Embryonic Stem Cell–Based Modeling of Tau Pathology in Human Neurons

• DOI: 10.1016/j.ajpath.2013.01.043
• Publication Date: 2013-03-13T03:34:19Z
• Authors: Jerome Mertens; Kathrin Stüber; Daniel Poppe; Jonas Doerr; Julia Ladewig; Oliver Brüstle; Philipp Koch
• Keywords: Neurons; 0301 basic medicine; Cell Death; Cell Differentiation; tau Proteins; Microtubules; Models, Biological; Axons; Pathology and Forensic Medicine; Mitochondria; 3. Good health; Mice; Oxidative Stress; Protein Transport; 03 medical and health sciences; Tauopathies; Nerve Degeneration; Animals; Humans; Phosphorylation; Oxidation-Reduction; Protein Processing, Post-Translational; Embryonic Stem Cells

Alterations in the microtubule (MT)-associated protein, tau, have emerged as a pivotal phenomenon several neurodegenerative disorders, including frontotemporal dementia and Alzheimer's disease. Although compelling lines of evidence from various experimental models suggest that hyperphosphorylation conformational changes tau can cause its aggregation into filaments, actual species effective mechanisms conspire to trigger degeneration human neurons remain obscure. Herein, we explored whether embryonic stem cell-derived neural cells be exploited study consequences an overexpression 2N4R (two normal N-terminal four MT-binding domains; n-tau) versus pseudohyperphosphorylated (p-tau) directly neurons. Given involvement MT integrity cellular homeostasis, focused on effects both variants subcellular transport neuronal survival. By using inducible lentiviral overexpression, show p-tau, but not n-tau, readily leads MC-1-positive protein conformation impaired mitochondrial transport. these alterations do induce cell death under standard culture conditions, p-tau-expressing cultured non-redox-protected conditions undergo with formation axonal varicosities sequestering transported proteins progressive death. Our data support causative link between phosphorylation state microtubuli-based transport, vulnerability oxidative stress. They further depict useful model for studying tau-associated authentic system.