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The aggregation of abnormally phosphorylated tau protein in neurons and glia is a neuropathological hallmark of several neurodegenerative disorders, collectively known as tauopathies. They are further subclassified based on the preferential pathological aggregation of three carboxyl-terminal repeat domains (3R) and/or 4R tau. Corticobasal degeneration (CBD) is a rare neurodegenerative disorder classified as a 4R tauopathy. In the present study, we extend analysis of CBD-tau cell-type specific pathology transmission with 3R and 4R tau isoform distinguishable changes. We use a humanized tau (hTau) mouse line, which overexpress all six human tau isoforms in a murine tau knockout background and perform intrastriatal inoculation of control and CBD-tau enriched human brain homogenate. We show that CBD-tau causes hyperphosphorylation of tau at Ser202 predominantly in oligodendrocytes. Next, we demonstrate the spread of tau pathology from striatum to the overlaying corpus callosum and further to the contralateral side. Finally, we demonstrate that the almost exclusive oligodendrocyte-based transmission of hyperphosphorylated tau is reflected in the endogenous 4R tau isoform expression and corresponds to subclassification of CBD as a 4R tauopathy. Additionally, we identify functional changes in oligodendrocytes reflected by myelin basic protein abnormalities upon CBD-tau inoculation. These changes are not observed in murine tau knockout mice lacking both human and murine tau. Our study presents not only  in vivo  tau isoform–driven region- and cell-specific tau pathology, but also underlines that tau pathology seeding and transmission might be oligodendrocyte-based. These results, which need to be extended to more cases, give new insights into why tauopathies might vary greatly in both histopathological and neuroanatomical patterns.

Tau Isoform-Driven CBD Pathology Transmission in Oligodendrocytes in Humanized Tau Mice