Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers


A pathological hallmark of Alzheimer’s disease is an accumulation of insoluble plaque containing the amyloid-β peptide of 40–42 amino acid residues1. Prefibrillar, soluble oligomers of amyloid-β have been recognized to be early and key intermediates in Alzheimer’s-disease-related synaptic dysfunction2,3,4,5,6,7,8,9. At nanomolar concentrations, soluble amyloid-β oligomers block hippocampal long-term potentiation7, cause dendritic spine retraction from pyramidal cells5,8 and impair rodent spatial memory2. Soluble amyloid-β oligomers have been prepared from chemical syntheses, transfected cell culture supernatants, transgenic mouse brain and human Alzheimer’s disease brain2,4,7,9. Together, these data imply a high-affinity cell-surface receptor for soluble amyloid-β oligomers on neurons—one that is central to the pathophysiological process in Alzheimer’s disease. Here we identify the cellular prion protein (PrPC) as an amyloid-β-oligomer receptor by expression cloning. Amyloid-β oligomers bind with nanomolar affinity to PrPC, but the interaction does not require the infectious PrPSc conformation. Synaptic responsiveness in hippocampal slices from young adult PrP null mice is normal, but the amyloid-β oligomer blockade of long-term potentiation is absent. Anti-PrP antibodies prevent amyloid-β-oligomer binding to PrPC and rescue synaptic plasticity in hippocampal slices from oligomeric amyloid-β. Thus, PrPC is a mediator of amyloid-β-oligomer-induced synaptic dysfunction, and PrPC-specific pharmaceuticals may have therapeutic potential for Alzheimer’s disease.

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Figure 1: Oligomeric Aβ42 binds to neurons and to cells expressing PrPC.
Figure 2: Characterization of Aβ42 oligomer binding sites.
Figure 3: Aβ42 oligomers bind to residues 95–110 of PrPC.
Figure 4: PrP C is required for Aβ42 oligomer inhibition of hippocampal LTP.


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We thank S. Tomita for cRNAs encoding GluR1–4 and stargazin (also known as CACNG2), B. Chesebro for providing us the Prnp null mice, M. Schachner for providing the PrP–Fc expression vector, E. Flechsig, C. Weismann and D. Harris for providing the PrPC deletion expression plasmids, D. Westaway for the Sprn expression plasmid and P. Seeburg for N-methyl-d-aspartate receptor subunit cDNAs. We thank S. Sodi for assistance with mouse husbandry. We thank E. Folta-Stogniew for SEC, and C. Rahner and M. Graham for electron microscopy. J.L. is a Brown-Coxe Postdoctoral Fellow, J.W.G. is supported by NIH Medical Scientist training Program grant 5T32GN07205, and S.M.S. is a member of the Kavli Institute for Neuroscience at Yale University. This work was supported by research grants from the Falk Medical Research Trust and the NIH to S.M.S. The SEC was supported by a NIDA-funded Neuroproteomic Center.

Author Contributions J.L. performed the amyloid-β binding and expression cloning experiments, D.A.G. conducted mouse breeding and tissue biochemistry, S.M.S. and H.B.N. performed the hippocampal electrophysiology experiments, and S.M.S., J.W.G. and J.L. performed the X. laevis studies. S.M.S. supervised all experiments. All authors participated in writing the manuscript.

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Correspondence to Stephen M. Strittmatter.

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Laurén, J., Gimbel, D., Nygaard, H. et al. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers. Nature 457, 1128–1132 (2009). https://doi.org/10.1038/nature07761

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