Alzheimer amyloid-Î 2 oligomer bound to postsynaptic prion protein activates Fyn to impair neurons

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

Research output: Contribution to journalArticle

376 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1227-1235
Number of pages9
JournalNature Neuroscience
Volume15
Issue number9
DOIs
StatePublished - Sep 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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    Um, J. W., Nygaard, H. B., Heiss, J. K., Kostylev, M. A., Stagi, M., Vortmeyer, A., Wisniewski, T., Gunther, E. C., & Strittmatter, S. M. (2012). Alzheimer amyloid-Î 2 oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nature Neuroscience, 15(9), 1227-1235. https://doi.org/10.1038/nn.3178