.....In 2009, cellular prion protein (PrPC) was identified in a genome-wide screen as a high-affinity receptor for Aβ oligomers, and since then, many studies have explored the role of PrPC in Alzheimer's disease. Herein, I systematically assess the current level of target validation for PrPC in Alzheimer's disease and the merits of the identified approaches to therapeutically affect the PrPC:Aβ oligomer-interaction. The interaction of Aβ oligomers with PrPC in mice impairs hippocampal long-term potentiation, memory, and learning in a manner that involves Fyn, tau, and glutamate receptors. Furthermore, PrPC acts to catalyze the formation of certain Aβ oligomeric species in the synapse and may mediate the toxic effects of other β-sheet rich oligomers as well. Therapeutic approaches utilizing soluble PrPC ectodomain or monoclonal antibodies targeting PrPC can at least partially prevent the neurotoxic effects of Aβ oligomers in mice.