Author:
Cheng Chialin,Reis Surya A.,Adams Emily T.,Fass Daniel M.,Angus Steven P.,Stuhlmiller Timothy J.,Richardson Jared,Olafson Hailey,Wang Eric T.,Patnaik Debasis,Beauchamp Roberta L.,Feldman Danielle A.,Silva M. Catarina,Sur Mriganka,Johnson Gary L.,Ramesh Vijaya,Miller Bruce L.,Temple Sally,Kosik Kenneth S.,Dickerson Bradford C.,Haggarty Stephen J.
Abstract
AbstractMutations 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 identified 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 image-processing pipeline optimized for analysis of morphologically complex human neuronal cultures, we report quantitative, subcellular localization-specific effects of multiple kinase inhibitors on tau, including ones under clinical investigation not previously reported to affect 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.
Funder
NIH
Tau Consortium
Marigold Foundation
F-Prime Biomedical Research Initiative
Massachusetts Life Sciences Center Novel Therapeutics Delivery Program
Stuart & Suzanne Steele MGH Research Scholars Program
Massachusetts Center for Alzheimer’s Therapeutic Science/Massachusetts Life Sciences Center
Publisher
Springer Science and Business Media LLC
Cited by
9 articles.
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