1. Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly
- Author
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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, and Südhof, TC
- Subjects
mental disorders - 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.
- Published
- 2015