Involvement of Oligodendrocytes in Tau Seeding and Spreading in Tauopathies.

Isidro Ferrer,Paula Garcia-Esparcia,Pol Andrés-Benito,Benjamin Torrejón-Escribano,Meritxell Aguiló García,José Antonio Del Rio,Margarita Carmona

doi:10.3389/fnagi.2019.00112

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.

Highlights

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
The main familial tauopathies are familial Alzheimer’s disease (AD), linked to mutations in the genes encoding β-amyloid precursor protein (APP); presenilin 1 (PSEN1) and presenilin 2 (PSEN2), with biochemical characteristics similar to those in sporadic AD (Bertram and Tanzi, 2011); and familial frontotemporal lobar degeneration linked to tau mutations, in which the clinical features, neuropathology, and biochemical attributes largely depend on the localization of the mutation in MAPT together with individual variations (Spillantini et al, 1997; Iseki et al, 2001; Muñoz and Ferrer, 2008; Spina et al, 2008; Ghetti et al, 2011; Tacik et al, 2016, 2017; Borrego-Écija et al, 2017)
Selected samples were from sporadic AD (Braak stage VI/C: one man and one woman aged 82 and 76 years, respectively); primary age related tauopathy (PART) (Braak stage IV: one man and one woman aged 68 and 72, respectively); pure agingrelated tau astrogliopathy (ARTAG); globular glial tauopathy (GGT); Pick’s disease (PiD) (a 67-year-old man); progressive supranuclear palsy (PSP); fFTLD-P301L; and one control

Summary

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. Tauopathies are progressive neurodegenerative diseases characterized by the accumulation of abnormal hyperphosphorylated tau deposits in neurons and glial cells These diseases are classified according to the clinical symptoms and neuropathological features, including particular regional and cellular vulnerability, together with biochemical and genetic determinants (Kovacs, 2015a,b). The main familial tauopathies are familial AD (fAD), linked to mutations in the genes encoding β-amyloid precursor protein (APP); presenilin 1 (PSEN1) and presenilin 2 (PSEN2), with biochemical characteristics similar to those in sporadic AD (sAD) (Bertram and Tanzi, 2011); and familial frontotemporal lobar degeneration linked to tau mutations (fFTLD-tau), in which the clinical features, neuropathology, and biochemical attributes largely depend on the localization of the mutation in MAPT together with individual variations (Spillantini et al, 1997; Iseki et al, 2001; Muñoz and Ferrer, 2008; Spina et al, 2008; Ghetti et al, 2011; Tacik et al, 2016, 2017; Borrego-Écija et al, 2017) The main sporadic tauopathies are Alzheimer’s disease (AD), which is a 4Rtau+3Rtau plus β-amyloidopathy characterized by the combined accumulation of abnormal tau and βamyloid in β-amyloid plaques and cerebral blood vessels in β-amyloid angiopathy (Duyckaerts and Dickson, 2011; Lowe and Kalaria, 2015); primary age related tauopathy (PART), a pure neuronal 3Rtau+4Rtau tauopathy; agingrelated tau astrogliopathy (ARTAG), a pure 4Rtau astroglial tauopathy characterized by thorn-shaped astrocytes (TSAs) and granular/fuzzy astrocytes; globular glial tauopathy (GGT), a 4Rtau neuronal and glial tauopathy with distinctive globular astroglial and oligodendroglial inclusions (GAIs and GOIs, respectively); Pick’s disease (PiD), a 3Rtau mainly neuronal tauopathy with some tau deposits in fibrillar astrocytes; progressive supranuclear palsy (PSP), a 4Rtau neuronal and glial tauopathy with characteristic tufted astrocytes (TAs) and coiled bodies; corticobasal degeneration (CBD), a 4Rtau neuronal and glial tauopathy with characteristic astrocytic plaques and coiled bodies; and argyrophilic grain disease (AGD), a 4Rtau neuronal and glial tauopathy with neuronal pre-tangles, grains in the neuropil, TSAs, and coiled bodies (Tolnay et al, 1997; Jellinger, 1998; Bigio et al, 2001; Ferrer et al, 2003, 2008, 2013; Powers et al, 2003; Piao et al, 2005; Josephs et al, 2006; Giaccone et al, 2008; Kovacs et al, 2008, 2016, 2017; Fu et al, 2010; Ahmed et al, 2011, 2013; Dickson et al, 2011; Muñoz et al, 2011; Tolnay and Braak, 2011; Crary et al, 2014; Duyckaerts et al, 2015; Jellinger et al, 2015; Ferrer, 2018a; Kovacs, 2018).

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