Amyloid-β and PrP^C: it takes two

For many researchers seeking to understand the pathophysiological basis of Alzheimer's disease (AD), soluble oligomeric forms of amyloid-β (Aβ) peptide, which can impair synaptic plasticity in vitro and in vivo, have recently become prime suspects. However, the mechanisms by which Aβ oligomers affect neuronal function were unknown. The unexpected results of a study by Strittmatter and colleagues now suggest that the cellular prion protein (PrP^C) might mediate the pathological actions of Aβ oligomers at neuronal synapses.

In order to identify the specific molecular targets of Aβ oligomers, the authors expressed each of a library of individual complementary DNAs (cDNAs) found in the mouse brain in COS-7 cells and examined the binding of synthetic biotin-tagged Aβ oligomers to the cells. They observed high levels of specific binding of Aβ oligomers to cells expressing mouse PrP^C (the non-infectious and non-toxic form of the protein). Purified PrP^C was also able to bind Aβ oligomers in a pull-down assay, confirming that there is a direct interaction between the proteins. Using mutated forms of PrP^C and antibodies that target specific regions of PrP^C, the authors showed that a specific charge cluster (amino acids 95–105) in the protein is responsible for Aβ oligomer binding.

The developmental stages at which PrP^C is expressed and its cellular localization in cultured hippocampal neurons also closely matched patterns of Aβ oligomer binding to neurons, further suggesting that the two are likely to interact in vivo. Next the authors investigated whether PrP^C has a role in Aβ oligomer-mediated pathology. In hippocampal slices taken from mice lacking PrP, or in slices pretreated with an antibody that blocked Aβ–PrP^C binding, the inhibition of long-term potentiation by soluble Aβ oligomers was abolished, suggesting that this interaction is crucial for the effects of Aβ oligomers at synapses.

These findings implicate PrP^C in the pathological effects of soluble Aβ oligomers at synapses, providing a new potential target for therapeutic approaches. Further work is required to determine how Aβ–PrP^C binding influences synaptic function and to demonstrate the importance of this interaction to disease progression in vivo.