title: The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer's disease.
abstract: Recent studies indicate that oxysterols, which are ligands for the nuclear hormone liver X receptors (LXR), decrease amyloid beta (Abeta) secretion in vitro. The effect was attributed primarily to the ATP-binding cassette transporter A1 (ABCA1) transcriptionally up-regulated by ligand-activated LXRs. We now examined the effect of the synthetic LXR ligand T0901317, which can be used in vivo, on Abeta production in vitro and in APP23 transgenic mice. T0901317 applied to a variety of in vitro models, including immortalized fibroblasts from Tangier patients, and primary embryonic mouse neurons caused a concentration-dependent decrease in Abeta secretion, and this effect was increased by the addition of apolipoprotein A-I. The inhibition of Abeta production by T0901317 was cell-type specific, being more prominent in primary neurons than in non-neuronal cells. Tangier fibroblasts lacking a functional ABCA1 secreted more Abeta than control fibroblasts, thus demonstrating the role of ABCA1 in amyloid precursor protein (APP) processing and Abeta generation. T0901317 treatment of 11-week-old APP23 mice for 6 days showed a significant increase in ABCA1 expression and a decrease in the ratio of soluble APP (sAPP)beta- to sAPPalpha-cleavage products. Most importantly, the treatment caused a statistically significant reduction in the levels of soluble Abeta40 and of Abeta42 in the brain these mice. Our experiments demonstrate that T0901317 decreases amyloidogenic processing of APP in vitro and in vivo, thus supporting the search for potent and specific LXR ligands with properties allowing therapeutic application.
authors.affiliation: Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. radak@pitt.edu
authors.forename: Radosveta P
authors.initials: RP
authors.lastname: Koldamova
authors.forename: Iliya M
authors.initials: IM
authors.lastname: Lefterov
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.forename: Darren
authors.initials: D
authors.lastname: Wolfe
authors.forename: Shaohua
authors.initials: S
authors.lastname: Huang
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Glorioso
authors.forename: Michael
authors.initials: M
authors.lastname: Walter
authors.forename: Michael G
authors.initials: MG
authors.lastname: Roth
authors.forename: John S
authors.initials: JS
authors.lastname: Lazo
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D016632:Apolipoprotein A-I / Q000737:chemistry; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D047468:Immunoprecipitation; D008024:Ligands; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018139:Simplexvirus / Q000378:metabolism; D013449:Sulfonamides; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D016564:Amyloid beta-Protein Precursor; D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides