title: Sodium selenate reduces hyperphosphorylated tau and improves outcomes after traumatic brain injury.
abstract: Traumatic brain injury is a common and serious neurodegenerative condition that lacks a pharmaceutical intervention to improve long-term outcome. Hyperphosphorylated tau is implicated in some of the consequences of traumatic brain injury and is a potential pharmacological target. Protein phosphatase 2A is a heterotrimeric protein that regulates key signalling pathways, and protein phosphatase 2A heterotrimers consisting of the PR55 B-subunit represent the major tau phosphatase in the brain. Here we investigated whether traumatic brain injury in rats and humans would induce changes in protein phosphatase 2A and phosphorylated tau, and whether treatment with sodium selenate-a potent PR55 activator-would reduce phosphorylated tau and improve traumatic brain injury outcomes in rats. Ninety young adult male Long-Evans rats were administered either a fluid percussion injury or sham-injury. A proportion of rats were killed at 2, 24, and 72 h post-injury to assess acute changes in protein phosphatase 2A and tau. Other rats were given either sodium selenate or saline-vehicle treatment that was continuously administered via subcutaneous osmotic pump for 12 weeks. Serial magnetic resonance imaging was acquired prior to, and at 1, 4, and 12 weeks post-injury to assess evolving structural brain damage and axonal injury. Behavioural impairments were assessed at 12 weeks post-injury. The results showed that traumatic brain injury in rats acutely reduced PR55 expression and protein phosphatase 2A activity, and increased the expression of phosphorylated tau and the ratio of phosphorylated tau to total tau. Similar findings were seen in post-mortem brain samples from acute human traumatic brain injury patients, although many did not reach statistical significance. Continuous sodium selenate treatment for 12 weeks after sham or fluid percussion injury in rats increased protein phosphatase 2A activity and PR55 expression, and reduced the ratio of phosphorylated tau to total tau, attenuated brain damage, and improved behavioural outcomes in rats given a fluid percussion injury. Notably, total tau levels were decreased in rats 12 weeks after fluid percussion injury, and several other factors, including the use of anaesthetic, the length of recovery time, and that some brain injury and behavioural dysfunction still occurred in rats treated with sodium selenate must be considered in the interpretation of this study. However, taken together these data suggest protein phosphatase 2A and hyperphosphorylated tau may be involved in the neurodegenerative cascade of traumatic brain injury, and support the potential use of sodium selenate as a novel traumatic brain injury therapy.
authors.affiliation: 1 Melbourne Brain Centre, Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia sshultz@unimelb.edu.au.
authors.forename: Sandy R
authors.initials: SR
authors.lastname: Shultz
authors.affiliation: 2 Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, 3010, Australia.
authors.forename: David K
authors.initials: DK
authors.lastname: Wright
authors.affiliation: 1 Melbourne Brain Centre, Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia.
authors.forename: Ping
authors.initials: P
authors.lastname: Zheng
authors.affiliation: 3 Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia.
authors.forename: Ryan
authors.initials: R
authors.lastname: Stuchbery
authors.affiliation: 1 Melbourne Brain Centre, Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia.
authors.forename: Shi-Jie
authors.initials: SJ
authors.lastname: Liu
authors.affiliation: 4 Australian Centre for Blood Disease, Monash University, Melbourne, Victoria, 3004, Australia.
authors.forename: Maithili
authors.initials: M
authors.lastname: Sashindranath
authors.affiliation: 4 Australian Centre for Blood Disease, Monash University, Melbourne, Victoria, 3004, Australia.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Medcalf
authors.affiliation: 5 Department of Electrical and Electronic Engineering, The University of Melbourne, Parkville, VIC, 3010, Australia.
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Johnston
authors.affiliation: 3 Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hovens
authors.affiliation: 1 Melbourne Brain Centre, Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia.
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Jones
authors.affiliation: 1 Melbourne Brain Centre, Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, 3050, Australia.
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D020318:Rats, Long-Evans; D064586:Selenic Acid / Q000494:pharmacology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; C489131:Mapt protein, rat; D016875:tau Proteins; D064586:Selenic Acid
keywords: DTI; MRI; protein phosphatase 2A; tau; traumatic brain injury