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Abstract. Alzheimer's disease (AD) is a neurodegenerative process involving amyloid-␤ (A␤) peptide deposition, neuroinflammation, 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 (A␤PP23) 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 A␤PP23 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 A␤PP23 mice requires co-activation of RAR␣,␤ and RXRs. RAR␣-positive microglia accumulated A␤ plaques in the A␤PP23 mice. Rat primary microglia co-treated with Am80/HX630 showed increased degradation activity towards 125 I-labeled oligomeric A␤ 1-42 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 A␤PP23 mice. Am80/HX630 also increased IL-4R␣ expression in microglial MG5 cells. The improvement in memory of Am80/HX630-treated A␤PP23 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 A␤PP23 mice. Combination treatment with RAR and RXR agonists may be an effective approach for AD therapy.

The purpose of this study is to investigate whether a synthetic retinoid Am80 (tamibarotene) exhibits any improving effects on amyloid precursor protein (

Peripheral lymphocyte counts, T-cell and B-cell populations, DNCB skin reactions, Mantoux reactions, mitogenic transformation using PHA, and determination of serum phenytoin concentration were carried out in 45 children with severe handicaps. Twenty two of these patients were receiving phenytoin treatment. When compared with control subjects, the skin reactions were significantly depressed in the handicapped children, amongst whom those treated with phenytoin had more impaired reactions than those who were untreated. No significant relationship between the results of the skin reactions and the other parameters was found.

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