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

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

doi:10.1016/j.isci.2021.103658

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

iScience. 2021 Dec 18;25(1):103658. doi: 10.1016/j.isci.2021.103658. eCollection 2022 Jan 21.

Affiliations

¹ Abbvie, Cambridge Research Center, 200 Sidney Street, Cambridge, MA 02139, USA.
² AbbVie Deutschland GmbH & Co. KG, Neuroscience Research, Knollstrasse, 67061 Ludwigshafen, Germany.
³ Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.

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.

Keywords: Cellular neuroscience; Molecular neuroscience; Stem cells research.