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- (A) peptide deposition, neuroinflam- mation, and progressive memory loss. Here, we evaluated whether oral administration of retinoic acid receptor (RAR), 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- protein precursor 23 (APP23) 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 APP23 mice, whereas administration of either agent alone produced no effect. Only co-administration significantly reduced the level of insoluble A peptide in the brain. These results thus indicate that effective memory improvement via reduction of insoluble A peptide in 8.5-month-old APP23 mice requires co-activation of RAR, and RXRs. RAR-positive microglia accumulated A plaques in the APP23 mice. Rat primary microglia co-treated with Am80/HX630 showed increased degradation activity towards 125 I-labeled oligomeric A1-42 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 A clearance in Am80/HX630-treated APP23 mice. Am80/HX630 also increased IL-4R expression in microglial MG5 cells. The improvement in memory of Am80/HX630- treated APP23 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 A peptides by restoring impaired IL-4 signaling in APP23 mice. Combination treatment with RAR and RXR agonists may be an effective approach for AD therapy.