Modulation of ABCA1 by an LXR Agonist Reduces Beta-Amyloid Levels and Improves Outcome after Traumatic Brain Injury

Traumatic brain injury (TBI) increases brain beta-amyloid (A beta) in humans and animals. Although the role of A beta in the injury cascade is unknown, multiple preclinical studies have demonstrated a correlation between reduced A beta and improved outcome. Therefore, therapeutic strategies that enhance A beta clearance may be beneficial after TBI. Increased levels of ATP-binding cassette A1 (ABCA1) transporters can enhance A beta clearance through an apolipoprotein E (apoE)-mediated pathway. By measuring A beta and ABCA1 after experimental TBI in C57BL/6J mice, we found that A beta peaked early after injury (1-3 days), whereas ABCA1 had a delayed response (beginning at 3 days). As ABCA1 levels increased, A beta levels returned to baseline levels-consistent with the known role of ABCA1 in A beta clearance. To test if enhancing ABCA1 levels could block TBI-induced A beta, we treated TBI mice with the liver X-receptor (LXR) agonist T0901317. Pre- and post-injury treatment increased ABCA1 levels at 24 h post-injury, and reduced the TBI-induced increase in A beta. This reduction in A beta was not due to decreased amyloid precursor protein processing, or a shift in the solubility of A beta, indicating enhanced clearance. T0901317 also limited motor coordination deficits in injured mice and reduced brain lesion volume. These data indicate that activation of LXR can reduce A beta accumulation after TBI, and is accompanied by improved functional recovery.