2 research outputs found
High-content image-based analysis and proteomic profiling identifies Tau phosphorylation inhibitors in a human iPSC-derived glutamatergic neuronal model of tauopathy
Mutations in MAPT (microtubule-associated protein tau) cause frontotemporal dementia (FTD). MAPT
mutations are associated with abnormal tau phosphorylation levels and accumulation of misfolded
tau protein that can propagate between neurons ultimately leading to cell death (tauopathy).
Recently, a p.A152T tau variant was identifed as a risk factor for FTD, Alzheimer’s disease, and
synucleinopathies. Here we used induced pluripotent stem cells (iPSC) from a patient carrying this
p.A152T variant to create a robust, functional cellular assay system for probing pathophysiological
tau accumulation and phosphorylation. Using stably transduced iPSC-derived neural progenitor cells
engineered to enable inducible expression of the pro-neural transcription factor Neurogenin 2 (Ngn2),
we generated disease-relevant, cortical-like glutamatergic neurons in a scalable, high-throughput
screening compatible format. Utilizing automated confocal microscopy, and an advanced imageprocessing pipeline optimized for analysis of morphologically complex human neuronal cultures,
we report quantitative, subcellular localization-specifc efects of multiple kinase inhibitors on tau,
including ones under clinical investigation not previously reported to afect tau phosphorylation.
These results demonstrate the potential for using patient iPSC-derived ex vivo models of tauopathy as
genetically accurate, disease-relevant systems to probe tau biochemistry and support the discovery of
novel therapeutics for tauopathies