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Edited by Samuel H. Gellman, University of Wisconsin–Madison, Madison, WI, and approved October 8, 2020 (received for review May 8, 2020)
Significance
Amyloid β (Aβ) aggregation has been the therapeutic target of several Alzheimer’s disease (AD) clinical trials. Aβ exists in many different aggregated forms, making it exceedingly challenging to target. Evidence links intracellular Aβ accumulation and AD pathogenesis. We report that amino acids 1 to 30 of Aβ, Aβ (1–30), do not aggregate yet display cellular uptake stereospecificity when compared to its mirror image, suggesting that Aβ uptake is predominantly receptor-mediated and may be independent from its aggregation state. Additionally, we found Aβ (1–30) internalization to depend on PrPC expression. Aβ (1–30) thus represents a powerful tool to study mechanisms of Aβ cellular internalization and suggests that Aβ uptake could be modulated by therapeutically targeting high-affinity Aβ receptors.
Abstract
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 Aβ uptake is aggregation-dependent and whether it is sequence-specific. We recently reported that the neuronal uptake of Aβ 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 Aβ-induced toxicity and of neuronal Aβ internalization. Here, we report that the soluble, nonfibrillizing Aβ (1–30) peptide recapitulates full-length Aβ stereoselective cellular uptake, allowing us to decouple aggregation from cellular, receptor-mediated internalization. Moreover, we found that Aβ (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 Aβ (1–30). Our findings therefore identify a specific sequence within Aβ 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 Aβ cellular internalization. Taken together, our results highlight the potential of targeting cellular surface receptors to inhibit Aβ cellular uptake as an alternative route for future therapeutic development for Alzheimer’s disease.
- Alzheimer’s disease
- amyloid β
- prion protein (PrP)
- mirror-image peptides
- receptor-mediated internalization
Footnotes
↵1A.R.F. and G.P.R. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: glennm{at}ucsc.edu or jraskato{at}ucsc.edu.
Author contributions: A.R.F., G.P.R., T.S.F., R.S.L., G.L.M., and J.A.R. designed research; A.R.F., G.P.R., K.C., A.S., and K.Y. performed research; A.R.F., G.P.R., K.C., A.S., K.Y., R.S.L., G.L.M., and J.A.R. contributed new reagents/analytic tools; A.R.F., G.P.R., K.C., A.S., T.S.F., K.Y., R.S.L., G.L.M., and J.A.R. analyzed data; and A.R.F., G.P.R., G.L.M., and J.A.R. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2009238117/-/DCSupplemental.
Data Availability.
All study data are included in the paper and SI Appendix.
Published under the PNAS license.
References
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Evidence for aggregation-independent, PrPC-mediated Aβ cellular internalization
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- Chemistry
- Biological Sciences
- Biochemistry
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