Elevated 4R-tau in astrocytes from asymptomatic carriers of the MAPT 10+16 intronic mutation.
journal contributionposted on 2022-02-17, 12:29 authored by Núria Setó-Salvia, Noemi Esteras, Rohan de Silva, Eduardo de Pablo-Fernandez, Charles Arber, Christina E Toomey, James M Polke, Huw R Morris, Jonathan D Rohrer, Andrey Y Abramov, Rickie Patani, Selina Wray, Thomas T Warner
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.