TY - JOUR
T1 - Liver X receptor activation restores memory in aged AD mice without reducing amyloid
AU - Vanmierlo, T.
AU - Rutten, K.
AU - Dederen, J.
AU - Bloks, V.W.
AU - Vark-van der Zee, L.C.
AU - Kuipers, F.
AU - Kiliaan, A.
AU - Blokland, A.
AU - Sijbrands, E.J.G.
AU - Steinbusch, H.
AU - Prickaerts, J.
AU - Lütjohann, D.
AU - Mulder, M.
PY - 2011/1/1
Y1 - 2011/1/1
N2 - 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.
AB - 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.
U2 - 10.1016/j.neurobiolaging.2009.07.005
DO - 10.1016/j.neurobiolaging.2009.07.005
M3 - Article
C2 - 19674815
SN - 0197-4580
VL - 32
SP - 1262
EP - 1272
JO - Neurobiology of Aging
JF - Neurobiology of Aging
IS - 7
ER -