Aging-Related Tau Astrogliopathy in Aging and Neurodegeneration

Abstract

Astrocytes are of vital importance to neuronal function and the health of the central nervous system (CNS), and astrocytic dysfunction as a primary or secondary event may predispose to neurodegeneration. Until recently, the main astrocytic tauopathies were the frontotemporal lobar degeneration with tau (FTLD-tau) group of disorders; however, aging-related tau astrogliopathy (ARTAG) has now been defined. This condition is a self-describing neuropathology mainly found in individuals over 60 years of age. Astrocytic tau accumulates with a thorny or granular/fuzzy morphology and is commonly found in normal aging as well as coexisting with diverse neurodegenerative disorders. However, there are still many unknown factors associated with ARTAG, including the cause/s, the progression, and the nature of any clinical associations. In addition to FTLD-tau, ARTAG has recently been associated with chronic traumatic encephalopathy (CTE), where it has been proposed as a potential precursor to these conditions, with the different ARTAG morphological subtypes perhaps having separate etiologies. This is an emerging area of exciting research that encompasses complex neurobiological and clinicopathological investigation.

Keywords: aging; aging-related tau astrogliopathy; astrocytes; neurodegeneration; tau propagation; tauopathy.

Figure 1

Astrocytic morphologies of frontotemporal lobar degeneration with tau (FTLD-tau) and aging-related tau astrogliopathy (ARTAG), immunostained with AT8-tau antibody. Dense tau fibrils in a tufted astrocyte in progressive supranuclear palsy (PSP, A); annular punctate tau in an astrocytic plaque in corticobasal degeneration (CBD, B); a globular astroglial inclusion in globular glial tauopathy (GGT, C); short, thick tau processes in a ramified astrocyte in Pick’s disease (PiD, D); ramified and bushy tau process in a granular/fuzzy astrocyte (E) and short dense tau deposits in thorny astroctyes (arrowhead) (F). Granular/fuzzy (E) and thorny (F) astrocytes are pathogno-monic of argyrophilic grain disease (AGD) and ARTAG. (A–E) images at 200× magnification and (F) at 400× magnification.

Figure 2

Thorn-shaped astrocytes in subpial (arrowheads) and perivascular sulcal depth (asterisk) arrangements in chronic traumatic encephalopathy (CTE), 50× magnification (A); subpial thorn-shaped astrocytes (arrowheads) adjacent to the substantia nigra region of the midbrain, 100× magnification (B). Immunostaining with AT8-tau antibody.

Figure 3

Schematic of two astrocytic tau propagation hypotheses. Small tau fibrils or “seeds” (red dots) may be formed in the cytoplasm of neurons or astrocytes after release from endosomal vesicles. Dissemination may occur from neuron-to-neuron by mechanisms such as trans-synaptic transmission, free uptake or vesicular or nanotube transfer to neighboring cells, while neuron-to-astrocyte and astrocyte-to-astrocyte transmission is not clear and may occur via trans-synaptic transmission, vesicular uptake or free transfer. Hypothesis 1 relies on neuronal release of tau, which is taken up by nearby astrocytes. Hypothesis 2 sees astrocytes upregulate tau and kinase expression leading to tau hyperphosphorylation and spread to other cells, however there is currently little evidence to support this.

Figure 4

A simplified schematic for aging-related tau astrogliopathy (ARTAG) staging systems based on Kovacs et al. Acta Neuropathol Commun. 2018. Staging is classified according to ARTAG location- subpial, white matter, subependymal thorn-shaped astrocytes (TSAs) and grey matter granular/fuzzy astrocytes (GFAs) in non-frontotemporal lobar degeneration tauopathies (FTLD-tau). No distinct pattern has been identified for subependymal ARTAG. Multiple patterns of spread have been proposed for all classifications (top panel). Basal regions = basal forebrain and amygdala; lobar regions = frontal, parietal, temporal and occipital lobes.