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

Tim Vanmierlo; Kris Rutten; Jos Dederen; Vincent W. Bloks; Leonie C. van Vark-van der Zee; Folkert Kuipers; Amanda Kiliaan; Arjan Blokland; Eric J. G. Sijbrands; Harry Steinbusch; Jos Prickaerts; Dieter Luetjohann; Monique Mulder

doi:10.1016/j.neurobiolaging.2009.07.005

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

Tim Vanmierlo, Kris Rutten, Jos Dederen, Vincent W. Bloks, Leonie C. van Vark-van der Zee, Folkert Kuipers, Amanda Kiliaan, Arjan Blokland, Eric J. G. Sijbrands, Harry Steinbusch, Jos Prickaerts, Dieter Luetjohann, Monique Mulder^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

111 Citations (Scopus)

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. (C) 2009 Elsevier Inc. All rights reserved.

Original language	English
Pages (from-to)	1262-1272
Number of pages	11
Journal	Neurobiology of Aging
Volume	32
Issue number	7
DOIs	https://doi.org/10.1016/j.neurobiolaging.2009.07.005
Publication status	Published - Jul-2011

Keywords

LXR
Alzheimer's disease
Cholesterol
T0901317
Amyloid
Apoe
Abca1
Abcg1
CENTRAL-NERVOUS-SYSTEM
ALZHEIMERS-DISEASE
PRECURSOR PROTEIN
CHOLESTEROL HOMEOSTASIS
TRANSGENIC MOUSE
APOLIPOPROTEIN-E
BETA-PEPTIDE
MUTANT PRESENILIN-1
BRAIN
DEPOSITION

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

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title = "Liver X receptor activation restores memory in aged AD mice without reducing amyloid",

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. (C) 2009 Elsevier Inc. All rights reserved.",

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author = "Tim Vanmierlo and Kris Rutten and Jos Dederen and Bloks, {Vincent W.} and {van Vark-van der Zee}, {Leonie C.} and Folkert Kuipers and Amanda Kiliaan and Arjan Blokland and Sijbrands, {Eric J. G.} and Harry Steinbusch and Jos Prickaerts and Dieter Luetjohann and Monique Mulder",

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Vanmierlo, T, Rutten, K, Dederen, J, Bloks, VW, van Vark-van der Zee, LC, Kuipers, F, Kiliaan, A, Blokland, A, Sijbrands, EJG, Steinbusch, H, Prickaerts, J, Luetjohann, D & Mulder, M 2011, 'Liver X receptor activation restores memory in aged AD mice without reducing amyloid', Neurobiology of Aging, vol. 32, no. 7, pp. 1262-1272. https://doi.org/10.1016/j.neurobiolaging.2009.07.005

TY - JOUR

T1 - Liver X receptor activation restores memory in aged AD mice without reducing amyloid

AU - Vanmierlo, Tim

AU - Rutten, Kris

AU - Dederen, Jos

AU - Bloks, Vincent W.

AU - van Vark-van der Zee, Leonie C.

AU - Kuipers, Folkert

AU - Kiliaan, Amanda

AU - Blokland, Arjan

AU - Sijbrands, Eric J. G.

AU - Steinbusch, Harry

AU - Prickaerts, Jos

AU - Luetjohann, Dieter

AU - Mulder, Monique

PY - 2011/7

Y1 - 2011/7

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. (C) 2009 Elsevier Inc. All rights reserved.

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. (C) 2009 Elsevier Inc. All rights reserved.

KW - LXR

KW - Alzheimer's disease

KW - Cholesterol

KW - T0901317

KW - Amyloid

KW - Apoe

KW - Abca1

KW - Abcg1

KW - CENTRAL-NERVOUS-SYSTEM

KW - ALZHEIMERS-DISEASE

KW - PRECURSOR PROTEIN

KW - CHOLESTEROL HOMEOSTASIS

KW - TRANSGENIC MOUSE

KW - APOLIPOPROTEIN-E

KW - BETA-PEPTIDE

KW - MUTANT PRESENILIN-1

KW - BRAIN

KW - DEPOSITION

U2 - 10.1016/j.neurobiolaging.2009.07.005

DO - 10.1016/j.neurobiolaging.2009.07.005

M3 - Article

SN - 0197-4580

VL - 32

SP - 1262

EP - 1272

JO - Neurobiology of Aging

JF - Neurobiology of Aging

IS - 7

ER -

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

Abstract

Keywords

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