Abstract
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.
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Acknowledgements
H.B.N. is an Ellison Medical Foundation American Federation for Aging Research Postdoctoral Fellow and S.M.S. is a member of the Kavli Institute for Neuroscience at Yale University. We acknowledge support from the US National Institutes of Health (R01AG034924, R37NS033020, R01NS074319 and P30DA018343), the Falk Medical Research Trust and the Alzheimer's Association (S.M.S.), and from the US National Institutes of Health (R01NS47433 and R01NS073502; T.W.).
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J.W.U., H.B.N., J.K.H., M.A.K., M.S., A.V., E.C.G. and S.M.S. designed various aspects of the research. J.W.U., H.B.N., J.K.H., M.S. and E.C.G. performed the research. J.W.U., H.B.N., J.K.H., M.S., T.W., E.C.G. and S.M.S. analyzed various parts of the data and wrote the paper.
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S.M.S. is a co-founder of Axerion Therapeutics, which seeks to develop NgR- and PrP-based therapeutics.
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Supplementary Text and Figures
Supplementary Figures 1–10 (PDF 28592 kb)
Supplementary Movie 1
Example of NMDA-induced intracellular calcium signal. (MOV 28335 kb)
Supplementary Movie 2
Example of three-dimensional reconstruction of images of dendritic spines. (MOV 4446 kb)
Supplementary Movie 3
Example of APP/PSen Transgenic Mouse Seizure. (WMV 10234 kb)
Supplementary Movie 4
Second Example of APP/PSen Transgenic Mouse Seizure. (WMV 9450 kb)
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Um, J., Nygaard, H., Heiss, J. et al. Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat Neurosci 15, 1227–1235 (2012). https://doi.org/10.1038/nn.3178
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DOI: https://doi.org/10.1038/nn.3178
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