Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

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 TadaMichio 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, Thomas C. Südhof

    Research output: Contribution to journalArticle

    66 Citations (Scopus)

    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 neuronspecific 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.

    Original languageEnglish
    Pages (from-to)E4465-E4474
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume112
    Issue number32
    DOIs
    Publication statusPublished - 2015 Aug 11

    Keywords

    • Abnormal protein-protein interaction in synapse
    • Computational modeling
    • Hyperexcitotoxicity
    • NMR
    • Protein-protein interaction inhibitors

    ASJC Scopus subject areas

    • General

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  • Cite this

    Ohnishi, T., Yanazawa, M., Sasahara, T., Kitamura, Y., Hiroaki, H., Fukazawa, Y., Kii, I., Nishiyama, T., Kakita, A., Takeda, H., Takeuchi, A., Arai, Y., Ito, A., Komura, H., Hirao, H., Satomura, K., Inoue, M., Muramatsu, S. I., Matsui, K., ... Südhof, T. C. (2015). Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly. Proceedings of the National Academy of Sciences of the United States of America, 112(32), E4465-E4474. https://doi.org/10.1073/pnas.1421182112