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  • Uncovering specificity of endogenous TAU aggregation in a human iPSC-neuron TAU seeding model.

Uncovering specificity of endogenous TAU aggregation in a human iPSC-neuron TAU seeding model.

iScience (2022-01-25)
Justine D Manos, Christina N Preiss, Nandini Venkat, Joseph Tamm, Peter Reinhardt, Taekyung Kwon, Jessica Wu, Allison D Winter, Thomas R Jahn, Kiran Yanamandra, Katherine Titterton, Eric Karran, Xavier Langlois
ABSTRACT

Tau pathobiology has emerged as a key component underlying Alzheimer's disease (AD) progression; however, human neuronal in vitro models have struggled to recapitulate tau phenomena observed in vivo. Here, we aimed to define the minimal requirements to achieve endogenous tau aggregation in functional neurons utilizing human induced pluripotent stem cell (hiPSC) technology. Optimized hiPSC-derived cortical neurons seeded with AD brain-derived competent tau species or recombinant tau fibrils displayed increases in insoluble, endogenous tau aggregates. Importantly, MAPT-wild type and MAPT-mutant hiPSC-neurons exhibited unique propensities for aggregation dependent on the seed strain rather than the repeat domain identity, suggesting that successful templating of the recipient tau may be driven by the unique conformation of the seed. The in vitro model presented here represents the first successful demonstration of combining human neurons, endogenous tau expression, and AD brain-derived competent tau species, offering a more physiologically relevant platform to study tau pathobiology.

MATERIALS
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Product Description

Sigma-Aldrich
Y-27632-CAS 331752-47-7-Calbiochem, Y-27632A, CAS 331752-47-7, is a cell-permeable, reversible, inhibitor of Rho kinases (Ki = 140 nM for p160ROCK). Enhances survival & cloning efficiency of ESC without affecting their pluripotency.
Sigma-Aldrich
Mitomycin C from Streptomyces caespitosus, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Laminin from Engelbreth-Holm-Swarm murine sarcoma basement membrane, 1-2 mg/mL in Tris-buffered saline, 0.2 μm filtered, BioReagent, suitable for cell culture
Sigma-Aldrich
Anti-Tau (3-repeat isoform RD3) Antibody, clone 8E6/C11, culture supernatant, clone 8E6/C11, Upstate®
Sigma-Aldrich
Cyclopamine, V. californicum, InSolution, ≥97%, controls the biological activity of Sonic Hedgehog signaling pathway