Differential rates of internalisation and effects on reactivity of postmortem human tau in human astrocytes

Abstract

BackgroundHighly phosphorylated tau aggregates emerge in affected areas of human tauopathy brain as disease progresses as a result of prion‐like spread and/or replication of seeds. Evidence suggests that astrocytes may influence tau spread. However, the efficiency of uptake of disease‐associated tau species is not well defined, nor are the effects of tau uptake on astrocyte reactivity and function. We are investigating tau uptake in human astrocytes, and how resulting changes in their reactivity and functions affect their support for human neurons in vitro.MethodHuman iPSC‐derived astrocytes were established, and their gene and protein expression profiles characterised. Aggregated tau was isolated from human postmortem Alzheimer’s disease (AD) brain. AD brain tau and corresponding extracts from control (CTRL) human brain were spiked into iPSC‐astrocyte cultures and the efficiency of tau uptake was measured, in parallel with assessment of reactivity markers. Mechanisms of tau uptake and its intracellular processing were investigated. Astrocyte conditioned media was collected and applied to iPSC derived cortical neurons to determine the impact of tau‐induced astrocyte changes on measures of neuron health.ResultiPSC‐derived astrocytes express mature astrocyte markers. Aggregated tau from AD brain was readily internalised by these cells. Morphological, gene expression and protein expression changes were detected, suggesting that exposure to AD‐brain tau is sufficient to induce reactive response in these astrocytes. Variations in the rate and extent of uptake, and in markers of reactivity, were observed that reflect heterogeneity between different AD cases. Preliminary data indicates that cells may degrade internalised tau aggregates via lysosomal pathways and that tau‐induced astrocyte reactivity negatively impacts neuron health.ConclusionOur data shows that human astrocytes readily internalise AD brain‐derived tau aggregates, inducing changes in astrocyte reactivity and function, related to characteristics of the tau, that are detrimental to neurons. This supports an emerging body of evidence that astrocytic tau may influence neurodegeneration in AD.