title: Cooperative therapeutic action of retinoic acid receptor and retinoid x receptor agonists in a mouse model of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a neurodegenerative process involving amyloid-β (Aβ) peptide deposition, neuroinflammation, and progressive memory loss. Here, we evaluated whether oral administration of retinoic acid receptor (RAR)α,β agonist Am80 (tamibarotene) or specific retinoid X receptor (RXR) pan agonist HX630 or their combination could improve deficits in an AD model, 8.5-month-old amyloid-β protein precursor 23 (AβPP23) mice. Co-administration of Am80 (0.5 mg/kg) and HX630 (5 mg/kg) for 17 days significantly improved memory deficits (Morris water maze) in AβPP23 mice, whereas administration of either agent alone produced no effect. Only co-administration significantly reduced the level of insoluble Aβ peptide in the brain. These results thus indicate that effective memory improvement via reduction of insoluble Aβ peptide in 8.5-month-old AβPP23 mice requires co-activation of RARα,β and RXRs. RARα-positive microglia accumulated Aβ plaques in the AβPP23 mice. Rat primary microglia co-treated with Am80/HX630 showed increased degradation activity towards 125I-labeled oligomeric Aβ1-42 peptide in an insulin-degrading enzyme (IDE)-dependent manner. The co-administration increased mRNA for IDE and membrane-associated IDE protein in vivo, suggesting that IDE contributes to Aβ clearance in Am80/HX630-treated AβPP23 mice. Am80/HX630 also increased IL-4Rα expression in microglial MG5 cells. The improvement in memory of Am80/HX630-treated AβPP23 mice was correlated with the levels and signaling of hippocampal interleukin-4 (IL-4). Therefore, Am80/HX630 may promote differentiation of IL-4-responsive M2-like microglia and increase their activity for clearance of oligomeric Aβ peptides by restoring impaired IL-4 signaling in AβPP23 mice. Combination treatment with RAR and RXR agonists may be an effective approach for AD therapy.
authors.affiliation: Department of Molecular Cell Function, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan Department of Pharmaceutical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kohichi
authors.initials: K
authors.lastname: Kawahara
authors.affiliation: Department of Molecular Cell Function, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan Department of Pharmaceutical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Michita
authors.initials: M
authors.lastname: Suenobu
authors.affiliation: Department of Molecular Cell Function, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan Department of Pharmaceutical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ohtsuka
authors.affiliation: Department of Molecular Cell Function, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan Department of Pharmaceutical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kuniyasu
authors.affiliation: Department of Pharmaceutical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sugimoto
authors.affiliation: Research Foundation ITSUU Laboratory, Setagaya-ku, Tokyo, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Nakagomi
authors.affiliation: Research Foundation ITSUU Laboratory, Setagaya-ku, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukasawa
authors.affiliation: Research Foundation ITSUU Laboratory, Setagaya-ku, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Shudo
authors.affiliation: Department of Molecular Cell Function, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakayama
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001552:Benzazepines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007339:Insulysin / Q000235:genetics / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D016564:Amyloid beta-Protein Precursor; D014150:Antipsychotic Agents; D001552:Benzazepines; D001565:Benzoates; C422175:HX 630; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; C061133:tamibarotene; D007339:Insulysin
keywords: Alzheimer's disease; Am80; HX630; amyloid-β peptides; interleukin-4; memory improvement