Spontaneous pathology in PS19 tauopathy mice progresses via brain networks.

Tauopathies are progressive neurodegenerative diseases characterized by cellular accumulation of the microtubule-associated protein tau. Evidence suggests tau is a prion, propagating pathology across brain networks via unique transmissible assemblies which mediate distinct neuropathologies in model systems. Neuroimaging has identified network alterations reflecting distinct patterns of brain atrophy in tauopathy patients. Preclinical studies confirmed transmission of pathological tau between connected brain areas, but relied on inoculation of pathogenic tau protein, leaving a gap in experimental evidence that spontaneous tau aggregates act as prions. We used anti-phospho-tau nanobodies in combination with serial two-photon tomography to immunostain and image whole brains from male and female PS19 mice, which have pan-neuronal expression of full-length human tau containing the P301S mutation. We analyzed patterns of phospho-tau deposition across established brain networks at multiple ages, testing the relationship between structural connectivity and patterns of progressive pathology. We identified core regions with early phospho-tau deposition, and used network propagation modeling to determine the link between tau pathology and connectivity strength. We found that tauopathy progression correlated with structural connectivity, consistent with the prion model. Spontaneous tau propagation was biased in the retrograde direction. These data suggest that despite widespread pathological human tau expression in PS19 mice, spontaneous phospho-tau pathology initiates and propagates along specific brain networks. This work establishes new preclinical methods for studying tau accumulation and propagation, and fills a major gap in our understanding of spontaneous tauopathy. Our novel approach establishes a fundamental role for brain networks in tau propagation, with implications for human disease. Significance statement Our novel methodology for whole brain imaging of p-tau deposition reveals retrograde-dominant network propagation in a tauopathy mouse model. This work establishes new preclinical methods for studying tau accumulation and propagation, and fills a major gap in our understanding of spontaneous tauopathy. Our results establish a fundamental role for brain networks in tau propagation, with implications for human disease.