Cooperative therapeutic action of retinoic acid receptor and retinoid x receptor agonists in a mouse model of Alzheimer's disease.
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.
['Kawahara|Kohichi|K|', 'Suenobu|Michita|M|', 'Ohtsuka|Hideyuki|H|', 'Kuniyasu|Akihiko|A|', 'Sugimoto|Yukihiko|Y|', 'Nakagomi|Madoka|M|', 'Fukasawa|Hiroshi|H|', 'Shudo|Koichi|K|', 'Nakayama|Hitoshi|H|']
D000544:Alzheimer Disease D016564:Amyloid beta-Protein Precursor D000818:Animals D000831:Animals, Newborn D014150:Antipsychotic Agents D001552:Benzazepines D001565:Benzoates D001921:Brain D002478:Cells, Cultured D004195:Disease Models, Animal D004359:Drug Therapy, Combination D005786:Gene Expression Regulation D006801:Humans D007339:Insulysin D008297:Male D018782:Maze Learning D051379:Mice D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D017628:Microglia D009154:Mutation D051381:Rats D017208:Rats, Wistar D018168:Receptors, Retinoic Acid D047488:Retinoid X Receptors D013764:Tetrahydronaphthalenes D013997:Time Factors
Alzheimer's disease Am80 HX630 memory improvement interleukin-4 amyloid-β peptides