Journal article
The Liver X Receptor Agonist GW3965 Improves Recovery from Mild Repetitive Traumatic Brain Injury in Mice Partly through Apolipoprotein E
PLoS One, Vol.8(1), e53529
2013
Abstract
Traumatic brain injury (TBI) increases Alzheimer's disease (AD) risk and leads to the deposition of neurofibrillary tangles and amyloid deposits similar to those found in AD. Agonists of Liver X receptors (LXRs), which regulate the expression of many genes involved in lipid homeostasis and inflammation, improve cognition and reduce neuropathology in AD mice. One pathway by which LXR agonists exert their beneficial effects is through ATP-binding cassette transporter A1 (ABCA1)-mediated lipid transport onto apolipoprotein E (apoE). To test the therapeutic utility of this pathway for TBI, we subjected male wild-type (WT) and apoE-/- mice to mild repetitive traumatic brain injury (mrTBI) followed by treatment with vehicle or the LXR agonist GW3965 at 15 mg/kg/day. GW3965 treatment restored impaired novel object recognition memory in WT but not apoE-/- mice. GW3965 did not significantly enhance the spontaneous recovery of motor deficits observed in all groups. Total soluble Aβ40 and Aβ42 levels were significantly elevated in WT and apoE-/- mice after injury, a response that was suppressed by GW3965 in both genotypes. WT mice showed mild but significant axonal damage at 2 d post-mrTBI, which was suppressed by GW3965. In contrast, apoE-/- mice showed severe axonal damage from 2 to 14 d after mrTBI that was unresponsive to GW3965. Because our mrTBI model does not produce significant inflammation, the beneficial effects of GW3965 we observed are unlikely to be related to reduced inflammation. Rather, our results suggest that both apoE-dependent and apoE-independent pathways contribute to the ability of GW3965 to promote recovery from mrTBI. © 2013 Namjoshi et al.
Details
- Title
- The Liver X Receptor Agonist GW3965 Improves Recovery from Mild Repetitive Traumatic Brain Injury in Mice Partly through Apolipoprotein E
- Authors
- D R Namjoshi (Author) - University of British Columbia, CanadaG Martin (Author) - University of British Columbia, CanadaJames J Donkin (Author) - University of British Columbia, CanadaA Wilkinson (Author) - University of British Columbia, CanadaS Stukas (Author) - University of British Columbia, CanadaJ Fan (Author) - University of British Columbia, CanadaM Carr (Author) - University of British Columbia, CanadaS Tabarestani (Author) - University of British Columbia, CanadaK Wuerth (Author) - University of British Columbia, CanadaR E W Hancock (Author) - University of British Columbia, CanadaC L Wellington (Author) - University of British Columbia, Canada
- Publication details
- PLoS One, Vol.8(1), e53529
- Publisher
- Public Library of Science
- Date published
- 2013
- DOI
- 10.1371/journal.pone.0053529
- ISSN
- 1932-6203
- Copyright note
- Copyright © 2013 Namjoshi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
- Organisation Unit
- UniSC Clinical Trials Centre; University of the Sunshine Coast, Queensland
- Language
- English
- Record Identifier
- 99450686702621
- Output Type
- Journal article
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