Amin L, Harris DA.
Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers.
Nat Commun. 2021 Jun 8;12(1):3451.
PubMed.
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.
References:
Willbold D, Strodel B, Schröder GF, Hoyer W, Heise H.
Amyloid-type Protein Aggregation and Prion-like Properties of Amyloids.
Chem Rev. 2021 Jul 14;121(13):8285-8307. Epub 2021 Jun 17
PubMed.
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.
References:
Corbett GT, Wang Z, Hong W, Colom-Cadena M, Rose J, Liao M, Asfaw A, Hall TC, Ding L, DeSousa A, Frosch MP, Collinge J, Harris DA, Perkinton MS, Spires-Jones TL, Young-Pearse TL, Billinton A, Walsh DM.
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.
Bove-Fenderson E, Urano R, Straub JE, Harris DA.
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.
Hellstrand E, Boland B, Walsh DM, Linse S.
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.
Walsh DM, Selkoe DJ.
A beta oligomers - a decade of discovery.
J Neurochem. 2007 Jun;101(5):1172-84.
PubMed.
Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL.
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.
Walsh DM, Hartley DM, Selkoe DJ.
The many faces of Aβ: structures and activity.
Current Medicinal Chemistry-Immunology, Endocrine and Metabolic agents 3. December 2003
Biasini E, Unterberger U, Solomon IH, Massignan T, Senatore A, Bian H, Voigtlaender T, Bowman FP, Bonetto V, Chiesa R, Luebke J, Toselli P, Harris DA.
A mutant prion protein sensitizes neurons to glutamate-induced excitotoxicity.
J Neurosci. 2013 Feb 6;33(6):2408-18.
PubMed.
Mallucci GR, White MD, Farmer M, Dickinson A, Khatun H, Powell AD, Brandner S, Jefferys JG, Collinge J.
Targeting cellular prion protein reverses early cognitive deficits and neurophysiological dysfunction in prion-infected mice.
Neuron. 2007 Feb 1;53(3):325-35.
PubMed.
Mengel D, Hong W, Corbett GT, Liu W, DeSousa A, Solforosi L, Fang C, Frosch MP, Collinge J, Harris DA, Walsh DM.
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.
Comments
Heinrich Heine University Düsseldorf; Forschungszentrum Jülich; and Priavoid GmbH, Düsseldorf, Germany
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.
References:
Willbold D, Strodel B, Schröder GF, Hoyer W, Heise H. Amyloid-type Protein Aggregation and Prion-like Properties of Amyloids. Chem Rev. 2021 Jul 14;121(13):8285-8307. Epub 2021 Jun 17 PubMed.
View all comments by Dieter WillboldBrigham & Women's Hospital
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.
References:
Corbett GT, Wang Z, Hong W, Colom-Cadena M, Rose J, Liao M, Asfaw A, Hall TC, Ding L, DeSousa A, Frosch MP, Collinge J, Harris DA, Perkinton MS, Spires-Jones TL, Young-Pearse TL, Billinton A, Walsh DM. 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.
Bove-Fenderson E, Urano R, Straub JE, Harris DA. 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.
Hellstrand E, Boland B, Walsh DM, Linse S. 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.
Walsh DM, Selkoe DJ. A beta oligomers - a decade of discovery. J Neurochem. 2007 Jun;101(5):1172-84. PubMed.
Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL. 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.
Walsh DM, Hartley DM, Selkoe DJ. The many faces of Aβ: structures and activity. Current Medicinal Chemistry-Immunology, Endocrine and Metabolic agents 3. December 2003
Biasini E, Unterberger U, Solomon IH, Massignan T, Senatore A, Bian H, Voigtlaender T, Bowman FP, Bonetto V, Chiesa R, Luebke J, Toselli P, Harris DA. A mutant prion protein sensitizes neurons to glutamate-induced excitotoxicity. J Neurosci. 2013 Feb 6;33(6):2408-18. PubMed.
Mallucci GR, White MD, Farmer M, Dickinson A, Khatun H, Powell AD, Brandner S, Jefferys JG, Collinge J. Targeting cellular prion protein reverses early cognitive deficits and neurophysiological dysfunction in prion-infected mice. Neuron. 2007 Feb 1;53(3):325-35. PubMed.
Mengel D, Hong W, Corbett GT, Liu W, DeSousa A, Solforosi L, Fang C, Frosch MP, Collinge J, Harris DA, Walsh DM. 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.
View all comments by Dominic WalshMake a Comment
To make a comment you must login or register.