An evaluation of the self-assembly enhancing properties of cell-derived hexameric amyloid-β.

[en] A key hallmark of Alzheimer's disease is the extracellular deposition of amyloid plaques composed primarily of the amyloidogenic amyloid-β (Aβ) peptide. The Aβ peptide is a product of sequential cleavage of the Amyloid Precursor Protein, the first step of which gives rise to a C-terminal Fragment (C99). Cleavage of C99 by γ-secretase activity releases Aβ of several lengths and the Aβ42 isoform in particular has been identified as being neurotoxic. The misfolding of Aβ leads to subsequent amyloid fibril formation by nucleated polymerisation. This requires an initial and critical nucleus for self-assembly. Here, we identify and characterise the composition and self-assembly properties of cell-derived hexameric Aβ42 and show its assembly enhancing properties which are dependent on the Aβ monomer availability. Identification of nucleating assemblies that contribute to self-assembly in this way may serve as therapeutic targets to prevent the formation of toxic oligomers.

Disciplines :

Chemistry

Author, co-author :

Vadukul, Devkee M.

Vrancx, Céline

Burguet, Pierre ; Université de Liège - ULiège > Département de chimie (sciences) > Laboratoire de spectrométrie de masse (L.S.M.)

Contino, Sabrina

Suelves, Nuria

Serpell, Louise C.

Quinton, Loïc ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie biologique

Kienlen-Campard, Pascal

Language :

English

Title :

An evaluation of the self-assembly enhancing properties of cell-derived hexameric amyloid-β.

Publication date :

2021

Journal title :

Scientific Reports

eISSN :

2045-2322

Publisher :

Nature Publishing Group, London, United Kingdom

Volume :

Issue :

Pages :

11570

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 25 August 2021

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Bibliography

Selkoe, D. J. & Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 8, 595–608. 10.15252/emmm.201606210 (2016). DOI: 10.15252/emmm.201606210
Takami, M. et al. gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J. Neurosci. 29, 13042–13052. 10.1523/JNEUROSCI.2362-09.2009 (2009). DOI: 10.1523/JNEUROSCI.2362-09.2009
Qi-Takahara, Y. et al. Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase. J. Neurosci. 25, 436–445. 10.1523/JNEUROSCI.1575-04.2005 (2005). DOI: 10.1523/JNEUROSCI.1575-04.2005
Bolduc, D. M., Montagna, D. R., Seghers, M. C., Wolfe, M. S. & Selkoe, D. J. The amyloid-beta forming tripeptide cleavage mechanism of gamma-secretase. Elife 10.7554/eLife.17578 (2016). DOI: 10.7554/eLife.17578
Serpell, L. C. Alzheimer’s amyloid fibrils: structure and assembly. Biochim. Biophys. Acta 1502, 16–30. 10.1016/s0925-4439(00)00029-6 (2000). DOI: 10.1016/s0925-4439(00)00029-6
Selkoe, D. J. Alzheimer’s disease: a central role for amyloid. J. Neuropathol. Exp. Neurol. 53, 438–447. 10.1097/00005072-199409000-00003 (1994). DOI: 10.1097/00005072-199409000-00003
Benilova, I., Karran, E. & De Strooper, B. The toxic Abeta oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat. Neurosci. 15, 349–357. 10.1038/nn.3028 (2012). DOI: 10.1038/nn.3028
McLean, C. A. et al. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann. Neurol. 46, 860–866. 10.1002/1531-8249(199912)46:6%3c860::aid-ana8%3e3.0.co;2-m (1999). DOI: 10.1002/1531-8249(199912)46:6<860::aid-ana8>3.0.co;2-m
Jongbloed, W. et al. Amyloid-beta oligomers relate to cognitive decline in Alzheimer’s disease. J. Alzheimers Dis. 45, 35–43. 10.3233/JAD-142136 (2015). DOI: 10.3233/JAD-142136
Amar, F. et al. The amyloid-beta oligomer Abeta*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation. Sci. Signal 10.1126/scisignal.aal2021 (2017). DOI: 10.1126/scisignal.aal2021
Lesne, S. E. et al. Brain amyloid-beta oligomers in ageing and Alzheimer’s disease. Brain 136, 1383–1398. 10.1093/brain/awt062 (2013). DOI: 10.1093/brain/awt062
Ladiwala, A. R. et al. Conformational differences between two amyloid beta oligomers of similar size and dissimilar toxicity. J. Biol. Chem. 287, 24765–24773. 10.1074/jbc.M111.329763 (2012). DOI: 10.1074/jbc.M111.329763
Broersen, K., Rousseau, F. & Schymkowitz, J. The culprit behind amyloid beta peptide related neurotoxicity in Alzheimer’s disease: oligomer size or conformation?. Alzheimers Res. Ther. 2, 12. 10.1186/alzrt36 (2010). DOI: 10.1186/alzrt36
Deshpande, A., Mina, E., Glabe, C. & Busciglio, J. Different conformations of amyloid beta induce neurotoxicity by distinct mechanisms in human cortical neurons. J. Neurosci. 26, 6011–6018. 10.1523/JNEUROSCI.1189-06.2006 (2006). DOI: 10.1523/JNEUROSCI.1189-06.2006
Lambert, M. P. et al. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. USA. 95, 6448–6453. 10.1073/pnas.95.11.6448 (1998). DOI: 10.1073/pnas.95.11.6448
Townsend, M., Shankar, G. M., Mehta, T., Walsh, D. M. & Selkoe, D. J. Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers. J. Physiol. 572, 477–492. 10.1113/jphysiol.2005.103754 (2006). DOI: 10.1113/jphysiol.2005.103754
Shankar, G. M. et al. Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J. Neurosci. 27, 2866–2875. 10.1523/JNEUROSCI.4970-06.2007 (2007). DOI: 10.1523/JNEUROSCI.4970-06.2007
Shankar, G. M. et al. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat. Med. 14, 837–842. 10.1038/nm1782 (2008). DOI: 10.1038/nm1782
Ferrone, F. Analysis of protein aggregation kinetics. Methods Enzymol. 309, 256–274. 10.1016/s0076-6879(99)09019-9 (1999). DOI: 10.1016/s0076-6879(99)09019-9
Roychaudhuri, R., Yang, M., Hoshi, M. M. & Teplow, D. B. Amyloid beta-protein assembly and Alzheimer disease. J. Biol. Chem. 284, 4749–4753. 10.1074/jbc.R800036200 (2009). DOI: 10.1074/jbc.R800036200
Scheidt, T. et al. Secondary nucleation and elongation occur at different sites on Alzheimer’s amyloid-beta aggregates. Sci. Adv. 5, eaau3112. 10.1126/sciadv.aau3112 (2019). DOI: 10.1126/sciadv.aau3112
Bernstein, S. L. et al. Amyloid-beta protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer’s disease. Nat. Chem. 1, 326–331. 10.1038/nchem.247 (2009). DOI: 10.1038/nchem.247
Bitan, G. et al. Amyloid beta -protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways. Proc. Natl. Acad. Sci. USA. 100, 330–335. 10.1073/pnas.222681699 (2003). DOI: 10.1073/pnas.222681699
Cernescu, M. et al. Laser-induced liquid bead ion desorption mass spectrometry: an approach to precisely monitor the oligomerization of the beta-amyloid peptide. Anal. Chem. 84, 5276–5284. 10.1021/ac300258m (2012). DOI: 10.1021/ac300258m
Ono, K., Condron, M. M. & Teplow, D. B. Structure-neurotoxicity relationships of amyloid beta-protein oligomers. Proc. Natl. Acad. Sci. USA. 106, 14745–14750. 10.1073/pnas.0905127106 (2009). DOI: 10.1073/pnas.0905127106
Bitan, G., Lomakin, A. & Teplow, D. B. Amyloid beta-protein oligomerization: prenucleation interactions revealed by photo-induced cross-linking of unmodified proteins. J. Biol. Chem. 276, 35176–35184. 10.1074/jbc.M102223200 (2001). DOI: 10.1074/jbc.M102223200
Bitan, G. & Teplow, D. B. Rapid photochemical cross-linking–a new tool for studies of metastable, amyloidogenic protein assemblies. Acc. Chem. Res. 37, 357–364. 10.1021/ar000214l (2004). DOI: 10.1021/ar000214l
Wolff, M. et al. Abeta42 pentamers/hexamers are the smallest detectable oligomers in solution. Sci. Rep. 7, 2493. 10.1038/s41598-017-02370-3 (2017). DOI: 10.1038/s41598-017-02370-3
Lesne, S. et al. A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440, 352–357. 10.1038/nature04533 (2006). DOI: 10.1038/nature04533
Bolognesi, B. et al. Single point mutations induce a switch in the molecular mechanism of the aggregation of the Alzheimer’s disease associated Abeta42 peptide. ACS Chem. Biol. 9, 378–382. 10.1021/cb400616y (2014). DOI: 10.1021/cb400616y
Luheshi, L. M. et al. Systematic in vivo analysis of the intrinsic determinants of amyloid Beta pathogenicity. PLoS Biol. 5, e290. 10.1371/journal.pbio.0050290 (2007). DOI: 10.1371/journal.pbio.0050290
Peralvarez-Marin, A. et al. Influence of residue 22 on the folding, aggregation profile, and toxicity of the Alzheimer’s amyloid beta peptide. Biophys. J. 97, 277–285. 10.1016/j.bpj.2009.04.017 (2009). DOI: 10.1016/j.bpj.2009.04.017
Johansson, A. S. et al. Physiochemical characterization of the Alzheimer’s disease-related peptides A beta 1–42Arctic and A beta 1–42wt. FEBS J. 273, 2618–2630. 10.1111/j.1742-4658.2006.05263.x (2006). DOI: 10.1111/j.1742-4658.2006.05263.x
Yang, X. et al. On the role of sidechain size and charge in the aggregation of Abeta42 with familial mutations. Proc. Natl. Acad. Sci. USA. 115, E5849–E5858. 10.1073/pnas.1803539115 (2018). DOI: 10.1073/pnas.1803539115
Ahmed, M. et al. Structural conversion of neurotoxic amyloid-beta(1–42) oligomers to fibrils. Nat. Struct. Mol. Biol. 17, 561–567. 10.1038/nsmb.1799 (2010). DOI: 10.1038/nsmb.1799
Melchor, J. P., McVoy, L. & Van Nostrand, W. E. Charge alterations of E22 enhance the pathogenic properties of the amyloid beta-protein. J. Neurochem. 74, 2209–2212. 10.1046/j.1471-4159.2000.0742209.x (2000). DOI: 10.1046/j.1471-4159.2000.0742209.x
Murakami, K. et al. Synthesis, aggregation, neurotoxicity, and secondary structure of various A beta 1–42 mutants of familial Alzheimer’s disease at positions 21–23. Biochem. Biophys. Res. Commun. 294, 5–10. 10.1016/S0006-291X(02)00430-8 (2002). DOI: 10.1016/S0006-291X(02)00430-8
Murakami, K. et al. Neurotoxicity and physicochemical properties of Abeta mutant peptides from cerebral amyloid angiopathy: implication for the pathogenesis of cerebral amyloid angiopathy and Alzheimer’s disease. J. Biol. Chem. 278, 46179–46187. 10.1074/jbc.M301874200 (2003). DOI: 10.1074/jbc.M301874200
Grabowski, T. J., Cho, H. S., Vonsattel, J. P., Rebeck, G. W. & Greenberg, S. M. Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann. Neurol. 49, 697–705. 10.1002/ana.1009 (2001). DOI: 10.1002/ana.1009
Hendriks, L. et al. Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat. Genet. 1, 218–221. 10.1038/ng0692-218 (1992). DOI: 10.1038/ng0692-218
Miravalle, L. et al. Substitutions at codon 22 of Alzheimer’s abeta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells. J. Biol. Chem. 275, 27110–27116. 10.1074/jbc.M003154200 (2000). DOI: 10.1074/jbc.M003154200
Nilsberth, C. et al. The “Arctic” APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation. Nat. Neurosci. 4, 887–893. 10.1038/nn0901-887 (2001). DOI: 10.1038/nn0901-887
Decock, M. et al. Glycines from the APP GXXXG/GXXXA transmembrane motifs promote formation of pathogenic abeta oligomers in cells. Front. Aging Neurosci. 8, 107. 10.3389/fnagi.2016.00107 (2016). DOI: 10.3389/fnagi.2016.00107
Pujol-Pina, R. et al. SDS-PAGE analysis of Abeta oligomers is disserving research into Alzheimer s disease: appealing for ESI-IM-MS. Sci. Rep. 5, 14809. 10.1038/srep14809 (2015). DOI: 10.1038/srep14809
Marshall, K. E. et al. A critical role for the self-assembly of Amyloid-beta1-42 in neurodegeneration. Sci. Rep. 6, 30182. 10.1038/srep30182 (2016). DOI: 10.1038/srep30182
Jarrett, J. T., Berger, E. P. & Lansbury, P. T. Jr. The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry 32, 4693–4697. 10.1021/bi00069a001 (1993). DOI: 10.1021/bi00069a001
Broersen, K. et al. A standardized and biocompatible preparation of aggregate-free amyloid beta peptide for biophysical and biological studies of Alzheimer’s disease. Protein Eng. Des. Sel. 24, 743–750. 10.1093/protein/gzr020 (2011). DOI: 10.1093/protein/gzr020
Vadukul, D. M., Gbajumo, O., Marshall, K. E. & Serpell, L. C. Amyloidogenicity and toxicity of the reverse and scrambled variants of amyloid-beta 1–42. FEBS Lett. 591, 822–830. 10.1002/1873-3468.12590 (2017). DOI: 10.1002/1873-3468.12590
Osterlund, N., Moons, R., Ilag, L. L., Sobott, F. & Graslund, A. Native ion mobility-mass spectrometry reveals the formation of beta-barrel shaped amyloid-beta Hexamers in a membrane-mimicking environment. J. Am. Chem. Soc. 141, 10440–10450. 10.1021/jacs.9b04596 (2019). DOI: 10.1021/jacs.9b04596
Cukalevski, R. et al. Role of aromatic side chains in amyloid beta-protein aggregation. ACS Chem. Neurosci. 3, 1008–1016. 10.1021/cn300073s (2012). DOI: 10.1021/cn300073s
Esler, W. P. et al. Point substitution in the central hydrophobic cluster of a human beta-amyloid congener disrupts peptide folding and abolishes plaque competence. Biochemistry 35, 13914–13921. 10.1021/bi961302+ (1996). DOI: 10.1021/bi961302+
Hilbich, C., Kisters-Woike, B., Reed, J., Masters, C. L. & Beyreuther, K. Substitutions of hydrophobic amino acids reduce the amyloidogenicity of Alzheimer’s disease beta A4 peptides. J. Mol. Biol. 228, 460–473. 10.1016/0022-2836(92)90835-8 (1992). DOI: 10.1016/0022-2836(92)90835-8
Wurth, C., Guimard, N. K. & Hecht, M. H. Mutations that reduce aggregation of the Alzheimer’s Abeta42 peptide: an unbiased search for the sequence determinants of Abeta amyloidogenesis. J. Mol. Biol. 319, 1279–1290. 10.1016/S0022-2836(02)00399-6 (2002). DOI: 10.1016/S0022-2836(02)00399-6
Gazit, E. A possible role for pi-stacking in the self-assembly of amyloid fibrils. FASEB J. 16, 77–83. 10.1096/fj.01-0442hyp (2002). DOI: 10.1096/fj.01-0442hyp
Masuda, Y. et al. Verification of the turn at positions 22 and 23 of the beta-amyloid fibrils with Italian mutation using solid-state NMR. Bioorg. Med. Chem. 13, 6803–6809. 10.1016/j.bmc.2005.07.071 (2005). DOI: 10.1016/j.bmc.2005.07.071
Murakami, K. et al. Formation and stabilization model of the 42-mer Abeta radical: implications for the long-lasting oxidative stress in Alzheimer’s disease. J. Am. Chem. Soc. 127, 15168–15174. 10.1021/ja054041c (2005). DOI: 10.1021/ja054041c
Roychaudhuri, R., Yang, M., Condron, M. M. & Teplow, D. B. Structural dynamics of the amyloid beta-protein monomer folding nucleus. Biochemistry 51, 3957–3959. 10.1021/bi300350p (2012). DOI: 10.1021/bi300350p
Grant, M. A. et al. Familial Alzheimer’s disease mutations alter the stability of the amyloid beta-protein monomer folding nucleus. Proc. Natl. Acad. Sci. USA. 104, 16522–16527. 10.1073/pnas.0705197104 (2007). DOI: 10.1073/pnas.0705197104
Lazo, N. D., Grant, M. A., Condron, M. C., Rigby, A. C. & Teplow, D. B. On the nucleation of amyloid beta-protein monomer folding. Protein Sci. 14, 1581–1596. 10.1110/ps.041292205 (2005). DOI: 10.1110/ps.041292205
Krone, M. G. et al. Effects of familial Alzheimer’s disease mutations on the folding nucleation of the amyloid beta-protein. J. Mol. Biol. 381, 221–228. 10.1016/j.jmb.2008.05.069 (2008). DOI: 10.1016/j.jmb.2008.05.069
Karamanos, T. K. et al. Structural mapping of oligomeric intermediates in an amyloid assembly pathway. Elife 10.7554/eLife.46574 (2019). DOI: 10.7554/eLife.46574
Kienlen-Campard, P. et al. Amyloidogenic processing but not amyloid precursor protein (APP) intracellular Cterminal domain production requires a precisely oriented APP dimer assembled by transmembrane GXXXG motifs. J. Biol. Chem. 283, 7733–7744. 10.1074/jbc.M707142200 (2008). DOI: 10.1074/jbc.M707142200
Ben Khalifa, N. et al. Structural features of the KPI domain control APP dimerization, trafficking, and processing. FASEB J. 26, 855–867. 10.1096/fj.11-190207 (2012). DOI: 10.1096/fj.11-190207
Hage, S. et al. Characterization of Pterocarpus erinaceus kino extract and its gamma-secretase inhibitory properties. J. Ethnopharmacol. 163, 192–202. 10.1016/j.jep.2015.01.028 (2015). DOI: 10.1016/j.jep.2015.01.028