Glial and Neuronal Tau Pathology in Tauopathies

Abstract

Tauopathies are degenerative diseases characterized by the accumulation of phosphorylated tau in neurons and glial cells. With some exceptions, tau deposits in neurons are mainly manifested as pretangles and tangles unrelated to the tauopathy. It is thought that abnormal tau deposition in neurons occurs following specific steps, but little is known about the progression of tau pathology in glial cells in tauopathies. We compared tau pathology in different astrocyte phenotypes and oligodendroglial inclusions with that in neurons in a large series of tauopathies, including progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, Pick disease, frontotemporal lobar degenerations (FTLD) associated with mutations in the tau gene, globular glial tauopathy (GGT), and tauopathy in the elderly. Our findings indicate that disease-specific astroglial phenotypes depend on i) the primary amino acid sequence of tau (mutated tau, 3Rtau, and 4Rtau); ii) phospho-specific sites of tau phosphorylation, tau conformation, tau truncation, and ubiquitination in that order (which parallel tau modifications related to pretangle and tangle stages in neurons); and iii) modifications of the astroglial cytoskeleton. In contrast to astrocytes, coiled bodies in oligodendrocytes have similar characteristics whatever the tauopathy, except glial globular inclusions in GGT, and coiled bodies and globular oligodendroglial inclusions in FTLD-tau/K317M. These observations indicate that tau pathology in glial cells largely parallels, but is not identical to, that in neurons in many tauopathies.

Astrogliopathy in Tauopathies

“…Granular/fuzzy astrocytes are seen in the elderly and ARTAG [26,70], but also in other tauopathies such as in PSP [37]. Interestingly, tau-containing astrocytes are early lesions in PSP, CBD and FTLD-tau [28,[74][75][76].…”

“…Most tau-containing astrocytes in tauopathies are not stained with the antibody tau-C3 which recognizes tau truncated at aspartic acid 421 [37]. Only small tau-C3 immunoreactive dots are occasionally seen in TSAs [71].…”

“…Only small tau-C3 immunoreactive dots are occasionally seen in TSAs [71]. Exceptions are astrocytes with globular inclusions in GGT, astrocytes in certain FTLD-tau (as in the familial tauopathy linked to MAPT K317M), and astrocytes in familial behavioral variant frontotemporal dementia associated with astrocyte-predominant tauopathy [37,87]. In such cases, tau-containing astrocytes are always ubiquitinated [37].…”

“…Granular/fuzzy astrocytes are seen in the elderly and ARTAG [26,70], but also in other tauopathies such as in PSP [37].…”

“…Various types of astrocytic inclusions are generated in familial FTLD-tau linked to mutations in exons 1 and 10 and in introns following exons 9 and 10, the morphology of which largely depends on the MAPT mutation. Intracytoplasmic tau-immunoreactive inclusions in FTLD-tau are represented by tufted-like astrocytes, astrocytic plaques, ramified astrocytes, TSAs, astrocytes with globular inclusions and other types with no specific names [17,33,34,36,37,66,[77][78][79][80][81][82][83][84][85][86]. Tufted astrocytes and astrocytic plaques practically do not co-exist in PSP and CBD [57], but these lesions appear in combination in FTLD-tau [29] (Figure 4).…”