Elevated 4R-tau in astrocytes from asymptomatic carriers of the MAPT 10+16 intronic mutation.

Núria Setó‐Salvia,Andrey Y Abramov,Charles Arber,Christina E Toomey,Rickie Patani,Eduardo Pablo‐Fernandez,Jonathan D Rohrer,Rohan Silva,Noemi Esteras,Selina Wray,James M Polke,Huw R Morris,Thomas T Warner

doi:10.1111/jcmm.17136

Abstract

The microtubule‐associated protein tau gene (MAPT) 10+16 intronic mutation causes frontotemporal lobar degeneration (FTLD) by increasing expression of four‐repeat (4R)‐tau isoforms. We investigated the potential role for astrocytes in the pathogenesis of FTLD by studying the expression of 4R‐tau. We derived astrocytes and neurons from induced pluripotent stem cells from two asymptomatic 10+16 carriers which, compared to controls, showed persistently increased 4R:3R‐tau transcript and protein ratios in both cell types. However, beyond 300 days culture, 10+16 neurons showed less marked increase of this 4R:3R‐tau transcript ratio compared to astrocytes. Interestingly, throughout maturation, both 10+16 carriers consistently displayed different 4R:3R‐tau transcript and protein ratios. These elevated levels of 4R‐tau in astrocytes implicate glial cells in the pathogenic process and also suggests a cell‐type‐specific regulation and may inform and help on treatment of pre‐clinical tauopathies.

Highlights

Glial cells, including astrocytes, play an important role in 4R tauopathy pathogenesis,[2,3] focussing on these cells in pre-symptomatic cases could lead to identification of biomarkers for pre-clinical detection of tauopathies
We have shown that astrocytes derived from Induced pluripotent stem cells (iPSC) from two carriers of the 10+16 mutation have increased 4R-tau, which is known to lead to tauopathy
We demonstrated microtubule-associated protein tau gene (MAPT) expression in both 10+16 and control astrocyte cultures, with detectable and increasing 4R-tau mRNA during maturation in 10+16 cell lines

Summary

Introduction

Increased incorporation of MAPT exon 10 results in excess levels of the more fibrillogenic 4R-tau isoforms in astrocytes and neurons.[1] the underlying processes contributing to neurodegeneration are unclear. Induced pluripotent stem cells (iPSC) can be used to develop cell models to study underlying disease mechanisms and identify decisive factors in other frontotemporal dementia cases.[4] In this study, we assessed long-term expression of 4R-tau mRNA and protein in iPSC-derived astrocytes and neurons from asymptomatic carriers of the 10+16 MAPT mutation and affected post- mortem brain. IPSC from two unrelated, asymptomatic female carriers with the 10+16 mutation (S1 and S2) and three healthy control cell lines were used as described previously.[5] The iPSC were differentiated into neurons and astrocytes adapting previously established protocols6-8 and assessed at the same time-points during maturation.

Results

Conclusion