Figure 8.

Crosstalk between carnosine, metals, APP, and PrP at the synapse. Zn, Cu, and glutamate accumulate in synaptic vesicles and are released into synaptic clefts during neuronal excitation. Under normal physiological conditions, APP binds Cu and regulates Cu levels by reducing Cu²⁺ to Cu⁺. The normal prion protein isoform PrP^C binds to Cu at its N-terminal domain and regulates synaptic Cu levels. It is possible that PrP^C provides Cu to APP or to NMDA-type glutamate receptors, thereby influencing the production of AβP or neuronal excitability. Both APP and PrP^C reportedly attenuate Cu-induced toxicity. PrP^C also controls Zn²⁺ influx into the cells as an analogue of ZIP transporters, with AMPA-type glutamate receptors regulating synaptic Zn²⁺ levels. ZnT-1 is localized to postsynaptic membranes that express NMDA-type glutamate receptors and regulates Zn homeostasis. APP binds ferroportin (FPN) and regulates Fe²⁺ efflux. By contrast, PrP^C acts as ferrireductase to regulate the Fe²⁺/Fe³⁺ ratio in synapses. The Fe²⁺ ions are transferred to enzymes, including neurotransmitter synthetases. Fe levels also regulate the expression of APP. It is plausible that carnosine binds to Zn²⁺ and Cu²⁺ and regulates homeostasis in these metals. ZnT-1: zinc transporter 1; NMDA-R: NMDA-type glutamate receptor; MT-3: metallothionein 3; CAR: carnosine.