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

Summary Frontotemporal 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.
Graphical Abstract Image 1
Highlights • Upregulation of tau and phospho-tau in FTD patient iPSC-derived tau A152T neurons • Upregulation of insoluble tau in A152T neurons • Altered proteostasis stress-inducible pathways in tau A152T neurons • Tau-dependent vulnerability to stress in A152T neurons reverted by tau downregulation
Haggarty and colleagues show in-depth phenotypic characterization of a human iPSC-derived neuronal model of tau-A152T associated with FTD. This study reveals upregulation of phospho-tau and detergent-insoluble oligomeric tau, dysregulation of proteostasis pathways, and consequent increased cell vulnerability to stress, unmasking potential disease biomarkers and therapeutic targets. This study further demonstrates that tau toxicity can be rescued by genetic and pharmacological downregulation of tau.