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Open Access Publications from the University of California

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

  • Author(s): 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, SI
  • Matsui, K
  • Tada, M
  • Sato, M
  • Saijo, E
  • Shigemitsu, Y
  • Sakai, S
  • Umetsu, Y
  • Goda, N
  • Takino, N
  • Takahashi, H
  • Hagiwara, M
  • Sawasaki, T
  • Iwasaki, G
  • Nakamura, Y
  • Nabeshima, YI
  • Teplow, DB
  • Hoshi, M
  • Südhof, TC
  • et al.

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.

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