Papers

Peer-reviewed
Aug, 2015

Na, K-ATPase alpha 3 is a death target of Alzheimer patient amyloid-beta assembly

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
  • Takayuki Ohnishi
  • ,
  • Masako Yanazawa
  • ,
  • Tomoya Sasahara
  • ,
  • Yasuki Kitamura
  • ,
  • Hidekazu Hiroaki
  • ,
  • Yugo Fukazawa
  • ,
  • Isao Kii
  • ,
  • Takashi Nishiyama
  • ,
  • Akiyoshi Kakita
  • ,
  • Hiroyuki Takeda
  • ,
  • Akihide Takeuchi
  • ,
  • Yoshie Arai
  • ,
  • Akane Ito
  • ,
  • Hitomi Komura
  • ,
  • Hajime Hirao
  • ,
  • Kaori Satomura
  • ,
  • Masafumi Inoue
  • ,
  • Shin-ichi Muramatsu
  • ,
  • Ko Matsui
  • ,
  • Mari Tada
  • ,
  • Michio Sato
  • ,
  • Eri Saijo
  • ,
  • Yoshiki Shigemitsu
  • ,
  • Satoko Sakai
  • ,
  • Yoshitaka Umetsu
  • ,
  • Natsuko Goda
  • ,
  • Naomi Takino
  • ,
  • Hitoshi Takahashi
  • ,
  • Masatoshi Hagiwara
  • ,
  • Tatsuya Sawasaki
  • ,
  • Genji Iwasaki
  • ,
  • Yu Nakamura
  • ,
  • Yo-ichi Nabeshima
  • ,
  • David B. Teplow
  • ,
  • Minako Hoshi

Volume
112
Number
32
First page
E4465
Last page
E4474
Language
English
Publishing type
Research paper (scientific journal)
DOI
10.1073/pnas.1421182112
Publisher
NATL ACAD SCIENCES

Neurodegeneration correlates with Alzheimer's disease (AD) symptoms, but the molecular identities of pathogenic amyloid beta-protein (A beta) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10- to 15-nm spherical A beta oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuronspecific Na+/K+-ATPase alpha 3 subunit (NAK alpha 3). ASPD-binding to NAK alpha 3 impaired NAK alpha 3-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-A beta-derived "thorns" responsible for target binding, which are distinct from low molecular-weight oligomers and dodecamers. The fourth extracellular loop (Ex4) region of NAK alpha 3 encompassing Asn(879) and Trp(880) is essential for ASPD-NAK alpha 3 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-NAK alpha 3 interaction.

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Link information
DOI
https://doi.org/10.1073/pnas.1421182112
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/26224839
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000359285100018&DestApp=WOS_CPL
ID information
  • DOI : 10.1073/pnas.1421182112
  • ISSN : 0027-8424
  • Pubmed ID : 26224839
  • Web of Science ID : WOS:000359285100018

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