Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability

Abstract

SummaryFrontotemporal dementia (FTD) and other tauopathies characterized by focal brain neurodegeneration and pathological accumulation of proteins are commonly associated with tau mutations. However, the mechanism of neuronal loss is not fully understood. To identify molecular events associated with tauopathy, we studied induced pluripotent stem cell (iPSC)-derived neurons from individuals carrying the tau-A152T variant. We highlight the potential of in-depth phenotyping of human neuronal cell models for pre-clinical studies and identification of modulators of endogenous tau toxicity. Through a panel of biochemical and cellular assays, A152T neurons showed accumulation, redistribution, and decreased solubility of tau. Upregulation of tau was coupled to enhanced stress-inducible markers and cell vulnerability to proteotoxic, excitotoxic, and mitochondrial stressors, which was rescued upon CRISPR/Cas9-mediated targeting of tau or by pharmacological activation of autophagy. Our findings unmask tau-mediated perturbations of specific pathways associated with neuronal vulnerability, revealing potential early disease biomarkers and therapeutic targets for FTD and other tauopathies.

Modeling tau pathology in human stem cell derived neurons

“…The best-characterised function of tau is its role as a microtubule-associated protein, prompting several groups to examine whether intracellular trafficking and axonal transport could be disrupted in iPSC-neurons with MAPT mutations. Dysregulated calcium signaling and an upregulation in markers of cell stress (including mitochondrial stress, altered endosome/lysosome composition, increased markers of stress granules) confirm the ability of tau mutations to induce neuronal dysfunction in vitro (19,46,53). Mitochondrial dysfunction and reduced ATP production was observed in neurons with the 10 1 16 mutation, which could be related to disrupted mitochondrial transport (10).…”

“…Mitochondrial dysfunction and reduced ATP production was observed in neurons with the 10 1 16 mutation, which could be related to disrupted mitochondrial transport (10). Dysregulated calcium signaling and an upregulation in markers of cell stress (including mitochondrial stress, altered endosome/lysosome composition, increased markers of stress granules) confirm the ability of tau mutations to induce neuronal dysfunction in vitro (19,46,53). Interestingly, neuronal connectivity may be disrupted by tau mutations: both splice-site and coding mutations in MAPT lead to an accelerated acquisition of electrical maturity in vitro (20).…”

MAPT Genetic Variation and Neuronal Maturity Alter Isoform Expression Affecting Axonal Transport in iPSC-Derived Dopamine Neurons

“…Similar expression patterns are noted in iPSC-derived cortical neuronal cultures. A detailed examination of tau proteins by mass spectrometry provided confirmation of the predominance of 0N3R tau peptides and the lack of peptides corresponding to exons 2 and 3 in 5-week iPSC-derived cortical neurons (Silva et al., 2016). Wray and colleagues (Sposito et al., 2015) noted that their iPSC-derived cortical cultures go through the developmental switch from fetal to adult tau after 365 days.…”

Integrative Research of Induction of Pluripotent Stem Cells

“…However, the mechanism of neuronal loss is not clear. In order to identify molecular events linked with tau protein disease, Silva et al [18] investigated neurons from iPSCs derived from tau-A152T variants. They stressed the importance of identifying preclinical studies of potential in-depth phenotypic human neuronal cell models and endogenous tau toxicity regulators.…”