title: Hypothermic Preconditioning Reverses Tau Ontogenesis in Human Cortical Neurons and is Mimicked by Protein Phosphatase 2A Inhibition.
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.
authors: Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Midlothian EH16 4SB, United Kingdom; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, Midlothian EH16 4UU, United Kingdom; Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, Midlothian EH16 4SB, United Kingdom. Electronic address: nina.rzechorzek@ed.ac.uk.
authors: Nina M
authors: NM
authors: Rzechorzek
authors: The Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, Midlothian EH16 4SB, United Kingdom.
authors: Peter
authors: P
authors: Connick
authors: Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, Midlothian EH16 4SB, United Kingdom; Centre for Integrative Physiology, University of Edinburgh, Edinburgh, Midlothian EH8 9XD, United Kingdom.
authors: Matthew R
authors: MR
authors: Livesey
authors: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, Midlothian EH16 4UU, United Kingdom; Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, Midlothian EH16 4SB, United Kingdom; The Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, Midlothian EH16 4SB, United Kingdom.
authors: Shyamanga
authors: S
authors: Borooah
authors: The Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, Midlothian EH16 4SB, United Kingdom; Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors: Rickie
authors: R
authors: Patani
authors: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, Midlothian EH16 4UU, United Kingdom; Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, Midlothian EH16 4SB, United Kingdom.
authors: Karen
authors: K
authors: Burr
authors: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, Midlothian EH16 4UU, United Kingdom; Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, Midlothian EH16 4SB, United Kingdom.
authors: David
authors: D
authors: Story
authors: Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, Midlothian EH16 4SB, United Kingdom; Centre for Integrative Physiology, University of Edinburgh, Edinburgh, Midlothian EH8 9XD, United Kingdom.
authors: David J A
authors: DJA
authors: Wyllie
authors: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, Midlothian EH8 9XD, United Kingdom.
authors: Giles E
authors: GE
authors: Hardingham
authors: Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Midlothian EH16 4SB, United Kingdom; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, Midlothian EH16 4UU, United Kingdom; Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, Midlothian EH16 4SB, United Kingdom; The Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, Midlothian EH16 4SB, United Kingdom. Electronic address: siddharthan.chandran@ed.ac.uk.
authors: Siddharthan
authors: S
authors: Chandran
mesh_terms: D002540:Cerebral Cortex / Q000166:cytology* / Q000378:metabolism*; D015870:Gene Expression; D018698:Glutamic Acid / Q000633:toxicity; D006801:Humans; D007035:Hypothermia; D007036:Hypothermia, Induced; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013696:Temperature; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D016875:tau Proteins; D018698:Glutamic Acid; D054648:Protein Phosphatase 2
keywords: Human cortical neuron; Hyperphosphorylation; Hypothermia; Neuroprotection; Preconditioning; Protein phosphatase 2A (PP2A); Tau protein