Involvement of Oligodendrocytes in Tau Seeding and Spreading in Tauopathies

Abstract

Introduction: Human tau seeding and spreading occur following intracerebral inoculation into different gray matter regions of brain homogenates obtained from tauopathies in transgenic mice expressing wild or mutant tau, and in wild-type (WT) mice. However, little is known about tau propagation following inoculation in the white matter. Objectives: The present study is geared to learning about the patterns of tau seeding and cells involved following unilateral inoculation in the corpus callosum of homogenates from sporadic Alzheimer's disease (AD), primary age-related tauopathy (PART: neuronal 4Rtau and 3Rtau), pure aging-related tau astrogliopathy (ARTAG: astroglial 4Rtau with thorn-shaped astrocytes TSAs), globular glial tauopathy (GGT: 4Rtau with neuronal tau and specific tau inclusions in astrocytes and oligodendrocytes, GAIs and GOIs, respectively), progressive supranuclear palsy (PSP: 4Rtau with neuronal inclusions, tufted astrocytes and coiled bodies), Pick's disease (PiD: 3Rtau with characteristic Pick bodies in neurons and tau containing fibrillar astrocytes), and frontotemporal lobar degeneration linked to P301L mutation (FTLD-P301L: 4Rtau familial tauopathy). Methods: Adult WT mice were inoculated unilaterally in the lateral corpus callosum with sarkosyl-insoluble fractions or with sarkosyl-soluble fractions from the mentioned tauopathies; mice were killed from 4 to 7 months after inoculation. Brains were fixed in paraformaldehyde, embedded in paraffin and processed for immunohistochemistry. Results: Tau seeding occurred in the ipsilateral corpus callosum and was also detected in the contralateral corpus callosum. Phospho-tau deposits were found in oligodendrocytes similar to coiled bodies and in threads. Moreover, tau deposits co-localized with active (phosphorylated) tau kinases p38 and ERK 1/2, suggesting active tau phosphorylation of murine tau. TSAs, GAIs, GOIs, tufted astrocytes, and tau-containing fibrillar astrocytes were not seen in any case. Tau deposits were often associated with slight myelin disruption and the presence of small PLP1-immunoreactive globules and dots in the ipsilateral corpus callosum 6 months after inoculation of sarkosyl-insoluble fractions from every tauopathy. Conclusions: Seeding and spreading of human tau in the corpus callosum of WT mice occurs in oligodendrocytes, thereby supporting the idea of a role of oligodendrogliopathy in tau seeding and spreading in the white matter in tauopathies. Slight differences in the predominance of threads or oligodendroglial deposits suggest disease differences in the capacity of tau seeding and spreading among tauopathies.

Capacity for Seeding and Spreading of Argyrophilic Grain Disease in a Wild-Type Murine Model; Comparisons With Primary Age-Related Tauopathy

“…Our previous studies have shown tau seeding and spreading following inoculation of sarkosyl-insoluble fractions from AD, primary age-related tauopathy (PART), aging-related tau astrogliopathy (ARTAG), progressive supranuclear palsy (PSP), Pick’s disease (PiD), frontotemporal lobar degeneration linked to MAPT P301L mutation, and sporadic and familial globular glial tauopathy (GGT) into the hippocampus and corpus callosum of WT mice ( Ferrer et al, 2018 , 2019 , 2020a , b ). The present study is focused on the capacity for and characteristics of seeding and propagation of phospho-tau from homogenates of “pure” (not associated with AD or other tauopathies) AGD cases in the hippocampus of WT mice.…”

Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy

“…However, no GAIs or GOIs, but only coiled bodies, are regularly seen in WT mice inoculated with sarkosyl-insoluble fractions of GGT linked to MAPT P301T mutation, sGGT, and GGT linked to MAPT K317M mutation in our study. The exception of a few bizarre oligodendroglial inclusions following inoculation of homogenates from MAPT K317M samples does not detract from the general concept that coiled bodies are the characteristic oligodendroglial phospho-tau inclusions in WT mice inoculated with homogenates from GGT and other tauopathies [36,37,41]. This suggests that host tau is crucial to recapitulate typical inclusions in human diseases.…”

“…Moreover, although GAIs and GOIs are typical of GGT, nothing is known about the functional alterations linked to the pathology of astrocytes and oligodendrocytes. Recent studies have shown the seeding capacity of GGT homogenates in vivo and in vitro [13,36,41]. However, little attention has been paid to the characteristics of tau deposits linked to the host tau.…”

“…Our previous studies have shown a rather homogeneous pattern of tau seeding and spreading following inoculation of sarkosyl-insoluble fractions into the hippocampus or into the corpus callosum of WT mice, independently of the tauopathy. Nerve fibres and coiled bodies were the only tau deposits in the corpus callosum following inoculation of homogenates from AD, primary age-related tauopathy (PART), ARTAG, GGT, PSP, Pick's disease (PiD), and frontotemporal lobar degeneration linked to MAPT P301L mutation (FTLD-P301L) [36]. Neurons and oligodendrocytes were the main targets following inoculation of sarkosyl-insoluble fractions of AD, PART, and ARTAG into the hippocampus of WT mice [37,41].…”

Degradation and Transmission of Tau by Autophagic-Endolysosomal Networks and Potential Therapeutic Targets for Tauopathy

“…A recent study injected brain homogenates from subjects with sporadic AD, primary age-related tauopathy (PART), pure aging-related tau astrogliopathy (ARTAG), globular glial tauopathy (GGT), PSP, PiD, and frontotemporal lobar degeneration linked to P301L mutation (FTLD-P301L) into the ipsilateral corpus callosum of adult wildtype mice induced tau seeding of murine tau in the contralateral corpus callosum ( Ferrer et al, 2019 ). Phospho-tau deposits were found mainly in oligodendrocytes.…”