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

T. Vanmierlo, K. Rutten, J. Dederen, V.W. Bloks, L.C. Vark-van der Zee, F. Kuipers, A. Kiliaan, A. Blokland, E.J.G. Sijbrands, H. Steinbusch, J. Prickaerts, D. Lütjohann, M. Mulder

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Abstract

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.
Original languageEnglish
Pages (from-to)1262-1272
JournalNeurobiology of Aging
Volume32
Issue number7
DOIs
Publication statusPublished - 1 Jan 2011

Cite this

Vanmierlo, T., Rutten, K., Dederen, J., Bloks, V. W., Vark-van der Zee, L. C., Kuipers, F., Kiliaan, A., Blokland, A., Sijbrands, E. J. G., Steinbusch, H., Prickaerts, J., Lütjohann, D., & Mulder, M. (2011). Liver X receptor activation restores memory in aged AD mice without reducing amyloid. Neurobiology of Aging, 32(7), 1262-1272. https://doi.org/10.1016/j.neurobiolaging.2009.07.005