Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

References

  1. Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002)

    Article  ADS  CAS  Google Scholar 

  2. Lesne, S. et al. A specific amyloid-β protein assembly in the brain impairs memory. Nature 440, 352–357 (2006)

    Article  ADS  CAS  Google Scholar 

  3. Cleary, J. P. et al. Natural oligomers of the amyloid-β protein specifically disrupt cognitive function. Nature Neurosci. 8, 79–84 (2005)

    Article  CAS  Google Scholar 

  4. Chromy, B. A. et al. Self-assembly of Aβ1–42 into globular neurotoxins. Biochemistry 42, 12749–12760 (2003)

    Article  CAS  Google Scholar 

  5. Lacor, P. N. et al. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J. Neurosci. 27, 796–807 (2007)

    Article  CAS  Google Scholar 

  6. Lacor, P. N. et al. Synaptic targeting by Alzheimer’s-related amyloid β oligomers. J. Neurosci. 24, 10191–10200 (2004)

    Article  CAS  Google Scholar 

  7. Walsh, D. M. et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo . Nature 416, 535–539 (2002)

    Article  ADS  CAS  Google Scholar 

  8. Shankar, G. M. et al. Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J. Neurosci. 27, 2866–2875 (2007)

    Article  CAS  Google Scholar 

  9. Shankar, G. M. et al. Amyloid-β protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nature Med. 14, 837–842 (2008)

    Article  CAS  Google Scholar 

  10. Hepler, R. W. et al. Solution state characterization of amyloid β-derived diffusible ligands. Biochemistry 45, 15157–15167 (2006)

    Article  CAS  Google Scholar 

  11. Lambert, M. P. et al. Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Proc. Natl Acad. Sci. USA 95, 6448–6453 (1998)

    Article  ADS  CAS  Google Scholar 

  12. Prusiner, S. B. Prions. Proc. Natl Acad. Sci. USA 95, 13363–13383 (1998)

    Article  ADS  CAS  Google Scholar 

  13. Yan, S. D. et al. RAGE and amyloid-β peptide neurotoxicity in Alzheimer’s disease. Nature 382, 685–691 (1996)

    Article  ADS  CAS  Google Scholar 

  14. Wang, H. Y. et al. β-Amyloid1–42 binds to α7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer’s disease pathology. J. Biol. Chem. 275, 5626–5632 (2000)

    Article  CAS  Google Scholar 

  15. Viles, J. H. et al. Copper binding to the prion protein: structural implications of four identical cooperative binding sites. Proc. Natl Acad. Sci. USA 96, 2042–2047 (1999)

    Article  ADS  CAS  Google Scholar 

  16. Jackson, G. S. et al. Location and properties of metal-binding sites on the human prion protein. Proc. Natl Acad. Sci. USA 98, 8531–8535 (2001)

    Article  ADS  CAS  Google Scholar 

  17. Baumann, F. et al. Lethal recessive myelin toxicity of prion protein lacking its central domain. EMBO J. 26, 538–547 (2007)

    Article  CAS  Google Scholar 

  18. Li, A. et al. Neonatal lethality in transgenic mice expressing prion protein with a deletion of residues 105–125. EMBO J. 26, 548–558 (2007)

    Article  Google Scholar 

  19. Riek, R. et al. NMR structure of the mouse prion protein domain PrP(121–321). Nature 382, 180–182 (1996)

    Article  ADS  CAS  Google Scholar 

  20. Bueler, H. et al. Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356, 577–582 (1992)

    Article  ADS  CAS  Google Scholar 

  21. Manson, J. C. et al. 129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal. Mol. Neurobiol. 8, 121–127 (1994)

    Article  CAS  Google Scholar 

  22. Lledo, P. M., Tremblay, P., DeArmond, S. J., Prusiner, S. B. & Nicoll, R. A. Mice deficient for prion protein exhibit normal neuronal excitability and synaptic transmission in the hippocampus. Proc. Natl Acad. Sci. USA 93, 2403–2407 (1996)

    Article  ADS  CAS  Google Scholar 

  23. Curtis, J., Errington, M., Bliss, T., Voss, K. & MacLeod, N. Age-dependent loss of PTP and LTP in the hippocampus of PrP-null mice. Neurobiol. Dis. 13, 55–62 (2003)

    Article  Google Scholar 

  24. Riemenschneider, M. et al. Prion protein codon 129 polymorphism and risk of Alzheimer disease. Neurology 63, 364–366 (2004)

    Article  CAS  Google Scholar 

  25. Papassotiropoulos, A. et al. The prion gene is associated with human long-term memory. Hum. Mol. Genet. 14, 2241–2246 (2005)

    Article  CAS  Google Scholar 

  26. Yehiely, F. et al. Identification of candidate proteins binding to prion protein. Neurobiol. Dis. 3, 339–355 (1997)

    Article  CAS  Google Scholar 

  27. Schmitt-Ulms, G. et al. Time-controlled transcardiac perfusion cross-linking for the study of protein interactions in complex tissues. Nature Biotechnol. 22, 724–731 (2004)

    Article  CAS  Google Scholar 

  28. Venkitaramani, D. V. et al. β-amyloid modulation of synaptic transmission and plasticity. J. Neurosci. 27, 11832–11837 (2007)

    Article  CAS  Google Scholar 

  29. Hsieh, H. et al. AMPAR removal underlies Aβ-induced synaptic depression and dendritic spine loss. Neuron 52, 831–843 (2006)

    Article  CAS  Google Scholar 

  30. Khosravani, H. et al. Prion protein attenuates excitotoxicity by inhibiting NMDA receptors. J. Cell Biol. 181, 551–565 (2008)

    Article  CAS  Google Scholar 

  31. Folta-Stogniew, E. Oligomeric states of proteins determined by size-exclusion chromatography coupled with light scattering, absorbance, and refractive index detectors. Methods Mol. Biol. 328, 97–112 (2006)

    CAS  PubMed  Google Scholar 

  32. Rajagopalan, S. et al. Neogenin mediates the action of repulsive guidance molecule. Nature Cell Biol. 6, 756–762 (2004)

    Article  CAS  Google Scholar 

  33. Fournier, A. E., GrandPre, T. & Strittmatter, S. M. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409, 341–346 (2001)

    Article  ADS  CAS  Google Scholar 

  34. Takahashi, T. et al. Plexin–neuropilin-1 complexes form functional semaphorin-3A receptors. Cell 99, 59–69 (1999)

    Article  CAS  Google Scholar 

  35. Takahashi, T., Nakamura, F., Jin, Z., Kalb, R. G. & Strittmatter, S. M. Semaphorins A and E act as antagonists of neuropilin-1 and agonists of neuropilin-2 receptors. Nature Neurosci. 1, 487–493 (1998)

    Article  CAS  Google Scholar 

  36. Weissmann, C. & Flechsig, E. PrP knock-out and PrP transgenic mice in prion research. Br. Med. Bull. 66, 43–60 (2003)

    Article  CAS  Google Scholar 

  37. Chen, S., Mange, A., Dong, L., Lehmann, S. & Schachner, M. Prion protein as trans-interacting partner for neurons is involved in neurite outgrowth and neuronal survival. Mol. Cell. Neurosci. 22, 227–233 (2003)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stephen M. Strittmatter.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-15 with Legends (PDF 3399 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07761

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing