Liver X receptor activation restores memory in aged AD mice without reducing amyloid

Alterations in cerebral cholesterol metabolism are thought to play a role in the progression of Alzheimer's disease (AD). Liver X receptors (LXRs) are key regulators of cholesterol metabolism. The synthetic LXR activator, T0901317 has been reported to improve memory functions in animal models for AD and to reduce amyloid-beta (A beta) deposition in the brain. Here we provide evidence that long-term administration of T0901317 to aged, 21-month-old APPSLxPS1mut mice restores impaired memory. Cerebral cholesterol turnover was enhanced as indicated by the increased levels of brain cholesterol precursors and the upregulation of LXR-target genes Abca1, Abcg1, and Apoe. Unexpectedly, the improved memory functions in the APPSLxPS1mut mice after T0901317 treatment were not accompanied by a decrease in A beta plaque load in the cortex or hippocampus DG, CA1 or CA3. T0901317 administration also enhanced cerebral cholesterol turnover in aged C57BL/6NCrl mice, but did not further improve their memory functions.

In conclusion, long-term activation of the LXR-pathway restored memory functions in aged APPSLxPS1mut mice with advanced A beta deposition. However the beneficial effects of T0901317 on memory in the APPSLxPS1mut mice were independent of the A beta plaque load in the hippocampus, but were associated with enhanced brain cholesterol turnover. (C) 2009 Elsevier Inc. All rights reserved.