Figure 2.

Slowed NMDA receptor desensitization is pathological only in conditions of prolonged excess of glutamate. Under normal conditions (WT), glutamate homeostasis is unperturbed and prevents glutamate accumulation, and NMDA receptors (NMDAR) undergo fast desensitization, thus limiting calcium entry. In the absence of PrP^C (PrP^C-null), NMDA receptor desensitization is slowed but glutamate homeostasis remains unperturbed, thus limited calcium entry occurs. However, in Alzheimer's disease (AD), Aβ oligomers bind to PrP^C and cause slowed NMDA receptor desensitization. This, in combination with Aβ-induced elevation of glutamate levels, for example by inhibiting glutamate re-uptake by astrocytic glutamate transporters, leads to enhanced calcium entry and pathology.