Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 32, Pages E4465-E4474Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1421182112
Keywords
NMR; computational modeling; abnormal protein-protein interaction in synapse; hyperexcitotoxicity; protein-protein interaction inhibitors
Categories
Funding
- Ministry of Health, Labor and Welfare (Research on Nanotechnical Medical and Initiative for Accelerating Regulatory Science in Innovative Drug, Medical Device, and Regenerative Medicine)
- Ministry of Education, Culture, Sports, Science and Technology
- Collaborative Research Project of the Brain Research Institute, Niigata University
- Takeda Science Foundation
- National Institutes of Health [NS038328, AG041295]
- Grants-in-Aid for Scientific Research [26117501, 25702054, 15K12765, 221S0003, 26750365, 15K21099] Funding Source: KAKEN
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Neurodegeneration correlates with Alzheimer's disease (AD) symptoms, but the molecular identities of pathogenic amyloid beta-protein (A beta) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10- to 15-nm spherical A beta oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuronspecific Na+/K+-ATPase alpha 3 subunit (NAK alpha 3). ASPD-binding to NAK alpha 3 impaired NAK alpha 3-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-A beta-derived thorns responsible for target binding, which are distinct from low molecular-weight oligomers and dodecamers. The fourth extracellular loop (Ex4) region of NAK alpha 3 encompassing Asn(879) and Trp(880) is essential for ASPD-NAK alpha 3 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-NAK alpha 3 interaction.
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