These oligomers are composed smaller Aβ plaques, and are the most damaging to the integrity of a neuron. The precise mechanism of soluble Aβ oligomers directly inducing neurotoxicity is unknown, and experimental deletion of PRNP in animals has yielded several conflicting findings. When Aβ oligomers were injected into the cerebral ventricles of a mouse model of Alzheimer's, PRNP deletion did not offer protection, only anti-PrPC antibodies prevented long-term memory and spatial learning deficits. This would suggest either an unequal relation between PRNP and Aβ oligomer-mediated neurodegeneration or a site-specific relational significance. In the case of direct injection of Aβ oligomers into the hippocampus, PRNP-knockout mice were found to be indistinguishable from control with respect to both neuronal death rates and measurements of synaptic plasticity. It was further found that Aβ-oligomers bind to PrPC at the postsynaptic density, indirectly overactivating the NMDA receptor via the Fyn enzyme, resulting in excitotoxicity. Soluble Aβ oligomers also bind to PrPC at the dendritic spines, forming a complex with Fyn and excessively activating tau, another protein implicated in Alzheimer's. As the gene FYN codes for the enzyme Fyn, FYN-knockout mice display neither excitotoxic events nor dendritic spine shrinkage when injected with Aβ oligomers. In mammals, the full functional significance of PRNP remains unclear, as PRNP deletion has been prophylactically implemented by the cattle industry without apparent harm. In mice, this same deletion phenotypically varies between Alzheimer's mouse lines, as hAPPJ20 mice and TgCRND8 mice show a slight increase in epileptic activity, contributing to conflicting results when examining Alzheimer's survival rates. Of note, the deletion of PRNP in both APPswe and SEN1dE9, two other transgenic models of Alzheimer's, attenuated the epilepsy-induced death phenotype seen in a subset of these animals. Taken collectively, recent evidence suggests PRNP may be important for conducing the neurotoxic effects of soluble Aβ-oligomers and the emergent disease state of Alzheimer's. In humans, the methionine/valine polymorphism at codon 129 of PRNP (rs1799990) is most closely associated with Alzheimer's disease. Variant V allele carriers (VV and MV) show a 13% decreased risk with respect to developing Alzheimer's compared to the methionine homozygote (MM). However, the protective effects of variant V carriers have been found exclusively in Caucasians. The decreased risk in V allele carriers is further limited to late-onset Alzheimer's disease only (≥ 65 years). PRNP can also functionally interact with polymorphisms in two other genes implicated in Alzheimer's, PSEN1 and APOE, to compound