Cooperative Therapeutic Action of Retinoic Acid Receptor and Retinoid X Receptor Agonists in a Mouse Model of Alzheimer's Disease

Autor: Kohichi Kawahara, Yukihiko Sugimoto, Hiroshi Fukasawa, Michita Suenobu, Madoka Nakagomi, Akihiko Kuniyasu, Hideyuki Ohtsuka, Koichi Shudo, Hitoshi Nakayama
Rok vydání: 2014
Předmět:
Male
Agonist
medicine.medical_specialty
Time Factors
Tetrahydronaphthalenes
Receptors
Retinoic Acid
medicine.drug_class
Morris water navigation task
Mice
Transgenic
Retinoid X receptor
Biology
Benzoates
Insulysin
Amyloid beta-Protein Precursor
Mice
chemistry.chemical_compound
Alzheimer Disease
Internal medicine
Memory improvement
medicine
Animals
Humans
Rats
Wistar
Maze Learning
Cells
Cultured
Neuroinflammation
Microglia
General Neuroscience
Brain
General Medicine
Benzazepines
Rats
Mice
Inbred C57BL
Disease Models
Animal
Psychiatry and Mental health
Clinical Psychology
Retinoic acid receptor
Retinoid X Receptors
Endocrinology
medicine.anatomical_structure
Animals
Newborn
Gene Expression Regulation
chemistry
Mutation
Drug Therapy
Combination
Tamibarotene
Geriatrics and Gerontology
Antipsychotic Agents
Zdroj: Journal of Alzheimer's Disease. 42:587-605
ISSN: 1875-8908
1387-2877
DOI: 10.3233/jad-132720
Popis: 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.
Databáze: OpenAIRE
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