Astrocytic tau inclusions lead to microglial abnormalities, but leave neuronal networks intact

Abstract

Astrocytic tau inclusions are commonly found in the aging brain and primary tauopathies, such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The functional consequences of these histopathological lesions, however, are unknown due to the lack of specific animal models. We have developed a mouse model of astrocytic tau pathology to study downstream effects on microglia and neuronal networks. We have designed an adeno-associated viral (AAV) vector expressing aggregation-prone human truncated tau (amino acids 151-391/4R) and red fluorophore mCherry in equal ratio under the astrocytic GFAP promotor. Injection of AAV-GFAP-htTau into the hippocampus of wild-type mice led to expression of human truncated tau in astrocytes and accumulation of soluble phosphorylated tau (p214, p231) but no detectable cognitive impairment. In vivo multiphoton imaging revealed alterations in microglial morphology in the vicinity of truncated tau positive astrocytes in the cortex. No alterations in firing patterns of excitatory cortical neurons surrounded by astrocytes overexpressing truncated tau were detected. These results suggest that early stages of astrocytic tau pathology lead to changes in microglial function, but not to functional impairment of neuronal networks.