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

作者：Um, Ji Won; Nygaard, Haakon B.; Heiss, Jacqueline K.; Kostylev, Mikhail A.; Stagi, Massimiliano; Vortmeyer, Alexander; Wisniewski, Thomas; Gunther, Erik C.; Strittmatter, Stephen M.^*

来源：Nature Neuroscience, 2012, 15(9): 1227-U85.

DOI：10.1038/nn.3178

• LONG-TERM POTENTIATION
• D-ASPARTATE RECEPTOR
• NR2B-CONTAINING NMDA-RECEPTORS
• TYROSINE PHOSPHORYLATION
• SYNAPTIC PLASTICITY
• SIGNAL-TRANSDUCTION
• PROTEOMIC ANALYSIS
• MASS-SPECTROMETRY
• TRANSGENIC MICE
• MOUSE MODELS

Amyloid-beta (A beta) oligomers are thought to trigger Alzheimer's disease pathophysiology. Cellular prion protein (PrPC) selectively binds oligomeric A beta and can mediate Alzheimer's disease-related phenotypes. We examined the specificity, distribution and signaling of A beta-PrPC complexes, seeking to understand how they might alter the function of NMDA receptors (NMDARs) in neurons. PrPC is enriched in postsynaptic densities, and A beta-PrPC interaction leads to Fyn kinase activation. Soluble A beta assemblies derived from the brains of individuals with Alzheimer's disease interacted with PrPC to activate Fyn. A beta 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. A beta-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 A beta oligomer signal transduction pathway that requires PrPC and Fyn to alter synaptic function, with deleterious consequences in Alzheimer's disease.

• 出版日期2012-9