title: The retinoic acid receptor agonist Am80 increases hippocampal ADAM10 in aged SAMP8 mice.
abstract: The retinoic acid (RA, a vitamin A metabolite) receptor (RAR) is a transcription factor. Vitamin A/RA administration improves the Alzheimer's disease (AD)- and age-related attenuation of memory/learning in mouse models. Recently, a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) was identified as a key molecule in RA-mediated anti-AD mechanisms. We investigated the effect of chronic administration of the RAR agonist Am80 (tamibarotene) on ADAM10 expression in senescence-accelerated mice (SAMP8). Moreover, we estimated changes in the expression of the amyloid precursor protein (APP), amyloid beta (Aβ), and hairy/enhancer of split (Hes), which are mediated by ADAM10. Spatial working memory and the levels of a hippocampal proliferation marker (Ki67) were also assessed in these mice. ADAM10 mRNA and protein expression was significantly reduced in the hippocampus of 13-month-old SAMP8 mice; their expression improved significantly after Am80 administration. Further, after Am80 administration, the expression levels of Hes5 and Ki67 were restored and the deterioration of working memory was suppressed, whereas APP and Aβ levels remained unchanged. Our results suggest that Am80 administration effectively improves dementia by activating the hippocampal ADAM10-Notch-Hes5 proliferative pathway.
authors.affiliation: Department of Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan. Electronic address: kitaoka@tokushima-u.ac.jp.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kitaoka
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Shimizu
authors.forename: Koji
authors.initials: K
authors.lastname: Ono
authors.forename: Sachiko
authors.initials: S
authors.lastname: Chikahisa
authors.forename: Madoka
authors.initials: M
authors.lastname: Nakagomi
authors.forename: Koichi
authors.initials: K
authors.lastname: Shudo
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ishimura
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Séi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yoshizaki
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D000375:Aging / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects*; D019394:Ki-67 Antigen / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D008817:Mice, Mutant Strains; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists; D012097:Repressor Proteins / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D051722:ADAM Proteins; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D001565:Benzoates; D019394:Ki-67 Antigen; D008565:Membrane Proteins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D013764:Tetrahydronaphthalenes; C489685:Hes5 protein, mouse; C061133:tamibarotene; C491234:Adam10 protein, mouse