title: Synthesis and identification of new flavonoids targeting liver X receptor β involved pathway as potential facilitators of Aβ clearance with reduced lipid accumulation.
abstract: Alzheimer's disease (AD) is associated with impaired Aβ degradation in the brain. Enhancing the process of Aβ clearance is an attractive potential AD therapy. Treatment with LXR agonists may reduce Aβ levels in vivo. However, the clinical potential of many LXR agonists is limited because of their nonselective actions on LXRα/β, which lead to undesired hepatic lipogenesis via LXRα-dependent pathways. In this study, ABCA1 up-regulators were identified from a series of flavonoids and were found to preferentially activate LXRβ and up-regulate expression of ABCA1 and apoE in different cell lines. Further investigations confirmed that these compounds facilitate intracellular Aβ clearance in Aβ-loaded BV2 cells. Administration of compound 19 reduced total brain Aβ and plaque burden in APP/PS1 double transgenic mice, associated with elevated ABCA1 and apoE expression. Compared with the nonselective LXR agonists, the active compounds reported here induced less accumulation of undesired lipids and triglycerides in HepG2 cells.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Hu
authors.forename: Yaqi
authors.initials: Y
authors.lastname: Yang
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Yu
authors.forename: Gesi
authors.initials: G
authors.lastname: Wen
authors.forename: Nana
authors.initials: N
authors.lastname: Shang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhuang
authors.forename: Dihan
authors.initials: D
authors.lastname: Lu
authors.forename: Binhua
authors.initials: B
authors.lastname: Zhou
authors.forename: Baoxia
authors.initials: B
authors.lastname: Liang
authors.forename: Xin
authors.initials: X
authors.lastname: Yue
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Du
authors.forename: Xianzhang
authors.initials: X
authors.lastname: Bu
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D047188:Chalcones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047309:Flavones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D008055:Lipids / Q000096:biosynthesis*; D000071518:Liver X Receptors; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D062105:Molecular Docking Simulation; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology; D014280:Triglycerides / Q000096:biosynthesis; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001565:Benzoates; D001596:Benzylamines; D047188:Chalcones; D047309:Flavones; D006845:Hydrocarbons, Fluorinated; D008055:Lipids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D053764:Presenilin-1; D013449:Sulfonamides; D014280:Triglycerides; C577836:ABCA1 protein, human; C473027:GW 3965; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides