Figure 8.

Model for copper-induced APP dimerization at the synapse. A, Under resting conditions, the copper transporter ATP7A is predominantly localized at the Golgi apparatus, and the copper concentration within the synaptic cleft is low (light blue). Under these conditions, APP present at presynaptic and postsynaptic sites is mainly monomeric. B, NMDA receptor activation during synaptic transmission causes an ATP7A-mediated release of copper into the synaptic cleft (dark blue). Our results suggest that increasing copper concentrations promote dimerization of APP in both cis- and trans-cellular manner contributing to APP synaptogenic activity. In the insets, the domain organization of monomeric and dimeric APP is shown. The N-terminal E1 domain, subdivided in the GFLD (gray) and the CuBD (black), is linked via a flexible acidic region to the E2 domain, the juxtamembrane/TM region, and the cytosolic domain. The copper-binding sites in the GFLD and CuBD (indicated by blue circles) are crucial for cis- and trans-interactions. The TM region could additionally contribute to lateral dimerization and the E2 domain to trans-cellular dimerization. CTR1, Copper transporter 1; NMDAR, NMDA receptor; PM, plasma membrane.