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Cooperative therapeutic action of retinoic acid receptor and retinoid x receptor agonists in a mouse model of Alzheimer's disease.
J Alzheimers Dis 2014; 42(2):587-605JA

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+Show Affiliations

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.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.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.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.Department of Pharmaceutical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.Research Foundation ITSUU Laboratory, Setagaya-ku, Tokyo, Japan.Research Foundation ITSUU Laboratory, Setagaya-ku, Tokyo, Japan.Research Foundation ITSUU Laboratory, Setagaya-ku, Tokyo, Japan.Department of Molecular Cell Function, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24916544

Citation

Kawahara, Kohichi, et al. "Cooperative Therapeutic Action of Retinoic Acid Receptor and Retinoid X Receptor Agonists in a Mouse Model of Alzheimer's Disease." Journal of Alzheimer's Disease : JAD, vol. 42, no. 2, 2014, pp. 587-605.
Kawahara K, Suenobu M, Ohtsuka H, et al. Cooperative therapeutic action of retinoic acid receptor and retinoid x receptor agonists in a mouse model of Alzheimer's disease. J Alzheimers Dis. 2014;42(2):587-605.
Kawahara, K., Suenobu, M., Ohtsuka, H., Kuniyasu, A., Sugimoto, Y., Nakagomi, M., ... Nakayama, H. (2014). Cooperative therapeutic action of retinoic acid receptor and retinoid x receptor agonists in a mouse model of Alzheimer's disease. Journal of Alzheimer's Disease : JAD, 42(2), pp. 587-605. doi:10.3233/JAD-132720.
Kawahara K, et al. Cooperative Therapeutic Action of Retinoic Acid Receptor and Retinoid X Receptor Agonists in a Mouse Model of Alzheimer's Disease. J Alzheimers Dis. 2014;42(2):587-605. PubMed PMID: 24916544.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cooperative therapeutic action of retinoic acid receptor and retinoid x receptor agonists in a mouse model of Alzheimer's disease. AU - Kawahara,Kohichi, AU - Suenobu,Michita, AU - Ohtsuka,Hideyuki, AU - Kuniyasu,Akihiko, AU - Sugimoto,Yukihiko, AU - Nakagomi,Madoka, AU - Fukasawa,Hiroshi, AU - Shudo,Koichi, AU - Nakayama,Hitoshi, PY - 2014/6/12/entrez PY - 2014/6/12/pubmed PY - 2015/7/21/medline KW - Alzheimer's disease KW - Am80 KW - HX630 KW - amyloid-β peptides KW - interleukin-4 KW - memory improvement SP - 587 EP - 605 JF - Journal of Alzheimer's disease : JAD JO - J. Alzheimers Dis. VL - 42 IS - 2 N2 - 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. SN - 1875-8908 UR - https://www.unboundmedicine.com/medline/citation/24916544/Cooperative_therapeutic_action_of_retinoic_acid_receptor_and_retinoid_x_receptor_agonists_in_a_mouse_model_of_Alzheimer's_disease_ L2 - https://content.iospress.com/openurl?genre=article&id=doi:10.3233/JAD-132720 DB - PRIME DP - Unbound Medicine ER -