Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons

Abstract

Here the authors show that the binding of amyloid-β (Aβ) oligomers to cellular prion protein (PrPc) activates Fyn kinase. Aβ stimulation of PrPc/Fyn signaling drives phosphorylation of the NR2B subunit of NMDA receptors, with a subsequent loss of receptor surface expression and dendritic spines. Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer's disease pathophysiology. Cellular prion protein (PrPC) selectively binds oligomeric Aβ and can mediate Alzheimer's disease–related phenotypes. We examined the specificity, distribution and signaling of Aβ-PrPC complexes, seeking to understand how they might alter the function of NMDA receptors (NMDARs) in neurons. PrPC is enriched in postsynaptic densities, and Aβ-PrPC interaction leads to Fyn kinase activation. Soluble Aβ assemblies derived from the brains of individuals with Alzheimer's disease interacted with PrPC to activate Fyn. Aβ engagement of PrPC-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-induced dendritic spine loss and lactate dehydrogenase release required both PrPC and Fyn, and human familial Alzheimer's disease transgene–induced convulsive seizures did not occur in mice lacking PrPC. These results delineate an Aβ oligomer signal transduction pathway that requires PrPC and Fyn to alter synaptic function, with deleterious consequences in Alzheimer's disease.