Hypothermic Preconditioning Reverses Tau Ontogenesis in Human Cortical Neurons and is Mimicked by Protein Phosphatase 2A Inhibition

Nina Marie Rzechorzek, Peter Connick, Matthew Livesey, Shyamanga Borooah, Rickie Patani, Karen Burr, David Story, David Wyllie, Giles Hardingham, Siddharthan Chandran

Research output: Contribution to journalArticlepeer-review

Abstract

Hypothermia is potently neuroprotective, but the molecular basis of this effect remains obscure. Changes in neuronal tau protein are of interest, since tau becomes hyperphosphorylated in injury-resistant, hypothermic brains. Noting inter-species differences in tau isoforms, we have used functional cortical neurons differentiated from human pluripotent stem cells (hCNs) to interrogate tau modulation during hypothermic preconditioning at clinically-relevant temperatures. Key tau developmental transitions (phosphorylation status and splicing shift) are recapitulated during hCN differentiation and subsequently reversed by mild (32 °C) to moderate (28 °C) cooling — conditions which reduce oxidative and excitotoxic stress-mediated injury in hCNs. Blocking a major tau kinase decreases hCN tau phosphorylation and abrogates hypothermic neuroprotection, whilst inhibition of protein phosphatase 2A mimics cooling-induced tau hyperphosphorylation and protects normothermic hCNs from oxidative stress. These findings indicate a possible role for phospho-tau in hypothermic preconditioning, and suggest that cooling drives human tau towards an earlier ontogenic phenotype whilst increasing neuronal resilience to common neurotoxic insults. This work provides a critical step forward in understanding how we might exploit the neuroprotective benefits of cooling without cooling patients.
Original languageEnglish
Pages (from-to)141-154
JournalEBioMedicine
Volume3
Early online date12 Dec 2015
DOIs
Publication statusPublished - 1 Jan 2016

Keywords

  • Hypothermia, Preconditioning, Neuroprotection, Tau protein, Protein phosphatase 2A (PP2A), Hyperphosphorylation, Human cortical neuron

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