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Genetically engineered MAPT 10+16 mutation causes pathophysiological excitability of human iPSC-derived neurons related to 4R tau-induced dementia

Kopach, Olga, Esteras, Noemí, Wray, Selina, Abramov, Andrey Y., Rusakov, Dmitri A.·2021·Cell Death & Disease
DOI 10.1038/s41419-021-04007-wPMC PMC8286258
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Abstract

Human iPSC lines represent a powerful translational model of tauopathies. We have recently described a pathophysiological phenotype of neuronal excitability of human cells derived from the patients with familial frontotemporal dementia and parkinsonism (FTDP-17) caused by the MAPT 10+16 splice-site mutation. This mutation leads to the increased splicing of 4R tau isoforms. However, the role of different isoforms of tau protein in initiating neuronal dementia-related dysfunction, and the causality between the MAPT 10+16 mutation and altered neuronal activity have remained unclear. Here, we employed genetically engineered cells, in which the IVS10+16 mutation was introduced into healthy donor iPSCs to increase the expression of 4R tau isoform in exon 10, aiming to explore key physiological traits of iPSC-derived MAPT IVS10+16 neurons using patch-clamp electrophysiology and multiphoton fluorescent imaging techniques. We found that during late in vitro neurogenesis (from ~180 to 230 days) iPSC-derived cortical neurons of the control group (parental wild-type tau) exhibited membrane properties compatible with “mature” neurons. In contrast,MAPT IVS10+16 neurons displayed impaired excitability, as reflected by a depolarized resting membrane potential, an increased input resistance, and reduced voltage-gated Na+- and K+-channel-mediated currents. The mutation changed the channel properties of fast-inactivating Na v and decreased the Na v 1.6 protein level.MAPT IVS10+16 neurons exhibited reduced firing accompanied by a changed action potential waveform and severely disturbed intracellular Ca 2+dynamics, both in the soma and dendrites, upon neuronal depolarization. These results unveil a causal link between the MAPT 10+16 mutation, hence overproduction of 4R tau, and a dysfunction of human cells, identifying a biophysical basis of changed neuronal activity in 4R tau-triggered dementia. Our study lends further support to using iPSC lines as a suitable platform for modelling tau-induced human neuropathology in vitro.

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Metadata

Authors
Kopach, O., Esteras, N., Wray, S., Abramov, A. Y., & Rusakov, D. A.
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2021-07-17
Volume
12
Issue
8
ISSN
2041-4889
DOI
10.1038/s41419-021-04007-w
PMC
PMC8286258
Cited by
26
References
6
Language
en
Licence
Funders
  • Alzheimer’s Research UK (ARUKSRF2016B-2)
  • NIHR UCLH/UCL Biomedical Research Centre
  • RCUK | Engineering and Physical Sciences Research Council (EP/R024898/1)
  • Wellcome Trust (212251_Z_18_Z)
  • European Commission (NEUROTWIN grant 857562)

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