title: Extracellular deposition of mouse senile AApoAII amyloid fibrils induced different unfolded protein responses in the liver, kidney, and heart.
abstract: Mouse senile amyloidosis is a disorder in which apolipoprotein A-II deposits extracellularly in many organs as amyloid fibrils (AApoAII). In this study, we intravenously injected 1 μg of isolated AApoAII fibrils into R1.P1-Apoa2(c) mice, to induce AApoAII amyloidosis. We observed that the unfolded protein response was induced by deposition of AApoAII amyloid. We found that the mRNA and the protein expression levels of heat shock protein A5 (HSPA5; also known as glucose-regulated protein 78) were increased in the liver with AApoAII amyloid deposits. Immunohistochemistry showed that HSPA5 was only detected in hepatocytes close to AApoAII amyloid deposits. Furthermore, gene transcription of several endoplasmic reticulum (ER) stress-related proteins increased, including eukaryotic translation initiation factor 2 alpha kinase 3 (Eif2ak3), activating transcription factor 6 (Atf6), activating transcription factor 4 (Atf4), X-box-binding protein 1 splicing (Xbp1s), DNA-damage inducible transcript 3 (Ddit3), and autophagy protein 5 (Atg5). Moreover, apoptosis-positive cells were increased in the liver. Similar results were seen in the kidney but not in the heart. Our study indicates that ER stress responses differed among tissues with extracellular AApoAII amyloid fibril deposition. Although upregulated HSPA5 and the activated unfolded protein response might have roles in protecting tissues against aggregated extracellular AApoAII amyloid deposition, prolonged ER stress induced apoptosis in the liver and the kidney.
authors.affiliation: 1] Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan [2] Third Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Luo
authors.affiliation: 1] Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan [2] Department of Biological Sciences for Intractable Neurological Diseases, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan.
authors.forename: Jinko
authors.initials: J
authors.lastname: Sawashita
authors.affiliation: 1] Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan [2] Shijiazhuang Obstetrics and Gynecology Hospital, Shijiazhuang, China.
authors.forename: Geng
authors.initials: G
authors.lastname: Tian
authors.affiliation: Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Yingye
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Xin
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Mu
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Miyahara
authors.affiliation: 1] Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan [2] Department of Advanced Medicine for Health Promotion, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Mori
authors.affiliation: 1] Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan [2] Department of Pathology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Jinze
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors.forename: Yaoyong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1] Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan [2] Department of Biological Sciences for Intractable Neurological Diseases, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Higuchi
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism; D000818:Animals; D016633:Apolipoprotein A-II / Q000378:metabolism*; D017209:Apoptosis; D015153:Blotting, Western; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005110:Extracellular Space / Q000378:metabolism; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism*; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D009928:Organ Specificity; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056811:Unfolded Protein Response
chemical_list: D000682:Amyloid; D016633:Apolipoprotein A-II; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; C079456:amyloidogenic apolipoprotein A-II, mouse