Abstract
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.
Highlights
Corticobasal degeneration (CBD) is a rare neurodegenerative disorder with 0.6–0.9 cases per 100,000 individuals per year [1, 2], and in a more recent study of a Russian population, it was estimated at 0.02 cases per 100,000 individuals per year [3]
The observed greater total tau load in the CBD case was due to tau pathology, not difference in total protein load
We performed immunohistochemistry analysis of frontal cortices from the control and CBD cases using CP13 antibody (Supplementary Figures 1D,F) specific for tau phosphorylated at Ser202, commonly used to detect tau pathology in both early and more advanced stages of neurofibrillary tangle accumulation [22,23,24]
Summary
Corticobasal degeneration (CBD) is a rare neurodegenerative disorder with 0.6–0.9 cases per 100,000 individuals per year [1, 2], and in a more recent study of a Russian population, it was estimated at 0.02 cases per 100,000 individuals per year [3]. The. CBD-Tau Pathology Transmission in Oligodendrocytes neuropathological hallmark of CBD is astrocytic plaque formation and accumulation of abnormally phosphorylated tau in neurons and glia (oligodendroglia and astrocytes) predominantly in forebrain structures [4]. The CBD tau pathology is mainly astrocytic and neuronal, the oligodendroglia tau aggregates are present in a form of numerous and widespread cytoplasmic process inclusions (argyrophilic threads) [5] and oligodendroglia cell body inclusions (coiled bodies) [6]. Astrogliopathy predominates in the earliest stage of CBD pathology, the oligodendroglia involvement in the early preclinical stages is reported [7]. In connection to the oligodendroglia pathology, the white matter volume loss in subcortical structure is observed in CBD [8, 9]. CBD is a predominantly sporadic disorder, familial cases with tau protein mutation (N296N) have been reported [10]
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