White matter degeneration precedes tau aggregation in rats with Alzheimer's-like tauopathy

Tau pathology is increasingly recognized as a primary driver of white matter (WM) microstructural damage in tauopathies, particularly in Alzheimer's disease. However, whether WM degeneration precedes detectable tau tangle deposition remains unclear. In this study, we used the McGill-R955-hTau transgenic rat model to investigate the temporal relationship between tau pathology and WM degeneration. In 12-month-old R955-hTau rats, early tau pathology was restricted to cortical neurons and characterized by phosphorylated tau accumulation and diffuse PHF1 immunoreactivity, in the absence of neurofibrillary aggregates and neuronal loss. Despite the absence of tau pathology in the WM, the corpus callosum exhibited significant atrophy, early axonal damage, and myelin fragmentation. These changes were accompanied by heightened glial activation, increased microglial phagocytic activity, and oligodendrocyte proliferation, without a net increase in total oligodendrocyte numbers. This early WM degeneration, occurring distal to tau accumulation, was associated with subtle social behavior deficits. At more advanced stages, R955-hTau rats displayed aggregated neurofibrillary tau, and the tau pathology spread into the WM. This exacerbated WM atrophy, axonal and myelin degeneration, oligodendrocyte proliferation, glial activation, and cognitive impairments. These findings reveal that initial WM pathology occurs independently of WM tau deposition and progresses alongside worsening grey matter tau pathology and its spread into the WM. These changes closely paralleled the onset and progression of cognitive decline. Overall, our results highlight WM degeneration as an early and significant consequence of grey matter tauopathy, suggesting that early therapeutic approaches targeting grey matter tauopathy should improve cognitive outcomes and help preserve both neuronal networks and WM integrity.