifications in a gradual, staged pathological process. While brain atrophy and cognitive decline are well-established in the advanced stages of tauopathy, it is unclear how the early pathological processes manifest prior to extensive neurodegeneration. For these studies we have applied a transgenic rat model of human-like tauopathy in its heterozygous form, named McGill-R955-hTau. The goal of the present study was to investigate whether lifelong accumulation of mutated human tau could reveal the earliest tau pathological processes in a context of advanced aging, and, at stages before the overt aggregated or fibrillary tau deposition. We characterized the phenotype of heterozygous R955-hTau rats at three endpoints, 10, 18 and 24–26 months of age, focusing on markers of cognitive capabilities, progressive tau pathology, neuronal health, neuroinflammation and brain ultrastructural integrity, using immunohistochemistry and electron microscopy. Heterozygous R955-hTau transgenic rats feature a modest, life-long accumulation of mutated human tau that led to tau hyperphosphorylation and produced deficits in learning and memory tasks after 24 months of age. Such impairments coincided with more extensive tau hyperphosphorylation in the brain at residues pThr231 and with evidence of oligomerization. Importantly, aged R955-hTau rats presented evidence of neuroinflammation, detriments to myelin morphology and detectable hippocampal neuronal loss in the absence of overt neurofibrillary lesions and brain atrophy. The slow-progressing tauopathy of R955-hTau rats should allow to better delineate the temporal progression of tau pathological events and therefore to distinguish early indicators of tauopathy as having the capability to induce degenerative events in the aged CNS. •The heterozygous R955-hTau rat was developed to investigate the earliest aspects of tauopathy in aged animals•Progressive accumulation of human tau led to neuronal somatodendritic tau mislocaliation and hyperphosphorylation•In the absence of tangles, early tauopathy leads to cognitive impairment, inflammation, myelin degeneration and neuronal loss•Early tauopathy was associated with ptau at Thr231-immunoreactivity and development of oligomeric species.