title: The LXR agonist TO901317 selectively lowers hippocampal Abeta42 and improves memory in the Tg2576 mouse model of Alzheimer's disease.
abstract: Recent studies show that intracellular cholesterol levels can modulate the processing of amyloid precursor protein to Abeta peptide. Moreover, cholesterol-rich apoE-containing lipoproteins may also promote Abeta clearance. Agonists of the liver X receptor (LXR) transcriptionally induce genes involved in intracellular lipid efflux and transport, including apoE. Thus, LXR agonists have the potential to both inhibit APP processing and promote Abeta clearance. Here we show that LXR agonist, TO901317, increased hippocampal ABCA1 and apoE and decreased Abeta42 levels in APP transgenic mice. TO901317 had no significant effects on levels of Abeta40, full length APP, or the APP processing products. Next, we examined the effects of TO901317 in the contextual fear conditioning paradigm; TO901317 completely reversed the contextual memory deficit in these mice. These data demonstrate that LXR agonists do not directly inhibit APP processing but rather facilitate the clearance of Abeta42 and may represent a novel therapeutic approach to Alzheimer's disease.
authors.affiliation: Discovery Neuroscience, Wyeth Research, CN8000, Princeton, NJ 08543, USA. riddeld@wyeh.com
authors.forename: David R
authors.initials: DR
authors.lastname: Riddell
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Comery
authors.forename: Evguenia
authors.initials: E
authors.lastname: Kouranova
authors.forename: C Frederick
authors.initials: CF
authors.lastname: Lo
authors.forename: Helen K
authors.initials: HK
authors.lastname: Warwick
authors.forename: Robert H
authors.initials: RH
authors.lastname: Ring
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Kirksey
authors.forename: Suzan
authors.initials: S
authors.lastname: Aschmies
authors.forename: Jane
authors.initials: J
authors.lastname: Xu
authors.forename: Katie
authors.initials: K
authors.lastname: Kubek
authors.forename: Warren D
authors.initials: WD
authors.lastname: Hirst
authors.forename: Catherine
authors.initials: C
authors.lastname: Gonzales
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Erin
authors.initials: E
authors.lastname: Murphy
authors.forename: Sarah
authors.initials: S
authors.lastname: Leonard
authors.forename: Dmytro
authors.initials: D
authors.lastname: Vasylyev
authors.forename: Aram
authors.initials: A
authors.lastname: Oganesian
authors.forename: Robert L
authors.initials: RL
authors.lastname: Martone
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.forename: Peter H
authors.initials: PH
authors.lastname: Reinhart
authors.forename: J Steve
authors.initials: JS
authors.lastname: Jacobsen
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000819:agonists*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors; D010446:Peptide Fragments / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010446:Peptide Fragments; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C577836:ABCA1 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C075222:amyloid beta-protein (1-42)