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Title: Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly
Authors: Ohnishi, Takayuki
Yanazawa, Masako
Sasahara, Tomoya
Kitamura, Yasuki
Hiroaki, Hidekazu
Fukazawa, Yugo
Kii, Isao
Nishiyama, Takashi
Kakita, Akiyoshi
Takeda, Hiroyuki
Takeuchi, Akihide
Arai, Yoshie
Ito, Akane
Komura, Hitomi
Hirao, Hajime
Satomura, Kaori
Inoue, Masafumi
Muramatsu, Shin-ichi
Matsui, Ko
Tada, Mari
Sato, Michio
Saijo, Eri
Shigemitsu, Yoshiki
Sakai, Satoko
Umetsu, Yoshitaka
Goda, Natsuko
Takino, Naomi
Takahashi, Hitoshi
Hagiwara, Masatoshi
Sawasaki, Tatsuya
Iwasaki, Genji
Nakamura, Yu
Nabeshima, Yo-ichi
Teplow, David B.
Hoshi, Minako
Keywords: Abnormal protein–protein interaction in synapse
Computational modeling
Protein-protein interaction inhibitors
Issue Date: 2015
Source: Ohnishi, T., Yanazawa, M., Sasahara, T., Kitamura, Y., Hiroaki, H., Fukazawa, Y., et al. (2015). Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly. Proceedings of the National Academy of Sciences, 112(32), 4465-4474.
Series/Report no.: Proceedings of the National Academy of Sciences of the United States of America
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 Asn879 and Trp880 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.
DOI: 10.1073/pnas.1421182112
Schools: School of Physical and Mathematical Sciences 
Rights: © 2015 The Authors (Published by National Academy of Sciences).
Fulltext Permission: none
Fulltext Availability: No Fulltext
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