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Evidence linking amyloid beta (Aβ) cellular uptake and toxicity has burgeoned, and mechanisms underlying this association are subjects of active research. Two major, interconnected questions are whether uptake is aggregation-dependent and whether it is sequence-specific. We recently reported that the neuronal uptake of 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 -induced toxicity and of neuronal internalization. Here, we report that the soluble, nonfibrillizing (1-30) peptide recapitulates full-length stereoselective cellular uptake, allowing us to decouple aggregation from cellular, receptor-mediated internalization. Moreover, we found that (1-30) uptake is also dependent on PrPC expression. NMR-based molecular-level characterization identified the docking site on PrPC that underlies the stereoselective binding of (1-30). Our findings therefore identify a specific sequence within 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 cellular internalization. Taken together, our results highlight the potential of targeting cellular surface receptors to inhibit cellular uptake as an alternative route for future therapeutic development for Alzheimer's disease.


Alejandro R Foley, Graham P Roseman, Ka Chan, Amanda Smart, Thomas S Finn, Kevin Yang, R Scott Lokey, Glenn L Millhauser, Jevgenij A Raskatov. Evidence for aggregation-independent, PrPC-mediated Aβ cellular internalization. Proceedings of the National Academy of Sciences of the United States of America. 2020 Nov 17;117(46):28625-28631

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PMID: 33139554

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