Amyloid-beta (Aβ 2) oligomers are thought to trigger Alzheimer's disease pathophysiology. Cellular prion protein (PrP C) selectively binds oligomeric Aβ 2 and can mediate Alzheimer's diseaseg-related phenotypes. We examined the specificity, distribution and signaling of Aβ 2-PrP C complexes, seeking to understand how they might alter the function of NMDA receptors (NMDARs) in neurons. PrP C is enriched in postsynaptic densities, and Aβ 2-PrP C interaction leads to Fyn kinase activation. Soluble Aβ 2 assemblies derived from the brains of individuals with Alzheimer's disease interacted with PrP C to activate Fyn. Aβ 2 engagement of PrP C-Fyn signaling yielded phosphorylation of the NR2B subunit of NMDARs, which was coupled to an initial increase and then a loss of surface NMDARs. Aβ 2-induced dendritic spine loss and lactate dehydrogenase release required both PrP C and Fyn, and human familial Alzheimer's disease transgeneg-induced convulsive seizures did not occur in mice lacking PrP C. These results delineate an Aβ 2 oligomer signal transduction pathway that requires PrP C and Fyn to alter synaptic function, with deleterious consequences in Alzheimer's disease.
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