Evidence For Aggregation-Independent, Prpc-Mediated A Beta Cellular Internalization

Evidence linking amyloid beta (A beta) cellular uptake and toxicity has burgeoned, and mechanisms underlying this association are subjects of active research. Two major, interconnected questions are whether A beta uptake is aggregation-dependent and whether it is sequence-specific. We recently reported that the neuronal uptake of A beta depends significantly on peptide chirality, suggesting that the process is predominantly receptor-mediated. Over the past decade, the cellular prion protein (PrPC) has emerged as an important mediator of A beta-induced toxicity and of neuronal A beta internalization. Here, we report that the soluble, nonfibrillizing A beta (1-30) peptide recapitulates full-length A beta stereoselective cellular uptake, allowing us to decouple aggregation from cellular, receptor me diated internalization. Moreover, we found that A beta (1-30) uptake is also dependent on PrPC expression. NMR-based molecularlevel characterization identified the docking site on PrPC that underlies the stereoselective binding of A beta (1-30). Our findings therefore identify a specific sequence within A beta that is responsible for the recognition of the peptide by PrPC, as well as PrPC-dependent cellular uptake. Further uptake stereodifferentiation in PrPC-free cells points toward additional receptor-mediated interactions as likely contributors for A beta cellular internalization. Taken together, our results highlight the potential of targeting cellular surface receptors to inhibit A beta cellular uptake as an alternative route for future therapeutic development for Alzheimer's disease.