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: Kohichi Kawahara, Michita Suenobu, Hideyuki Ohtsuka, Akihiko Kuniyasu, Yukihiko Sugimoto, Madoka Nakagomi, Hiroshi Fukasawa, Koichi Shudo, Hitoshi Nakayama
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 42 Issue 2 Pg. 587-605 ( 2014) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 24916544 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Protein Precursor
• Antipsychotic Agents
• Benzazepines
• Benzoates
• HX 630
• Receptors, Retinoic Acid
• Retinoid X Receptors
• Tetrahydronaphthalenes
• tamibarotene
• Insulysin

Topics

• Alzheimer Disease (drug therapy, genetics, metabolism, pathology)
• Amyloid beta-Protein Precursor (genetics)
• Animals
• Animals, Newborn
• Antipsychotic Agents (therapeutic use)
• Benzazepines (chemistry, pharmacology, therapeutic use)
• Benzoates (chemistry, pharmacology, therapeutic use)
• Brain (drug effects, metabolism)
• Cells, Cultured
• Disease Models, Animal
• Drug Therapy, Combination
• Gene Expression Regulation (drug effects, genetics)
• Humans
• Insulysin (genetics, metabolism)
• Male
• Maze Learning (drug effects)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Microglia (drug effects, metabolism)
• Mutation (genetics)
• Rats
• Rats, Wistar
• Receptors, Retinoic Acid (agonists, genetics, metabolism)
• Retinoid X Receptors (agonists, genetics, metabolism)
• Tetrahydronaphthalenes (chemistry, pharmacology, therapeutic use)
• Time Factors