title: Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons.
abstract: Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer's disease pathophysiology. Cellular prion protein (PrP(C)) selectively binds oligomeric Aβ and can mediate Alzheimer's disease-related phenotypes. We examined the specificity, distribution and signaling of Aβ-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-PrP(C) interaction leads to Fyn kinase activation. Soluble Aβ assemblies derived from the brains of individuals with Alzheimer's disease interacted with PrP(C) to activate Fyn. Aβ 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-induced dendritic spine loss and lactate dehydrogenase release required both PrP(C) and Fyn, and human familial Alzheimer's disease transgene-induced convulsive seizures did not occur in mice lacking PrP(C). These results delineate an Aβ oligomer signal transduction pathway that requires PrP(C) and Fyn to alter synaptic function, with deleterious consequences in Alzheimer's disease.
authors: Cellular Neuroscience, Neurodegeneration and Repair Program, Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Ji Won
authors: JW
authors: Um
authors: Haakon B
authors: HB
authors: Nygaard
authors: Jacqueline K
authors: JK
authors: Heiss
authors: Mikhail A
authors: MA
authors: Kostylev
authors: Massimiliano
authors: M
authors: Stagi
authors: Alexander
authors: A
authors: Vortmeyer
authors: Thomas
authors: T
authors: Wisniewski
authors: Erik C
authors: EC
authors: Gunther
authors: Stephen M
authors: SM
authors: Strittmatter
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D020013:Calcium Signaling / Q000502:physiology; D002460:Cell Line; D049229:Dendritic Spines / Q000378:metabolism; D004569:Electroencephalography; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology*; D010766:Phosphorylation; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051076:Proto-Oncogene Proteins c-fyn / Q000502:physiology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism / Q000502:physiology; D012640:Seizures / Q000235:genetics / Q000517:prevention & control; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; C121001:NR2B NMDA receptor; D018621:PrPC Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn