ABCA1 in the CNS increases apoE lipidation and greatly decreases amyloid deposits in AD mice. Transcription of ABCA1 and apoE is induced by agonists of Liver X receptors, which regulate many genes involved in lipid metabolism and inflammation. Genetic deficiency of LXRs increases amyloid burden in AD mice. Synthetic LXR agonists including TO901317 and GW3965 cross the blood-brain barrier, induce ABCA1 and apoE expression, improve Orbifloxacin memory and reduce Ab levels in AD mice. Importantly, ABCA1 is required for several beneficial effects of GW3965 in AD mice, including increased CSF apoE levels, reduced amyloid load, and improved memory. These observations provide a compelling rationale for testing the therapeutic potential of LXR agonists for TBI. Indeed, TO901317 reduces Ab accumulation and promotes cognitive recovery in a controlled cortical impact model of moderatesevere brain injury in 
mice. Approximately 80% of human TBI are mild injuries without skull fracture and loss of consciousness. It is increasingly appreciated that repetitive mild TBI, commonly experienced by athletes in high-contact sports may lead to chronic traumatic encephalopathy, which is characterized by cognitive, executive, and motor function disturbances, tau deposition and, in some cases, amyloid deposits similar to those found in AD. We established a mouse model of mild repetitive TBI, wherein a gravity-driven weight drop device was used to deliver two consecutive injuries 24 h apart. Here we report that GW3965 improves cognitive recovery and suppresses axonal damage in an apoE-dependent manner. Surprisingly, apoE was not required for GW3965 to suppress the transient increase in Ab levels. Our results provide additional support for the therapeutic potential of LXR agonists in TBI, and demonstrate that both apoE-dependent and apoE-independent pathways contribute to their beneficial effects. The goal of this study was to evaluate the ability of GW3965 to promote recovery in a model of mrTBI specifically designed to mimic repeated concussion. We found that therapeutic administration of GW3965 improved NOR performance, suppressed Ab accumulation, and reduced axonal damage after mrTBI. Loss of apoE exacerbated the severity of motor impairment and axonal damage and eliminated the ability of GW3965 to restore NOR performance and to promote axonal recovery. These results are consistent with the role of apoE in neuronal repair and synaptic restoration. ApoE levels did not change after TBI or after GW3965 treatment, which suggests that injury severity was not sufficient to elevate apoE as well as Lomitapide Mesylate reflects the poor sensitivity of apoE as an LXR target compared to ABCA1. However, it is possible that apoE may show localized upregulation in regions with more severe damage where microglial activation is pronounced. Future studies will test whether ABCA1-mediated lipidation of apoE contributes to the beneficial effects of GW3965 after mrTBI. Surprisingly, apoE was not required for GW3965 to suppress the transient increase in Ab levels induced in our model. Further studies will be required to characterize these apoE-independent pathways that promote Ab clearance after TBI. This will be an important endeavor, as axonal APP accumulation is a hallmark of TBI. Theoretically, the Ab produced after TBI could trigger Ab-dependent toxic pathways that exacerbate damage. In support of this c-secretase inhibitors, which block Ab production, reduce cognitive and pathological changes following CCI in mice. However, the relationship between Ab levels and TBI recovery is complex.