Eye of the dSTORM. Super resolution microscopy reveals that PrP (green, arrowed) only binds to one end of an Aβ fibril (red). [Courtesy of Amin and Harris, Nature Communications.]

Though the function, if any, of Aβ remains mysterious, there is no shortage of proposed Aβ “receptors.” Evidence for more than a dozen has surfaced, with no real consensus emerging about how they change the tide of Aβ biology, or how relevant they truly are in Alzheimer's disease. Now Ladan Amin in the lab of David Harris at Boston University School of Medicine, has taken the field by storm. dSTORM, to be precise, aka direct stochastic optical reconstruction microscopy. This super-resolution technique would knock the clogs off van Leeuwenhoek since it brings into focus structures as teeny as 20 nM wide. Combining this method of direct imaging with biochemical polymerization assays, the scientists detailed how individual cellular prion protein molecules flirt with Aβ. In the June 8 Nature Communications, they report that by binding to the rapidly elongating end of a fibril, PrP shuts down its growth, leading to the generation of a much greater number of oligomers instead. Two other purported cell-surface receptors, LiLrB2 and FcγRIIb, behave similarly. All three bind and stabilize protofibrils and oligomers, and the authors believe that by trapping such entities on the neuronal surface, the receptors exacerbate neurotoxicity.

  • Prion protein binds to the fast-growing end of Aβ fibrils.
  • This neuronal receptor stabilizes toxic oligomers and protofibrils.
  • Ditto for the purported Aβ receptors LiLrB2 and FcγRIIb.

Researchers in Stephen Strittmatter’s lab at Yale University, New Haven, Connecticut, were the first to report that Aβ binds cellular prion protein, an association that has held up in other studies (Feb 2009 conference news; Barry et al., 2011Feb 2020 news). Harris’s group found that PrP prevented elongation of Aβ fibrils, but didn't know why (Bove-Fenderson et al., 2017). 

Aβ fibrils grow when a monomer binds to either end, but because each end has a different shape, one end binds monomer more readily. Now, with a combination of dSTORM and structured illumination microscopy, Amin reports that PrP binds exclusively to this fast-growing end (see images above and below).

PrP’s Preference. Aβ fibrils form when monomers (green) bind to either end of a misfolded Aβ seed (red). PrP (purple) only binds to the fibril end that grows fast. [Courtesy of Amin and Harris, Nature Communications.]

The upshot? In solution, PrP promotes the formation of a multitude of small fibrils, rather than fewer, longer species. Amin also found that PrP binds synthetic protofibrils in a similar fashion, i.e., only on one end. Protofibrils are smaller than the fibrils found in amyloid plaques and are thought to be more toxic (Oct 1999 news; June 2008 news; Jan 2017 news). The prion protein also bound Aβ-derived diffusible ligands. ADDLs are a synthetic form of Aβ oligomers that assume globular or ellipsoid shapes (Lambert et al., 1998). Again, PrP seemed to bind asymmetrically to these species, favoring one side. 

Short, but Not Sweet. Hippocampal neurons lose dendritic spines when doused with Aβ that has been allowed to form fibrils. Adding PrP keeps fibrils short, making the brew more toxic to spines (right panels). [Courtesy of Amin and Harris, Nature Communications.]

Is this binding of any consequence in vivo? The authors began to test this by examining the effects of various Aβ species on dendritic spines. When incubated with ADDLs or protofibrils before they were added to hippocampal neurons, PrP suppressed spine loss. In a slightly more quantitative experiment, Amin allowed Aβ to polymerize in the presence of growing concentrations of PrP to see if its penchant for keeping Aβ fibrils short had knock-on effects. Sure enough, when just enough PrP was spiked into the polymerization step, twice as many spines vanished after the mixture was added to the neurons (see image above).

Toxic Model. In vitro, Aβ receptors (green) retard the elongation of Aβ fibrils (top). Receptors also bind small oligomers and protofibrils (bottom left). In vivo, these receptors may trap smaller Aβ species on the neuronal cell surface, increasing the likelihood of a toxic response. [Courtesy of Amin and Harris, Nature Communications.]

Curiously, LiLrB2 and FcγRIIb seem to work in the same fashion. Extracellular domains of both blocked elongation of fibrils, culminating in Aβ species that were more toxic. These two cell-surface receptors are thought to be bind the notoriously sticky Aβ via their immunoglobulin-binding domains, which bear no structural resemblance to PrP. “It remains to be determined how structurally diverse receptors and chaperones selectively recognize localized binding sites on Aβ fibrils and oligomers,” write the authors. “One possibility is that Aβ binding induces conformational changes in the receptors that enhance their affinity for specific structural features on these assemblies.”

As for the physiological importance of this binding, Amin and Harris believe that from their perch on the cell surface, PrP and other receptors influence Aβ polymerization in the extracellular space, trapping nascent oligomers or protofibrils and increasing their chances of unleashing a wave of neurotoxic signals.—Tom Fagan


  1. Amyloids play an important role in neurodegenerative diseases. Although it is still not clear how amyloid growth, in general, is causing toxicity, cells and organisms must, during evolution, have developed strategies and molecules that oppose amyloid-related toxicity. In our recently published review on amyloid-type protein aggregation (Willbold et al., 2021), we speculate whether the cellular form of the prion protein (PrPC) is such a molecule.

    This may even be the long-sought function of PrPC. Versions of PrPC that have lost their membrane anchoring by protease cleavage have been reported to decrease cytotoxicity of amyloid fibrils. Membrane anchored PrPC , however, has been described to mediate toxicity from amyloid fibrils and oligomers via mGluR5 and Fyn.

    This new work by Ladan Amin and David Harris is impressively demonstrating the highly specific binding of PrPC to the fast-growing ends of amyloid fibrils and oligomers. This is exactly what one would expect from a molecule evolutionarily developed for slowing fibril growth and thus reducing the general toxicity of fibrils. That said, the specific and well-described role of membrane-anchored PrPC in mediating cytotoxicity of amyloid fibrils is calling for more investigation of the “normal” physiological function of PrPC.


    . Amyloid-type Protein Aggregation and Prion-like Properties of Amyloids. Chem Rev. 2021 Jul 14;121(13):8285-8307. Epub 2021 Jun 17 PubMed.

  2. This report builds on compelling data from multiple laboratories demonstrating that PrP preferentially binds to soluble Aβ aggregates, weakly interacts with Aβ fibrils, and shows little affinity for Aβ monomers (reviewed in Corbett et al., 2020). The current study is an extension of a 2017 study, which used a continuous ThT flavin assay to impute that PrP inhibits Aβ fibril elongation, but does not alter primary or secondary nucleation (Bove-Fenderson et al., 2017; Hellstrand et al., 2010). Here, Amin and Harris used high-resolution microscopy to directly confirm that PrP inhibits elongation. They show that Aβ growth is polarized and that PrP retards fibrillogenesis by binding to the fast-growing end of the aggregate.

    While these studies are elegant, it is worth mentioning that structure illumination microscopy (SIM), the predominant technique used, requires exogenous labeling and that the resolution of this technique (100 nm) limits the species detected. The fact that aggregates, which by definition must be larger than 100 nm, are detectable in zero time point samples (and in certain experiments this is when maximal aggregate density was detected—Fig. 2e) indicate that the monomer solutions used were either not truly monomeric, or that drying of samples required for SIM gives rise to artefacts. These limitations do not detract from the findings that PrP causes a concentration-dependent reduction of fibril length and is selectively associated with faster growing fibril ends.

    Since soluble Aβ aggregates are thought to be more toxic than end-stage fibrils (Walsh and Selkoe, 2007), the authors went on to investigate the effects of PrP on synthetic soluble aggregates referred to as ADDLs, and those generated when Aβ is incubated with PrP (Lambert et al., 1998). Using dSTORM, which has better resolution compared to SIM (20 nm vs. 100 nm), they show that PrP can bind directly to ADDLs, and when co-incubated at sub-stochiometric concentrations with putatively monomeric Aβ, PrP prevents fibril growth and accentuates Aβ-mediated toxicity. In contrast, high concentrations of PrP—presumably by saturating PrP binding—ameliorated toxicity. These data are consistent with the notion that toxicity mediated by small Aβ aggregates is due to the dynamic nature of these aggregates and that toxicity can be neutralized by directly binding to their most dynamic surfaces (Walsh et al., 2003). 

    Amin and Harris also investigated whether two other receptors implicated in Aβ toxicity had a proclivity for growing aggregates. The authors showed that although not as potent as PrP, both FcγRIIb and LilrB2 inhibited the growth of Aβ fibrils and increased the number of small aggregates. These preliminary experiments suggest that FcγRIIb and LilrB2 may also mediate toxicity by binding to the dynamic surface of aggregates. In this regard it should be noted that PrPc is absolutely required for prion toxicity (reviewed in Biasini and Harris, 2013). Thus, if PrPc recognizes generic dynamic surfaces on PrP and Aβ aggregates, it must be distinct from other Aβ receptors, otherwise they too would recognize toxic prions and PrPc suppression would not prevent toxicity. But even in the presence of high levels of PrP aggregates, ablation or immunoneutralization of PrPc is known to prevent toxicity (e.g., Mallucci et al., 2007). 

    As with many good studies, this report by Amin and Harris raises numerous questions. For instance, if at least three different Aβ receptors act by the same, or similar, mechanism, why then does suppressing the expression of each one protect against toxicities mediated by apparently similar soluble aggregates? Beyond PrPc, FcγRIIb, and LilrB2, what about other putative Aβ receptors? Do they too recognize the dynamic surfaces of aggregates? And what role, if any, does the secreted form of PrP (N1) play? This form of PrP retains Aβ binding sites I and II, and can ameliorate toxicity mediated by Aβ present in the soluble phase of AD brain (Mengel et al., 2019), but apparently does not inhibit in vitro fibril elongation (Bove-Fenderson et al., 2017). 

    Most importantly, what relevance do Amin and Harris’ findings have for the development of anti-Aβ therapies? If multiple receptors were to act by recognizing the dynamic surface of Aβ aggregates, then targeting individual receptors would not be beneficial. On the other hand, since extensive networks of end-stage fibrils are present even in stage 1 AD, targeting the dynamic surface of aggregates would require not just prevention of elongation, but the sequestration of soluble aggregates generated by primary and secondary nucleation.


    . PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins. Acta Neuropathol. 2020 Mar;139(3):503-526. Epub 2019 Dec 18 PubMed.

    . Cellular prion protein targets amyloid-β fibril ends via its C-terminal domain to prevent elongation. J Biol Chem. 2017 Oct 13;292(41):16858-16871. Epub 2017 Aug 23 PubMed.

    . Amyloid β-protein aggregation produces highly reproducible kinetic data and occurs by a two-phase process. ACS Chem Neurosci. 2010 Jan 20;1(1):13-8. PubMed.

    . A beta oligomers - a decade of discovery. J Neurochem. 2007 Jun;101(5):1172-84. PubMed.

    . Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448-53. PubMed.

    . The many faces of Aβ: structures and activity. Current Medicinal Chemistry-Immunology, Endocrine and Metabolic agents 3. December 2003

    . A mutant prion protein sensitizes neurons to glutamate-induced excitotoxicity. J Neurosci. 2013 Feb 6;33(6):2408-18. PubMed.

    . Targeting cellular prion protein reverses early cognitive deficits and neurophysiological dysfunction in prion-infected mice. Neuron. 2007 Feb 1;53(3):325-35. PubMed.

    . PrP-grafted antibodies bind certain amyloid β-protein aggregates, but do not prevent toxicity. Brain Res. 2019 May 1;1710:125-135. Epub 2018 Dec 26 PubMed.

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News Citations

  1. Keystone: Partners in Crime—Do Aβ and Prion Protein Pummel Plasticity?
  2. A Central Role for Prion Protein in Neurodegeneration?
  3. Toxic Protofibrillar Aβ
  4. Paper Alert: Patient Aβ Dimers Impair Plasticity, Memory
  5. Sweat the Small Stuff: Teeniest Aβ Oligomers Wreak Most Havoc

Paper Citations

  1. . Alzheimer's disease brain-derived amyloid-β-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein. J Neurosci. 2011 May 18;31(20):7259-63. PubMed.
  2. . Cellular prion protein targets amyloid-β fibril ends via its C-terminal domain to prevent elongation. J Biol Chem. 2017 Oct 13;292(41):16858-16871. Epub 2017 Aug 23 PubMed.
  3. . Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448-53. PubMed.

Further Reading


  1. . Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Aβo-PrPC binding and downstream pathways. Chem Sci. 2021 Feb 1;12(10):3768-3785. PubMed.

Primary Papers

  1. . Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers. Nat Commun. 2021 Jun 8;12(1):3451. PubMed.