Investigating astrocytes as mediators of tau spread.

Abstract

Highly phosphorylated tau aggregates spread in a prion-like manner through tauopathy brain. Increasing evidence suggests that astrocytes may influence tau spread, with recent data describing mechanisms of tau uptake my astrocytes. However, the efficiency of uptake of different disease-associated tau species is not well defined, nor is the effects of tau uptake on astrocyte reactivity and function. We have investigated the relationship between tau seeds and reactive astrocytes in htau mice and in human astrocyte cultures. Tau was isolated from human postmortem control (CTRL), Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and Pick's disease (PiD) brain and injected intraperitoneally into 4-month old wild-type and htau mice. Brains and other tissues were collected for biochemical and immunohistochemical analysis of tau aggregated burden in different brain regions when mice reached 18 months of age. Human iPSC-derived astrocytes and iNPC-astrocytes were established and their gene and protein expression profiles characterised. Aggregated tau was isolated from postmortem human brain for spiking into astrocyte cultures. Cells were analysed for efficiency of tau uptake and astrocyte reactivity. Peripheral injection of brain extracts from AD, PSP and PiD brain resulted in regional differences in the patterns of tau aggregate accumulation in htau mouse brain. Tau pathology was commonly associated with reactive astrocytes. Cultures of human iPSC-derived astrocytes and iNPC-astrocytes that express mature astrocyte markers were established. Both types of cell culture were found to internalise tau extracts from human postmortem brain. Furthermore, preliminary analysis indicates alterations in astrocyte reactivity following tau uptake. Our data suggests that neurons in different regions are selectively vulnerable to tau aggregates from different tauopathies. Our human astrocyte cultures demonstrate that astrocytes can internalise tau seeds and alter their reactivity and potentially their functions. Further investigations will determine the mechanisms of tau uptake and the downstream effects on astrocyte signalling and functional changes, providing further insights into how astrocytes may affect the spread of tau and potentially contribute to selective regional vulnerability in tauopathies.