Na, K-ATPase alpha 3 is a death target of Alzheimer patient amyloid- beta assembly

Neurodegeneration correlates with Alzheimer's disease (AD) symptoms, but the molecular identities of pathogenic amyloid ...-protein (A...) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10- to 15-nm spherical A... oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuron-specific Na+/K+-ATPase ...3 subunit (NAK...3). ASPD-binding to NAK...3 impaired NAK...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...-derived "thorns" responsible for target binding, which are distinct from low molecular-weight oligomers and dodecamers. The fourth extracellular loop (Ex4) region of NAK...3 encompassing Asn... and Trp... is essential for ASPD-NAK...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...3 interaction. (ProQuest: ... denotes formulae/symbols omitted.)