Editors' ChoiceNeuroscience

Destructive Duo

See allHide authors and affiliations

Science Signaling  03 Mar 2009:
Vol. 2, Issue 60, pp. ec81
DOI: 10.1126/scisignal.260ec81

Alzheimer’s disease (AD) is associated with the accumulation of insoluble β-amyloid (Aβ) protein to form plaques in the brain; however, the formation of soluble, oligomeric Aβ precedes plaque formation. Oligomeric Aβ blocks hippocampal long-term potentiation (LTP), among other effects, but how these effects are mediated is unclear. Laurén et al. made a synthetic, biotin-tagged form of Aβ peptide that could be denatured to form oligomeric Aβ. Oligomeric, but not monomeric, Aβ bound to hippocampal neurons, being most concentrated at postsynaptic densities. A screen of a mouse brain cDNA library, expressed in COS-7 cells, for binding of oligomeric Aβ identified the cellular prion protein (PrPC) as a candidate. Oligomeric Aβ did not bind to COS-7 cells expressing PrPSc, a misfolded version of PrPC that causes Creutzfeldt-Jakob disease (CJD). Although PrPC was the best candidate from the in vitro screen, binding of oligomeric Aβ to hippocampal neurons from PrPC-deficient (Prnp–/–) mice was 50% of that to neurons from wild-type (WT) mice, indicating that other potential receptors might exist. Analysis of deletion mutants of PrP mapped the oligomeric Aβ binding site to between residues 95 and 110. Electrophysiology experiments showed that oligomeric Aβ blocked LTP in hippocampal slices from WT mice, which was prevented by an anti-PrP antibody, but had no effect on LTP in slices from Prnp–/– mice. Together, these data suggest that PrPC mediates oligomeric Aβ-induced synaptic dysfunction. As Cisse and Mucke discuss, this potential link between AD and CJD should lead to interesting therapeutic possibilities.

J. Laurén, D. A. Gimbel, H. B. Nygaard, J. W. Gilbert, S. M. Strittmatter, Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers. Nature 457, 1128–1132 (2009). [PubMed]

M. Cisse, L. Mucke, A prion protein connection. Nature 457, 1090–1091 (2009). [PubMed]

Stay Connected to Science Signaling