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

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 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.NMR | computational modeling | abnormal protein-protein interaction in synapse | hyperexcitotoxicity | protein-protein interaction inhibitors

Clustering of Tau fibrils impairs the synaptic composition of α3‐Na + /K + ‐ ATP ase and AMPA receptors

“…The list of membrane proteins with extracellular domains that interact with Fib-Tau is given in Fig 4D. Among the proteins with extracellular domains, we identified are key neurotransmitter receptors namely GluA1 and GluA2 subunits of AMPA receptors (identified through 8 and 12 unique peptides, respectively, Appendix Fig S6), and GluN1 and GluN2B subunits of NMDA receptors (identified through 16 and 12 unique peptides, respectively, Appendix Fig S6). Fib-Tau also interacts with NKA (sodium-potassium ATPase) a3 subunit (identified through 27 peptides, 15 unique, Appendix Fig S6), in a manner similar to fibrillar a-Syn and oligomeric Ab (Ohnishi et al, 2015). Fib-Tau also interacts with NKA (sodium-potassium ATPase) a3 subunit (identified through 27 peptides, 15 unique, Appendix Fig S6), in a manner similar to fibrillar a-Syn and oligomeric Ab (Ohnishi et al, 2015).…”

“…This finding strongly suggests that exogenous Fib-Tau may directly interact with excitatory PSD (postsynaptic density) super-complex (Loh et al, 2016). Fib-Tau also interacts with NKA (sodium-potassium ATPase) a3 subunit (identified through 27 peptides, 15 unique, Appendix Fig S6), in a manner similar to fibrillar a-Syn and oligomeric Ab (Ohnishi et al, 2015). Fib-Tau also interacts with the a1 subunit (identified through 17 peptides, 7 unique) and the b1 subunit (identified through 6 unique peptides) of NKA.…”

“…NKA a3 subunit was recently reported to interact with extracellular amylospheroids (Ohnishi et al, 2015) and a-Syn oligomers/fibrils . The minimal functional unit of NKA is either a3b1 or a1b1 complexes, the a3b1 complex being exclusively expressed in neurons.…”

“…The minimal functional unit of NKA is either a3b1 or a1b1 complexes, the a3b1 complex being exclusively expressed in neurons. NKA a3 subunit was recently reported to interact with extracellular amylospheroids (Ohnishi et al, 2015) and a-Syn oligomers/fibrils . While a-Syn fibril clusters acted as diffusion trap for NKA a3 subunit leading to compromised NKA activity , Fib-Tau clusters destabilized NKA.…”

Astrocytic transporters in Alzheimer's disease

“…With reference to the glial isoforms, exogenous application of Aβ [25][26][27][28][29][30][31][32][33][34][35] resulted in a decrease in α1 subunit protein levels (206). Most recently, the α3 neuronal specific Na + .K + -ATPase isoform is a target for Aβ assemblies, presenting a potential novel therapeutic strategy (207). (209)(210)(211).…”