Astrocytic 4R tau expression drives astrocyte reactivity and dysfunction.

Lubov A Ezerskiy,Kanta Horie,Randall J Bateman,Mariana Beltcheva,Ryan Martynowicz,Chihiro Sato,Timothy M Miller,Celeste M Karch,Kathleen M Schoch,Frank Rigo

doi:10.1172/jci.insight.152012

Abstract

The protein tau and its isoforms are associated with several neurodegenerative diseases, many of which are characterized by greater deposition of the 4-repeat (4R) tau isoform; however, the role of 4R tau in disease pathogenesis remains unclear. We created antisense oligonucleotides (ASOs) that alter the ratio of 3R to 4R tau to investigate the role of specific tau isoforms in disease. Preferential expression of 4R tau in human tau–expressing (hTau-expressing) mice was previously shown to increase seizure severity and phosphorylated tau deposition without neuronal or synaptic loss. In this study, we observed strong colocalization of 4R tau within reactive astrocytes and increased expression of pan-reactive and neurotoxic genes following 3R to 4R tau splicing ASO treatment in hTau mice. Increasing 4R tau levels in primary astrocytes provoked a similar response, including a neurotoxic genetic profile and diminished homeostatic function, which was replicated in human induced pluripotent stem cell–derived (iPSC-derived) astrocytes harboring a mutation that exhibits greater 4R tau. Healthy neurons cultured with 4R tau–expressing human iPSC–derived astrocytes exhibited a higher firing frequency and hypersynchrony, which could be prevented by lowering tau expression. These findings support a potentially novel pathway by which astrocytic 4R tau mediates reactivity and dysfunction and suggest that astrocyte-targeted therapeutics against 4R tau may mitigate neurodegenerative disease progression.

Highlights

Tauopathies are a class of neurodegenerative diseases characterized by the pathogenic aggregation of hyperphosphorylated tau protein in neurofibrillary tangles [1]
Reactive astrocytes express 4R tau in vivo. human tau (hTau) mice, which express all isoforms of hTau in a mouse tau– knockout background, were treated with antisense oligonucleotides (ASOs) that bias toward the inclusion of tau exon 10 (3R to 4R splicing ASO) or exclusion of exon 10 (4R to 3R splicing ASO)
Tissue from hTau mice treated with the 3R to 4R tau splicing ASO exhibited a change in 4R tau localization coincident with astrocyte morphology (Figure 1, G–I) not seen in the hTau mice treated with the control ASO or the 4R to 3R tau splicing ASO

Summary

Introduction

Tauopathies are a class of neurodegenerative diseases characterized by the pathogenic aggregation of hyperphosphorylated tau protein in neurofibrillary tangles [1]. In a mouse model expressing all 6 isoforms of human tau (hTau), including both 3R and 4R tau [16], an antisense oligonucleotide (ASO) strategy to increase 4R tau alone induced tau phosphorylation and aggregation and increased seizure severity [17]. These results further confirmed that 4R tau toxicity might be involved in tau pathology and disease. This discrepancy prompted us to consider non-neuronal cells as a potential contributor to 4R tau toxicity, focusing first on astrocytes because of the well-described pathological changes within astrocytes in human disease [18,19,20,21,22]

Methods

Results

Conclusion