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-β (Aβ) 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 Aβ 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 Aβ deposition. However the beneficial effects of T0901317 on memory in the APPSLxPS1mut mice were independent of the Aβ plaque load in the hippocampus, but were associated with enhanced brain cholesterol turnover.
Vanmierlo
Tim
T
Department of Neuroscience, Maastricht University, Maastricht, The Netherlands.
Rutten
Kris
K
Dederen
Jos
J
Bloks
Vincent W
VW
van Vark-van der Zee
Leonie C
LC
Kuipers
Folkert
F
Kiliaan
Amanda
A
Blokland
Arjan
A
Sijbrands
Eric J G
EJ
Steinbusch
Harry
H
Prickaerts
Jos
J
Lütjohann
Dieter
D
Mulder
Monique
M
D000375:Aging / Q000235:genetics; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D000071518:Liver X Receptors; D008568:Memory / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D016229:Amyloid beta-Peptides; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides