Connexin-43 and aquaporin-4 are markers of ageing-related tau astrogliopathy (ARTAG)-related astroglial response.

ABSTRACT

AIMS: Ageing-related tau astrogliopathy (ARTAG) appears in subependymal, subpial, perivascular, white matter (WM) and grey matter (GM) locations. Physical effects, blood-brain barrier dysfunction and blood- or vessel-related factors have been considered as aetiology. As connexin-43 (Cx43) and aquaporin-4 (AQP4) are related to these, we hypothesized that their immunoreactivity (IR) varies with ARTAG in a location-specific manner. METHODS: We performed a morphometric immunohistochemical study measuring the densities of IR of Cx43, AQP4, AT8 (phospho-tau) and glial fibrillar acidic protein (GFAP). We analysed the amygdala and hippocampus in age-matched cases with (n = 19) and without (n = 20) ARTAG in each of the locations it aggregates. RESULTS: We show a dramatic increase (>6-fold; P < 0.01) of Cx43 density of IR in ARTAG cases correlating strongly with AT8 density of IR, irrespective of the presence of neuronal tau pathology or reactive gliosis measured by GFAP density of IR, in the GM. In contrast, AQP4 density of IR was increased only in the WM and GM, and was associated with increased AT8 density of IR only in WM and perivascular areas. DISCUSSION: Our study reveals distinctive astroglial responses in each of the locations associated with ARTAG. Our observations support the concept that factors related to brain-fluid interfaces and water-ion imbalances most likely play a role in the generation of ARTAG. As Cx43 is crucial for maintaining neuronal homeostasis, the ARTAG-dependent increase of Cx43 density of IR suggests that the development of ARTAG in the GM most likely indicates an early response to the degeneration of neurons.