title: C-terminal sequence of amyloid-resistant type F apolipoprotein A-II inhibits amyloid fibril formation of apolipoprotein A-II in mice.
abstract: In murine senile amyloidosis, misfolded serum apolipoprotein (apo) A-II deposits as amyloid fibrils (AApoAII) in a process associated with aging. Mouse strains carrying type C apoA-II (APOA2C) protein exhibit a high incidence of severe systemic amyloidosis. Previously, we showed that N- and C-terminal sequences of apoA-II protein are critical for polymerization into amyloid fibrils in vitro. Here, we demonstrate that congenic mouse strains carrying type F apoA-II (APOA2F) protein, which contains four amino acid substitutions in the amyloidogenic regions of APOA2C, were absolutely resistant to amyloidosis, even after induction of amyloidosis by injection of AApoAII. In vitro fibril formation tests showed that N- and C-terminal APOA2F peptides did not polymerize into amyloid fibrils. Moreover, a C-terminal APOA2F peptide was a strong inhibitor of nucleation and extension of amyloid fibrils during polymerization. Importantly, after the induction of amyloidosis, we succeeded in suppressing amyloid deposition in senile amyloidosis-susceptible mice by treatment with the C-terminal APOA2F peptide. We suggest that the C-terminal APOA2F peptide might inhibit further extension of amyloid fibrils by blocking the active ends of nuclei (seeds). We present a previously unidentified model system for investigating inhibitory mechanisms against amyloidosis in vivo and in vitro and believe that this system will be useful for the development of novel therapies.
authors: Department of Biological Sciences for Intractable Neurological Diseases, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan; Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan; jinkos@shinshu-u.ac.jp.
authors: Jinko
authors: J
authors: Sawashita
authors: Department of Nephrology, Shengjing-Hospital of China Medical University, Shenyang, Liaoning, 110004, China;
authors: Beiru
authors: B
authors: Zhang
authors: Division of Molecular Pathology, Department of Pathological Sciences, Faculty of Medical Science, University of Fukui, Yoshida-gun, Fukui 910-1193, Japan;
authors: Kazuhiro
authors: K
authors: Hasegawa
authors: Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan; Department of Advanced Medicine for Health Promotion, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan; and.
authors: Masayuki
authors: M
authors: Mori
authors: Division of Molecular Pathology, Department of Pathological Sciences, Faculty of Medical Science, University of Fukui, Yoshida-gun, Fukui 910-1193, Japan;
authors: Hironobu
authors: H
authors: Naiki
authors: Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
authors: Fuyuki
authors: F
authors: Kametani
authors: Department of Biological Sciences for Intractable Neurological Diseases, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan; Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan;
authors: Keiichi
authors: K
authors: Higuchi
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000682:Amyloid / Q000378:metabolism* / Q000648:ultrastructure; D000686:Amyloidosis / Q000097:blood / Q000473:pathology; D000818:Animals; D016633:Apolipoprotein A-II / Q000737:chemistry* / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D058105:Polymerization; D013329:Structure-Activity Relationship
chemical_list: D000682:Amyloid; D016633:Apolipoprotein A-II; D008075:Lipoproteins, HDL; D050505:Mutant Proteins; D010455:Peptides; D002784:Cholesterol
keywords: amyloid fibril formation; apolipoprotein A-II; inhibitory peptide; mouse; senile amyloidosis