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., 2011; Feb 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
- Keystone: Partners in Crime—Do Aβ and Prion Protein Pummel Plasticity?
- A Central Role for Prion Protein in Neurodegeneration?
- Toxic Protofibrillar Aβ
- Paper Alert: Patient Aβ Dimers Impair Plasticity, Memory
- Sweat the Small Stuff: Teeniest Aβ Oligomers Wreak Most Havoc
- Barry AE, Klyubin I, Mc Donald JM, Mably AJ, Farrell MA, Scott M, Walsh DM, Rowan MJ. 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.
- 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.
- 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.
- Grayson JD, Baumgartner MP, Santos Souza CD, Dawes SJ, El Idrissi IG, Louth JC, Stimpson S, Mead E, Dunbar C, Wolak J, Sharman G, Evans D, Zhuravleva A, Roldan MS, Colabufo NA, Ning K, Garwood C, Thomas JA, Partridge BM, de la Vega de Leon A, Gillet VJ, Rauter AP, Chen B. 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.
- 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.