The Liver X Receptor Agonist GW3965 Improves Recovery from Mild Repetitive Traumatic Brain Injury in Mice Partly through Apolipoprotein E

Dhananjay R. Namjoshi, Georgina Martin, James Donkin, Anna Wilkinson, Sophie Stukas, Jianjia Fan, Michael Carr, Sepideh Tabarestani, Kelli Wuerth, Robert Hancock, Cheryl L. Wellington

Research output: Contribution to journalArticle

36 Citations (Scopus)

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.

LanguageEnglish
Article numbere53529
JournalPloS one
Volume8
Issue number1
DOIs
Publication statusPublished - 17 Jan 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Namjoshi, D. R., Martin, G., Donkin, J., Wilkinson, A., Stukas, S., Fan, J., ... Wellington, C. L. (2013). The Liver X Receptor Agonist GW3965 Improves Recovery from Mild Repetitive Traumatic Brain Injury in Mice Partly through Apolipoprotein E. PloS one, 8(1), [e53529]. https://doi.org/10.1371/journal.pone.0053529
Namjoshi, Dhananjay R. ; Martin, Georgina ; Donkin, James ; Wilkinson, Anna ; Stukas, Sophie ; Fan, Jianjia ; Carr, Michael ; Tabarestani, Sepideh ; Wuerth, Kelli ; Hancock, Robert ; Wellington, Cheryl L. / The Liver X Receptor Agonist GW3965 Improves Recovery from Mild Repetitive Traumatic Brain Injury in Mice Partly through Apolipoprotein E. In: PloS one. 2013 ; Vol. 8, No. 1.
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Namjoshi, DR, Martin, G, Donkin, J, Wilkinson, A, Stukas, S, Fan, J, Carr, M, Tabarestani, S, Wuerth, K, Hancock, R & Wellington, CL 2013, 'The Liver X Receptor Agonist GW3965 Improves Recovery from Mild Repetitive Traumatic Brain Injury in Mice Partly through Apolipoprotein E', PloS one, vol. 8, no. 1, e53529. https://doi.org/10.1371/journal.pone.0053529

The Liver X Receptor Agonist GW3965 Improves Recovery from Mild Repetitive Traumatic Brain Injury in Mice Partly through Apolipoprotein E. / Namjoshi, Dhananjay R.; Martin, Georgina; Donkin, James; Wilkinson, Anna; Stukas, Sophie; Fan, Jianjia; Carr, Michael; Tabarestani, Sepideh; Wuerth, Kelli; Hancock, Robert; Wellington, Cheryl L.

In: PloS one, Vol. 8, No. 1, e53529, 17.01.2013.

Research output: Contribution to journalArticle

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T1 - The Liver X Receptor Agonist GW3965 Improves Recovery from Mild Repetitive Traumatic Brain Injury in Mice Partly through Apolipoprotein E

AU - Namjoshi, Dhananjay R.

AU - Martin, Georgina

AU - Donkin, James

AU - Wilkinson, Anna

AU - Stukas, Sophie

AU - Fan, Jianjia

AU - Carr, Michael

AU - Tabarestani, Sepideh

AU - Wuerth, Kelli

AU - Hancock, Robert

AU - Wellington, Cheryl L.

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N2 - 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.

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