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

  • Author(s): 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
  • et al.
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.

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