Here, we briefly review properties of the NMDA receptor and focus on evidence supporting a role for PrPC in preventing NMDA receptor-mediated excitotoxicity, a process that may contribute to the pathogenesis of a variety of disorders including ischemic stroke, Alzheimer's disease (AD), Huntington's disease, and epilepsy (Lai et al., 2014; Parsons and Raymond, 2014). Here, PRNP is linked to early-onset autosomal dominant Alzheimer disease.