Dataset Information

Maturation and phenotype of pathophysiological neuronal excitability of human cells in tau-related dementia.

ABSTRACT: Frontotemporal dementia and parkinsonism (FTDP-17) caused by the 10+16 splice-site mutation in the gene encoding microtubule-associated protein tau (MAPT) provides an established platform to model tau-related dementia in vitro Neurons derived from human induced pluripotent stem cells (iPSCs) have been shown to recapitulate the neurodevelopmental profile of tau pathology during in vitro corticogenesis, as in the adult human brain. However, the neurophysiological phenotype of these cells has remained unknown, leaving unanswered questions regarding the functional relevance and the gnostic power of this disease model. In this study, we used electrophysiology to explore the membrane properties and intrinsic excitability of the generated neurons and found that human cells mature by ?150?days of neurogenesis to become compatible with matured cortical neurons. In earlier FTDP-17, however, neurons exhibited a depolarized resting membrane potential associated with increased resistance and reduced voltage-gated Na+- and K+-channel-mediated conductance. Expression of the Nav1.6 protein was reduced in FTDP-17. These effects led to reduced cell capability of induced firing and changed the action potential waveform in FTDP-17. The revealed neuropathology might thus contribute to the clinicopathological profile of the disease. This sheds new light on the significance of human in vitro models of dementia.

SUBMITTER: Kopach O

PROVIDER: S-EPMC7272359 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Maturation and phenotype of pathophysiological neuronal excitability of human cells in tau-related dementia.

Kopach Olga O Esteras Noemí N Wray Selina S Rusakov Dmitri A DA Abramov Andrey Y AY

Journal of cell science 20200527 10

Frontotemporal dementia and parkinsonism (FTDP-17) caused by the 10+16 splice-site mutation in the gene encoding microtubule-associated protein tau (MAPT) provides an established platform to model tau-related dementia in vitro Neurons derived from human induced pluripotent stem cells (iPSCs) have been shown to recapitulate the neurodevelopmental profile of tau pathology during in vitro corticogenesis, as in the adult human brain. However, the neurophysiological phenotype of ...[more]

PMID: 32299835

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Project description: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 Nav and decreased the Nav1.6 protein level. MAPT IVS10+16 neurons exhibited reduced firing accompanied by a changed action potential waveform and severely disturbed intracellular Ca2+ 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.

Project description:Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4 Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants-nonsense, frameshift, and missense-in early-onset Alzheimer's disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05-4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28-5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel Kv4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or Kv4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause neuronal hyperexcitability and behavioral alterations in Dpp6-KO mice. Taken together, the results of our genomic, genetic, expression and modeling analyses, provided direct evidence supporting the involvement of DPP6 loss in dementia. We propose that loss of function variants have a higher penetrance and disease impact, whereas the missense variants have a variable risk contribution to disease that can vary from high to low penetrance. Our findings of DPP6, as novel gene in dementia, strengthen the involvement of neuronal hyperexcitability and alteration in the homeostasis of neuronal firing as a disease mechanism to further investigate.

Dataset Information

Maturation and phenotype of pathophysiological neuronal excitability of human cells in tau-related dementia.

Publications

Maturation and phenotype of pathophysiological neuronal excitability of human cells in tau-related dementia.

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