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.
Highlights
Traumatic brain injury (TBI) is a leading cause of death and disability in North America with an estimated annual incidence of 500 cases per 100,000 persons [1]
GW3965 treatment failed to improve novel object recognition (NOR) performance in apoE2/2 mice at any post-mild repetitive traumatic brain injury (mrTBI) time points (Figure 1B, black bars, p.0.05 compared to training, twoway ANOVA)
NOR performance was not affected by motor impairment as indicated by no significant difference between the total path length covered by sham and injured WT as well as apoE2/2 mice during NOR testing (Figure S1, p.0.05, two-way ANOVA)
Summary
Traumatic brain injury (TBI) is a leading cause of death and disability in North America with an estimated annual incidence of 500 cases per 100,000 persons [1]. Sports injuries, and falls are the most common causes of TBI in civilians [2]. The mechanical forces experienced during TBI deform brain tissue, causing a primary injury that directly affects blood vessels, axons, neurons, and glia in a focal, multifocal or diffuse pattern. This primary injury initiates a cascade of secondary processes that result in complex cellular, inflammatory, neurochemical, and metabolic alterations in the hours to weeks after injury [4]. Few options are available to manage the primary injury, the ensuing secondary injury pathways are potentially treatable [5]
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