{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T15:22:55Z","timestamp":1772810575042,"version":"3.50.1"},"reference-count":64,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,6,25]],"date-time":"2020-06-25T00:00:00Z","timestamp":1593043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease is associated with the aggregation of the amyloid-\u03b2 peptide (A\u03b2), resulting in the deposition of amyloid plaques in brain tissue. Recent scrutiny of the mechanisms by which A\u03b2 aggregates induce neuronal dysfunction has highlighted the importance of the A\u03b2 oligomers of this protein fragment. Because of the transient and heterogeneous nature of these oligomers, however, it has been challenging to investigate the detailed mechanisms by which these species exert cytotoxicity. To address this problem, we demonstrate here the use of rationally designed single-domain antibodies (DesAbs) to characterize the structure\u2013toxicity relationship of A\u03b2 oligomers. For this purpose, we use Zn2+-stabilized oligomers of the 40-residue form of A\u03b2 (A\u03b240) as models of brain A\u03b2 oligomers and two single-domain antibodies (DesAb18-24 and DesAb34-40), designed to bind to epitopes at residues 18\u201324 and 34\u201340 of A\u03b240, respectively. We found that the DesAbs induce a change in structure of the Zn2+-stabilized A\u03b240 oligomers, generating a simultaneous increase in their size and solvent-exposed hydrophobicity. We then observed that these increments in both the size and hydrophobicity of the oligomers neutralize each other in terms of their effects on cytotoxicity, as predicted by a recently proposed general structure\u2013toxicity relationship, and observed experimentally. These results illustrate the use of the DesAbs as research tools to investigate the biophysical and cytotoxicity properties of A\u03b2 oligomers.<\/jats:p>","DOI":"10.3390\/ijms21124542","type":"journal-article","created":{"date-parts":[[2020,6,26]],"date-time":"2020-06-26T05:19:36Z","timestamp":1593148776000},"page":"4542","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Rationally Designed Antibodies as Research Tools to Study the Structure\u2013Toxicity Relationship of Amyloid-\u03b2 Oligomers"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6030-6656","authenticated-orcid":false,"given":"Ryan","family":"Limbocker","sequence":"first","affiliation":[{"name":"Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK"},{"name":"Department of Chemistry and Life Science, United States Military Academy, West Point, NY 10996, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6812-7348","authenticated-orcid":false,"given":"Benedetta","family":"Mannini","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3862-7824","authenticated-orcid":false,"given":"Rodrigo","family":"Cataldi","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shianne","family":"Chhangur","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aidan K.","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Life Science, United States Military Academy, West Point, NY 10996, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan P.","family":"Kreiser","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Life Science, United States Military Academy, West Point, NY 10996, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Alex","family":"Albright","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Life Science, United States Military Academy, West Point, NY 10996, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean","family":"Chia","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johnny","family":"Habchi","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pietro","family":"Sormanni","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3887-4964","authenticated-orcid":false,"given":"Janet R.","family":"Kumita","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1232-1907","authenticated-orcid":false,"given":"Francesco S.","family":"Ruggeri","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher M.","family":"Dobson","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabrizio","family":"Chiti","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Science, University of Florence, 50134 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5040-4420","authenticated-orcid":false,"given":"Francesco A.","family":"Aprile","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3616-1610","authenticated-orcid":false,"given":"Michele","family":"Vendruscolo","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/nrm3810","article-title":"The amyloid state and its association with protein misfolding diseases","volume":"15","author":"Knowles","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1146\/annurev-biochem-061516-045115","article-title":"Protein misfolding, amyloid formation, and human disease: A summary of progress over the last decade","volume":"86","author":"Chiti","year":"2017","journal-title":"Annu. Rev. Biochem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nrm2101","article-title":"Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer\u2019s amyloid \u03b2-peptide","volume":"8","author":"Haass","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/nn.3028","article-title":"The toxic A\u03b2 oligomer and Alzheimer\u2019s disease: An emperor in need of clothes","volume":"15","author":"Benilova","year":"2012","journal-title":"Nat. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Fontana, I.C., Zimmer, A.R., Rocha, A.S., Gosmann, G., Souza, D.O., Lourenco, M.V., Ferreira, S.T., and Zimmer, E.R. (2020). Amyloid-\u03b2 oligomers in cellular models of Alzheimer\u2019s disease. J. Neurochem.","DOI":"10.1111\/jnc.15030"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Li, S., and Selkoe, D.J. (2020). A mechanistic hypothesis for the impairment of synaptic plasticity by soluble A\u03b2 oligomers from Alzheimer\u2019s brain. J. Neurochem.","DOI":"10.1111\/jnc.15007"},{"key":"ref_8","first-page":"146","article-title":"The future of anti-amyloid trials","volume":"7","author":"Aisen","year":"2020","journal-title":"J. Prev. Alzheimers Dis."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Linse, S., Scheidt, T., Bernfur, K., Vendruscolo, M., Dobson, C.M., Cohen, S.I.A., Sileikis, E., Lundquist, M., Qian, F., and O\u2019Malley, T. (2020). Kinetic fingerprints differentiate anti-A\u03b2 therapies. bioRxiv, 815308.","DOI":"10.1101\/815308"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1002\/ana.24188","article-title":"A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease","volume":"76","author":"Karran","year":"2014","journal-title":"Ann. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/alzrt269","article-title":"Alzheimer\u2019s disease drug-development pipeline: Few candidates, frequent failures","volume":"6","author":"Cummings","year":"2014","journal-title":"Alzheimers Res. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"114ps48","DOI":"10.1126\/scitranslmed.3003529","article-title":"Mapping the road forward in Alzheimer\u2019s disease","volume":"3","author":"Holtzman","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"111cm33","DOI":"10.1126\/scitranslmed.3002609","article-title":"Testing the right target and the right drug at the right stage","volume":"3","author":"Sperling","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/nrd3842-c1","article-title":"Moving towards early clinical trials for amyloid-targeted therapy in Alzheimer\u2019s disease","volume":"12","author":"Aisen","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.tips.2013.12.005","article-title":"Chemical kinetics for drug discovery to combat protein aggregation diseases","volume":"35","author":"Arosio","year":"2014","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10948","DOI":"10.1038\/ncomms10948","article-title":"Kinetic analysis reveals the diversity of microscopic mechanisms through which molecular chaperones suppress amyloid formation","volume":"7","author":"Arosio","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nprot.2016.010","article-title":"Molecular mechanisms of protein aggregation from global fitting of kinetic models","volume":"11","author":"Meisl","year":"2016","journal-title":"Nat. Protoc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e1700488","DOI":"10.1126\/sciadv.1700488","article-title":"Selective targeting of primary and secondary nucleation pathways in A\u03b242 aggregation using a rational antibody scanning method","volume":"3","author":"Aprile","year":"2017","journal-title":"Sci. Adv."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Habchi, J., Chia, S., Limbocker, R., Mannini, B., Ahn, M., Perni, M., Hansson, O., Arosio, P., Kumita, J.R., and Challa, P.K. (2016). Systematic development of small molecules to inhibit specific microscopic steps of A\u03b242 aggregation in Alzheimer\u2019s disease. Proc. Natl. Acad. Sci. USA, 201615613.","DOI":"10.1073\/pnas.1615613114"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10245","DOI":"10.1073\/pnas.1807884115","article-title":"SAR by kinetics for drug discovery in protein misfolding diseases","volume":"115","author":"Chia","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/s41557-020-0452-1","article-title":"Dynamics of oligomer populations formed during the aggregation of Alzheimer\u2019s A\u03b242 peptide","volume":"12","author":"Michaels","year":"2020","journal-title":"Nat. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/nrd2399","article-title":"Protein therapeutics: A summary and pharmacological classification","volume":"7","author":"Leader","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ijpharm.2011.12.039","article-title":"Therapeutic antibodies: Market considerations, disease targets and bioprocessing","volume":"440","author":"Elvin","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1186\/s40478-019-0777-4","article-title":"Soluble aggregates present in cerebrospinal fluid change in size and mechanism of toxicity during Alzheimer\u2019s disease progression","volume":"7","author":"De","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1038\/s41467-019-09477-3","article-title":"Different soluble aggregates of A\u03b242 can give rise to cellular toxicity through different mechanisms","volume":"10","author":"De","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nature19323","article-title":"The antibody aducanumab reduces A\u03b2 plaques in Alzheimer\u2019s disease","volume":"537","author":"Sevigny","year":"2016","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Aprile, F.A., Sormanni, P., Podpolny, M., Chhangur, S., Needham, L.-M., Ruggeri, F.S., Perni, M., Limbocker, R., Heller, G.T., and Sneideris, T. (2020). Rational design of a conformation-specific antibody for the quantification of A\u03b2 oligomers. Proc. Natl. Acad. Sci. USA, 201919464.","DOI":"10.1073\/pnas.1919464117"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Yang, T., O\u2019Malley, T.T., Kanmert, D., Jerecic, J., Zieske, L.R., Zetterberg, H., Hyman, B.T., Walsh, D.M., and Selkoe, D.J. (2015). A highly sensitive novel immunoassay specifically detects low levels of soluble A\u03b2 oligomers in human cerebrospinal fluid. Alzheimers Res. Ther., 7.","DOI":"10.1186\/s13195-015-0100-y"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/s41467-018-07699-5","article-title":"Trodusquemine enhances A\u03b242 aggregation but suppresses its toxicity by displacing oligomers from cell membranes","volume":"10","author":"Limbocker","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2309","DOI":"10.1021\/cb500505m","article-title":"Toxicity of protein oligomers is rationalized by a function combining size and surface hydrophobicity","volume":"9","author":"Mannini","year":"2014","journal-title":"ACS Chem. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3146","DOI":"10.1128\/MCB.01187-10","article-title":"Sequestration of toxic oligomers by HspB1 as a cytoprotective mechanism","volume":"31","author":"Ojha","year":"2011","journal-title":"Mol. Cell. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Mannini, B., and Chiti, F. (2017). Chaperones as suppressors of protein misfolded oligomer toxicity. Front. Mol. Neurosci., 10.","DOI":"10.3389\/fnmol.2017.00098"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"12479","DOI":"10.1073\/pnas.1117799109","article-title":"Molecular mechanisms used by chaperones to reduce the toxicity of aberrant protein oligomers","volume":"109","author":"Mannini","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1038\/nchembio.283","article-title":"A causative link between the structure of aberrant protein oligomers and their toxicity","volume":"6","author":"Campioni","year":"2010","journal-title":"Nat. Chem. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1515\/hsz-2015-0250","article-title":"Effect of molecular chaperones on aberrant protein oligomers in vitro: Super-versus sub-stoichiometric chaperone concentrations","volume":"397","author":"Cappelli","year":"2016","journal-title":"Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1021\/cb1001203","article-title":"ANS binding reveals common features of cytotoxic amyloid species","volume":"5","author":"Bolognesi","year":"2010","journal-title":"ACS Chem. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"9902","DOI":"10.1073\/pnas.1422401112","article-title":"Rational design of antibodies targeting specific epitopes within intrinsically disordered proteins","volume":"112","author":"Sormanni","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9758","DOI":"10.1073\/pnas.1218402110","article-title":"Proliferation of amyloid-\u03b242 aggregates occurs through a secondary nucleation mechanism","volume":"110","author":"Cohen","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"15595","DOI":"10.1073\/pnas.1001740107","article-title":"Stabilization of neurotoxic Alzheimer amyloid-\u03b2 oligomers by protein engineering","volume":"107","author":"Sandberg","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1073\/pnas.222681699","article-title":"Amyloid \u03b2-protein (A\u03b2) assembly: A\u03b240 and A\u03b242 oligomerize through distinct pathways","volume":"100","author":"Bitan","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/S0197-0186(02)00050-5","article-title":"A\u03b2 toxicity in Alzheimer\u2019s disease: Globular oligomers (ADDLs) as new vaccine and drug targets","volume":"41","author":"Klein","year":"2002","journal-title":"Neurochem. Int."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2959","DOI":"10.1021\/acschemneuro.8b00141","article-title":"Stabilization and characterization of cytotoxic A\u03b240 oligomers isolated from an aggregation reaction in the presence of zinc ions","volume":"9","author":"Mannini","year":"2018","journal-title":"ACS Chem. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/S0022-2836(65)80111-5","article-title":"The interaction of a naphthalene dye with apomyoglobin and apohemoglobin: A fluorescent probe of non-polar binding sites","volume":"13","author":"Stryer","year":"1965","journal-title":"J. Mol. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1021\/acschembio.9b00324","article-title":"The toxicity of misfolded protein oligomers is independent of their secondary structure","volume":"14","author":"Cascella","year":"2019","journal-title":"ACS Chem. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"31155","DOI":"10.1038\/srep31155","article-title":"Nanoscale studies link amyloid maturity with polyglutamine diseases onset","volume":"6","author":"Ruggeri","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.abb.2019.02.001","article-title":"Atomic force microscopy for single molecule characterisation of protein aggregation","volume":"664","author":"Ruggeri","year":"2019","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3950","DOI":"10.2174\/1381612822666160518141911","article-title":"AFM-based single molecule techniques: Unraveling the amyloid pathogenic species","volume":"22","author":"Ruggeri","year":"2016","journal-title":"Curr. Pharm. Des."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/nnano.2010.59","article-title":"Understanding amyloid aggregation by statistical analysis of atomic force microscopy images","volume":"5","author":"Adamcik","year":"2010","journal-title":"Nat. Nanotechnol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3890","DOI":"10.1038\/s41467-018-06345-4","article-title":"Microfluidic deposition for resolving single-molecule protein architecture and heterogeneity","volume":"9","author":"Ruggeri","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.neuint.2017.08.010","article-title":"Alzheimer\u2019s disease as oligomeropathy","volume":"119","author":"Ono","year":"2018","journal-title":"Neurochem. Int."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"14745","DOI":"10.1073\/pnas.0905127106","article-title":"Structure\u2013neurotoxicity relationships of amyloid \u03b2-protein oligomers","volume":"106","author":"Ono","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"23186","DOI":"10.1074\/jbc.M109.086496","article-title":"Effects of the English (H6R) and Tottori (D7N) familial Alzheimer disease mutations on amyloid \u03b2-protein assembly and toxicity","volume":"285","author":"Ono","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"19590","DOI":"10.1074\/jbc.M115.691840","article-title":"Amyloid-\u03b2(1\u201342) aggregation initiates its cellular uptake and cytotoxicity","volume":"291","author":"Jin","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"11506","DOI":"10.1002\/anie.201706279","article-title":"Suppression of oligomer formation and formation of non-toxic fibrils upon addition of mirror-image A\u03b242 to the natural L-enantiomer","volume":"56","author":"Dutta","year":"2017","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1002\/cbic.201800708","article-title":"Chirality dependence of amyloid\u2005\u03b2 cellular uptake and a new mechanistic perspective","volume":"20","author":"Dutta","year":"2019","journal-title":"ChemBioChem"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"E1009","DOI":"10.1073\/pnas.1610586114","article-title":"A natural product inhibits the initiation of \u03b1-synuclein aggregation and suppresses its toxicity","volume":"114","author":"Perni","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2308","DOI":"10.1021\/acschembio.8b00466","article-title":"Multistep inhibition of \u03b1-synuclein aggregation and toxicity in vitro and in vivo by trodusquemine","volume":"13","author":"Perni","year":"2018","journal-title":"ACS Chem. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"8599","DOI":"10.1021\/jo981344z","article-title":"Synthesis of Squalamine utilizing a readily accessible Spermidine equivalent","volume":"63","author":"Zhang","year":"1998","journal-title":"J. Org. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1021\/np990514f","article-title":"Aminosterols from the Dogfish Shark Squalus acanthias","volume":"63","author":"Rao","year":"2000","journal-title":"J. Nat. Prod."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e1501244","DOI":"10.1126\/sciadv.1501244","article-title":"An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic A\u03b242 aggregates linked with Alzheimer\u2019s disease","volume":"2","author":"Habchi","year":"2016","journal-title":"Sci. Adv."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2462","DOI":"10.1002\/anie.201409050","article-title":"Influence of the \u03b2-sheet content on the mechanical properties of aggregates during amyloid fibrillization","volume":"54","author":"Ruggeri","year":"2015","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Capitini, C., Conti, S., Perni, M., Guidi, F., Cascella, R., De Poli, A., Penco, A., Relini, A., Cecchi, C., and Chiti, F. (2014). TDP-43 inclusion bodies formed in bacteria are structurally amorphous, non-amyloid and inherently toxic to neuroblastoma cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0086720"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"32721","DOI":"10.1038\/srep32721","article-title":"Binding affinity of amyloid oligomers to cellular membranes is a generic indicator of cellular dysfunction in protein misfolding diseases","volume":"6","author":"Evangelisti","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_64","first-page":"2416","article-title":"Membrane lipid composition and its physicochemical properties define cell vulnerability to aberrant protein oligomers","volume":"125","author":"Evangelisti","year":"2012","journal-title":"J. Cell Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/12\/4542\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:43:03Z","timestamp":1760175783000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/12\/4542"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,25]]},"references-count":64,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["ijms21124542"],"URL":"https:\/\/doi.org\/10.3390\/ijms21124542","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,25]]}}}