title: Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly.
abstract: Neurodegeneration correlates with Alzheimer's disease (AD) symptoms, but the molecular identities of pathogenic amyloid β-protein (Aβ) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10- to 15-nm spherical Aβ oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuron-specific Na(+)/K(+)-ATPase α3 subunit (NAKα3). ASPD-binding to NAKα3 impaired NAKα3-specific activity, activated N-type voltage-gated calcium channels, and caused mitochondrial calcium dyshomeostasis, tau abnormalities, and neurodegeneration. NMR and molecular modeling studies suggested that spherical ASPD contain N-terminal-Aβ-derived "thorns" responsible for target binding, which are distinct from low molecular-weight oligomers and dodecamers. The fourth extracellular loop (Ex4) region of NAKα3 encompassing Asn(879) and Trp(880) is essential for ASPD-NAKα3 interaction, because tetrapeptides mimicking this Ex4 region bound to the ASPD surface and blocked ASPD neurotoxicity. Our findings open up new possibilities for knowledge-based design of peptidomimetics that inhibit neurodegeneration in AD by blocking aberrant ASPD-NAKα3 interaction.
authors.affiliation: Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation (FBRI), Kobe 650-0047, Japan; TAO Health Life Pharma Co. Ltd. (TAO), Medical Innovation Center in Kyoto University, Kyoto 606-8507, Japan;
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ohnishi
authors.affiliation: Mitsubishi Kagaku Institute of Life Sciences (MITILS; dissolved in March 2010);
authors.forename: Masako
authors.initials: M
authors.lastname: Yanazawa
authors.affiliation: Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation (FBRI), Kobe 650-0047, Japan; TAO Health Life Pharma Co. Ltd. (TAO), Medical Innovation Center in Kyoto University, Kyoto 606-8507, Japan;
authors.forename: Tomoya
authors.initials: T
authors.lastname: Sasahara
authors.affiliation: Mitsubishi Kagaku Institute of Life Sciences (MITILS; dissolved in March 2010);
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Kitamura
authors.affiliation: Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya 464-8601, Japan;
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Hiroaki
authors.affiliation: Department of Histological and Physiological Sciences, Faculty of Medical Science, University of Fukui, Yoshida 910-1193, Japan;
authors.forename: Yugo
authors.initials: Y
authors.lastname: Fukazawa
authors.affiliation: Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Isao
authors.initials: I
authors.lastname: Kii
authors.affiliation: Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation (FBRI), Kobe 650-0047, Japan; Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishiyama
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan;
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.affiliation: Proteo-Science Center, Ehime University, Matsuyama 790-8577, Japan;
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takeda
authors.affiliation: Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Akihide
authors.initials: A
authors.lastname: Takeuchi
authors.affiliation: Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation (FBRI), Kobe 650-0047, Japan; TAO Health Life Pharma Co. Ltd. (TAO), Medical Innovation Center in Kyoto University, Kyoto 606-8507, Japan;
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Mitsubishi Kagaku Institute of Life Sciences (MITILS; dissolved in March 2010);
authors.forename: Akane
authors.initials: A
authors.lastname: Ito
authors.affiliation: Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation (FBRI), Kobe 650-0047, Japan; TAO Health Life Pharma Co. Ltd. (TAO), Medical Innovation Center in Kyoto University, Kyoto 606-8507, Japan;
authors.forename: Hitomi
authors.initials: H
authors.lastname: Komura
authors.affiliation: School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371;
authors.forename: Hajime
authors.initials: H
authors.lastname: Hirao
authors.affiliation: Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation (FBRI), Kobe 650-0047, Japan; TAO Health Life Pharma Co. Ltd. (TAO), Medical Innovation Center in Kyoto University, Kyoto 606-8507, Japan;
authors.forename: Kaori
authors.initials: K
authors.lastname: Satomura
authors.affiliation: Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation (FBRI), Kobe 650-0047, Japan; TAO Health Life Pharma Co. Ltd. (TAO), Medical Innovation Center in Kyoto University, Kyoto 606-8507, Japan;
authors.forename: Masafumi
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Department of Medicine, Jichi Medical University, Shimotsuke 329-0498, Japan;
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Muramatsu
authors.affiliation: Division of Interdisciplinary Medical Science, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan;
authors.forename: Ko
authors.initials: K
authors.lastname: Matsui
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan;
authors.forename: Mari
authors.initials: M
authors.lastname: Tada
authors.affiliation: Mitsubishi Kagaku Institute of Life Sciences (MITILS; dissolved in March 2010);
authors.forename: Michio
authors.initials: M
authors.lastname: Sato
authors.affiliation: Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation (FBRI), Kobe 650-0047, Japan; TAO Health Life Pharma Co. Ltd. (TAO), Medical Innovation Center in Kyoto University, Kyoto 606-8507, Japan;
authors.forename: Eri
authors.initials: E
authors.lastname: Saijo
authors.affiliation: Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya 464-8601, Japan;
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Shigemitsu
authors.affiliation: Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation (FBRI), Kobe 650-0047, Japan; TAO Health Life Pharma Co. Ltd. (TAO), Medical Innovation Center in Kyoto University, Kyoto 606-8507, Japan;
authors.forename: Satoko
authors.initials: S
authors.lastname: Sakai
authors.affiliation: Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya 464-8601, Japan;
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Umetsu
authors.affiliation: Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya 464-8601, Japan;
authors.forename: Natsuko
authors.initials: N
authors.lastname: Goda
authors.affiliation: TAO Health Life Pharma Co. Ltd. (TAO), Medical Innovation Center in Kyoto University, Kyoto 606-8507, Japan;
authors.forename: Naomi
authors.initials: N
authors.lastname: Takino
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan;
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hagiwara
authors.affiliation: Proteo-Science Center, Ehime University, Matsuyama 790-8577, Japan;
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sawasaki
authors.affiliation: Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki 370-0033, Japan;
authors.forename: Genji
authors.initials: G
authors.lastname: Iwasaki
authors.affiliation: Department of Neuropsychiatry, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan;
authors.forename: Yu
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation (FBRI), Kobe 650-0047, Japan;
authors.forename: Yo-ichi
authors.initials: Y
authors.lastname: Nabeshima
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
authors.forename: David B
authors.initials: DB
authors.lastname: Teplow
authors.affiliation: Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation (FBRI), Kobe 650-0047, Japan; Mitsubishi Kagaku Institute of Life Sciences (MITILS; dissolved in March 2010); Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; hoshi.minako.8w@kyoto-u.ac.jp.
authors.forename: Minako
authors.initials: M
authors.lastname: Hoshi
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D057809:HEK293 Cells; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D013058:Mass Spectrometry; D008954:Models, Biological; D008958:Models, Molecular; D057054:Molecular Imaging; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D066329:Protein Aggregates; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D002118:Calcium; D010455:Peptides; D066329:Protein Aggregates; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; C541459:Atp1a3 protein, rat; C488756:ATP1A3 protein, human
keywords: NMR; abnormal protein–protein interaction in synapse; computational modeling; hyperexcitotoxicity; protein–protein interaction inhibitors