{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T08:21:08Z","timestamp":1791534068481,"version":"4.3.4"},"reference-count":105,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T00:00:00Z","timestamp":1648598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Protein aggregation into amyloid fibrils affects many proteins in a variety of diseases, including neurodegenerative disorders, diabetes, and cancer. Physicochemically, amyloid formation is a phase transition process, where soluble proteins are transformed into solid fibrils with the characteristic cross-\u03b2 conformation responsible for their fibrillar morphology. This phase transition proceeds via an initial, rate-limiting nucleation step followed by rapid growth. Several well-defined nucleation pathways exist, including homogenous nucleation (HON), which proceeds spontaneously; heterogeneous nucleation (HEN), which is catalyzed by surfaces; and seeding via preformed nuclei. It has been hypothesized that amyloid aggregation represents a protein-only (nucleic-acid free) replication mechanism that involves transmission of structural information via conformational templating (the prion hypothesis). While the prion hypothesis still lacks mechanistic support, it is also incompatible with the fact that proteins can be induced to form amyloids in the absence of a proteinaceous species acting as a conformational template as in the case of HEN, which can be induced by lipid membranes (including viral envelopes) or polysaccharides. Additionally, while amyloids can be formed from any protein sequence and via different nucleation pathways, they invariably adopt the universal cross-\u03b2 conformation; suggesting that such conformational change is a spontaneous folding event that is thermodynamically favorable under the conditions of supersaturation and phase transition and not a templated replication process. Finally, as the high stability of amyloids renders them relatively inert, toxicity in some amyloid pathologies might be more dependent on the loss of function from protein sequestration in the amyloid state rather than direct toxicity from the amyloid plaques themselves.<\/jats:p>","DOI":"10.3390\/biology11040535","type":"journal-article","created":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T21:22:14Z","timestamp":1648675334000},"page":"535","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Proteins Do Not Replicate, They Precipitate: Phase Transition and Loss of Function Toxicity in Amyloid Pathologies"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4186-0675","authenticated-orcid":false,"given":"Kariem","family":"Ezzat","sequence":"first","affiliation":[{"name":"Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, 141 57 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Sturchio","sequence":"additional","affiliation":[{"name":"Department of Clinical Neuroscience, Neuro Svenningsson, Karolinska Institutet, 171 76 Stockholm, Sweden"},{"name":"James J. and Joan A. Gardner Family Center for Parkinson\u2019s Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH 45221, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto J.","family":"Espay","sequence":"additional","affiliation":[{"name":"James J. and Joan A. Gardner Family Center for Parkinson\u2019s Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH 45221, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"eaaf4382","DOI":"10.1126\/science.aaf4382","article-title":"Liquid phase condensation in cell physiology and disease","volume":"357","author":"Brangwynne","year":"2017","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.cell.2018.12.035","article-title":"Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates","volume":"176","author":"Alberti","year":"2019","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"138","DOI":"10.3389\/fbioe.2021.643110","article-title":"Tropoelastin and elastin assembly","volume":"9","author":"Ozsvar","year":"2021","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1146\/annurev-biophys-042910-155359","article-title":"Actin structure and function","volume":"40","author":"Dominguez","year":"2011","journal-title":"Annu. Rev. Biophys."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1146\/annurev.biochem.77.032207.120833","article-title":"Collagen structure and stability","volume":"78","author":"Shoulders","year":"2009","journal-title":"Annu. Rev. Biochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/35065514","article-title":"Amyloid fibrils from muscle myoglobin","volume":"410","author":"Fletcher","year":"2001","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9196","DOI":"10.1073\/pnas.142459399","article-title":"The protofilament structure of insulin amyloid fibrils","volume":"99","author":"Nettleton","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"20733","DOI":"10.1021\/jp064861r","article-title":"Amyloid fibril formation and other aggregate species formed by human serum albumin association","volume":"110","author":"Taboada","year":"2006","journal-title":"J. Phys. Chem. B"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5682","DOI":"10.1093\/emboj\/cdf573","article-title":"The behaviour of polyamino acids reveals an inverse side chain effect in amyloid structure formation","volume":"21","author":"Dobson","year":"2002","journal-title":"EMBO J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"a023648","DOI":"10.1101\/cshperspect.a023648","article-title":"The amyloid phenomenon and its links with human disease","volume":"9","author":"Dobson","year":"2017","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"12825","DOI":"10.1073\/pnas.0506136102","article-title":"Primary sequence independence for prion formation","volume":"102","author":"Ross","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/S0968-0004(99)01445-0","article-title":"Dobson Protein misfolding, evolution and disease","volume":"24","author":"Christopher","year":"1999","journal-title":"Trends Biochem. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1038\/nature02261","article-title":"Protein folding and misfolding","volume":"426","author":"Dobson","year":"2003","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1146\/annurev-biochem-061516-045104","article-title":"Structural studies of amyloid proteins at the molecular level","volume":"86","author":"Eisenberg","year":"2017","journal-title":"Annu. Rev. Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4857","DOI":"10.1016\/j.cell.2021.08.013","article-title":"The expanding amyloid family: Structure, stability, function, and pathogenesis","volume":"184","author":"Sawaya","year":"2021","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/nature20416","article-title":"The activities of amyloids from a structural perspective","volume":"539","author":"Riek","year":"2016","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1016\/j.cell.2012.02.022","article-title":"The amyloid state of proteins in human diseases","volume":"148","author":"Eisenberg","year":"2012","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5473","DOI":"10.1039\/C9CS00199A","article-title":"Half a century of amyloids: Past, present and future","volume":"49","author":"Ke","year":"2020","journal-title":"Chem. Soc. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1900","DOI":"10.1126\/science.1150057","article-title":"Role of intermolecular forces in defining material properties of protein nanofibrils","volume":"318","author":"Knowles","year":"2007","journal-title":"Science"},{"key":"ref_20","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_21","doi-asserted-by":"crossref","first-page":"W431","DOI":"10.1093\/nar\/gkab314","article-title":"Mol* viewer: Modern web app for 3D visualization and analysis of large biomolecular structures","volume":"49","author":"Sehnal","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5468","DOI":"10.1073\/pnas.1219476110","article-title":"Atomic structure and hierarchical assembly of a cross-\u03b2 amyloid fibril","volume":"110","author":"Fitzpatrick","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1039\/B912163N","article-title":"Structure and dynamics of cross-linked actin networks","volume":"6","author":"Lieleg","year":"2010","journal-title":"Soft Matter"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.tibs.2011.02.002","article-title":"Recent progress in understanding Alzheimer\u2019s \u03b2-amyloid structures","volume":"36","author":"Schmidt","year":"2011","journal-title":"Trends Biochem. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1126\/science.1105850","article-title":"Self-propagating, molecular-level polymorphism in Alzheimer\u2019s \u00df-amyloid fibrils","volume":"307","author":"Petkova","year":"2005","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e48907","DOI":"10.7554\/eLife.48907","article-title":"Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy","volume":"8","author":"Taylor","year":"2019","journal-title":"eLife"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.1016\/S0021-9258(19)56522-X","article-title":"The thermodynamic hypothesis of protein folding: The work of Christian Anfinsen","volume":"281","author":"Kresge","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1126\/science.181.4096.223","article-title":"Principles that govern the folding of protein chains","volume":"181","author":"Anfinsen","year":"1973","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.tips.2014.12.004","article-title":"Supersaturation is a major driving force for protein aggregation in neurodegenerative diseases","volume":"36","author":"Ciryam","year":"2015","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/0092-8674(93)90635-4","article-title":"Seeding \u201cone dimensional cristallization\u201d of amyloid: A pathogenic mechanism in Alzheimer\u2019s disease and scrapie?","volume":"73","author":"Jarrett","year":"1993","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Buell, A.K. (2017). The Nucleation of Protein Aggregates\u2014From Crystals to Amyloid Fibrils, Elsevier Inc.. [1st ed.].","DOI":"10.1016\/bs.ircmb.2016.08.014"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1107\/S0907444902014312","article-title":"Solvent entropy contribution to the free energy of protein crystallization","volume":"58","author":"Vekilov","year":"2002","journal-title":"Acta Crystallogr. Sect. D Biol. Crystallogr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1039\/C4FD00217B","article-title":"Recent advances in the understanding of two-step nucleation of protein crystals","volume":"179","author":"Vorontsova","year":"2015","journal-title":"Faraday Discuss."},{"key":"ref_34","first-page":"15","article-title":"Kinetics and mechanisms of protein crystallization at the molecular level","volume":"300","author":"Vekilov","year":"2005","journal-title":"Methods Mol. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/S0959-440X(97)80003-6","article-title":"Submillisecond kinetics of protein folding","volume":"7","author":"Eaton","year":"1997","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Banach, M., Konieczny, L., and Roterman, I. (2019). The amyloid as a ribbon-like micelle in contrast to spherical micelles represented by globular proteins. Molecules, 24.","DOI":"10.3390\/molecules24234395"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6654","DOI":"10.1073\/pnas.1322602111","article-title":"Heat of supersaturation-limited amyloid burst directly monitored by isothermal titration calorimetry","volume":"111","author":"Ikenoue","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7995","DOI":"10.1039\/C8CC02718H","article-title":"Energy landscape of polymorphic amyloid generation of \u03b22-microglobulin revealed by calorimetry","volume":"54","author":"Kinoshita","year":"2018","journal-title":"Chem. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6663","DOI":"10.1021\/acs.cgd.6b00794","article-title":"A review of classical and nonclassical nucleation theories","volume":"16","author":"Karthika","year":"2016","journal-title":"Cryst. Growth Des."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5007","DOI":"10.1021\/cg1011633","article-title":"Nucleation","volume":"10","author":"Vekilov","year":"2010","journal-title":"Cryst. Growth Des."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"57","DOI":"10.2113\/0540057","article-title":"Principles of Crystal Nucleation and Growth","volume":"54","year":"2003","journal-title":"Rev. Mineral. Geochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.molliq.2014.11.021","article-title":"Quantitative evaluation on the heterogeneous nucleation of amino acid by a thermodynamic analysis","volume":"200","author":"Kamano","year":"2014","journal-title":"J. Mol. Liq."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Hu, G., Cai, X., and Rong, Y. (2021). Phase Transformation and Properties, De Gruyter.","DOI":"10.1515\/9783110495379"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/s41557-018-0031-x","article-title":"Cholesterol catalyses A\u03b242 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes","volume":"10","author":"Habchi","year":"2018","journal-title":"Nat. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1074\/jbc.M114.592527","article-title":"Small liposomes accelerate the fibrillation of amyloid beta (1\u201340)","volume":"290","author":"Terakawa","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1016\/j.bbamem.2018.04.012","article-title":"Impact of membrane curvature on amyloid aggregation","volume":"1860","author":"Terakawa","year":"2018","journal-title":"Biochim. Biophys. Acta-Biomembr."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1016\/j.jmb.2004.06.086","article-title":"Phospholipid catalysis of diabetic amyloid assembly","volume":"341","author":"Knight","year":"2004","journal-title":"J. Mol. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"8691","DOI":"10.1073\/pnas.0701250104","article-title":"A Nucleation of protein fibrillation by nanoparticles","volume":"104","author":"Linse","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"11242","DOI":"10.1002\/anie.201605151","article-title":"Gold-induced fibril growth: The mechanism of surface-facilitated amyloid aggregation","volume":"55","author":"Gladytz","year":"2016","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1002\/ppsc.201400222","article-title":"Structure-making effects of metal nanoparticles in amyloid peptide fibrillation","volume":"32","author":"Gladytz","year":"2015","journal-title":"Part. Part. Syst. Charact."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1038\/s41467-019-10192-2","article-title":"The viral protein corona directs viral pathogenesis and amyloid aggregation","volume":"10","author":"Ezzat","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2510","DOI":"10.3390\/molecules20022510","article-title":"The effect of glycosaminoglycans (GAGs) on amyloid aggregation and toxicity","volume":"20","author":"Iannuzzi","year":"2015","journal-title":"Molecules"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1021\/bi011711s","article-title":"Heparin and other glycosaminoglycans stimulate the formation of amyloid fibrils from \u03b1-synuclein in vitro","volume":"41","author":"Cohlberg","year":"2002","journal-title":"Biochemistry"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Liu, C., and Zhang, Y. (2011). Nucleic Acid-Mediated Protein Aggregation and Assembly, Elsevier Inc.. [1st ed.].","DOI":"10.1016\/B978-0-12-386483-3.00005-7"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"8667","DOI":"10.1039\/C8CC02204F","article-title":"Secondary nucleation in amyloid formation","volume":"54","author":"Michaels","year":"2018","journal-title":"Chem. Commun."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"8021","DOI":"10.1021\/acs.jpcb.1c01997","article-title":"Insulin fibril formation caused by mechanical shock and cavitation","volume":"125","author":"Wu","year":"2021","journal-title":"J. Phys. Chem. B"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ijpharm.2011.04.024","article-title":"Probing the mechanism of insulin aggregation during agitation","volume":"413","author":"Malik","year":"2011","journal-title":"Int. J. Pharm."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e2104148118","DOI":"10.1073\/pnas.2104148118","article-title":"Amyloid particles facilitate surface-catalyzed cross-seeding by acting as promiscuous nanoparticles","volume":"118","author":"Aubrey","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/nrm2867","article-title":"A nucleator arms race: Cellular control of actin assembly","volume":"11","author":"Campellone","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.ceb.2010.10.007","article-title":"New mechanisms and functions of actin nucleation","volume":"23","author":"Welch","year":"2011","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s11340-007-9105-1","article-title":"The molecular mechanics of collagen degradation: Implications for human disease","volume":"49","author":"Stultz","year":"2009","journal-title":"Exp. Mech."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"jcs219832","DOI":"10.1242\/jcs.219832","article-title":"Dynamic stability of the actin ecosystem","volume":"132","author":"Plastino","year":"2019","journal-title":"J. Cell Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1016\/j.str.2006.09.008","article-title":"Proline and glycine control protein self-organization into elastomeric or amyloid fibrils","volume":"14","author":"Rauscher","year":"2006","journal-title":"Structure"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Morgan, A.A., and Rubenstein, E. (2013). Proline: The Distribution, Frequency, Positioning, and Common Functional Roles of Proline and Polyproline Sequences in the Human Proteome. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0053785"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1146\/annurev-genet-110711-155524","article-title":"Biology and genetics of prions causing neurodegeneration","volume":"47","author":"Prusiner","year":"2013","journal-title":"Annu. Rev. Genet."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nature12481","article-title":"Self-propagation of pathogenic protein aggregates in neurodegenerative diseases","volume":"501","author":"Jucker","year":"2013","journal-title":"Nature"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1126\/science.abb8577","article-title":"Shifts and drifts in prion science","volume":"370","author":"Aguzzi","year":"2020","journal-title":"Science"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"256","DOI":"10.3389\/fnins.2020.00256","article-title":"Disentangling the amyloid pathways: A mechanistic approach to etiology","volume":"14","author":"Malmberg","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e02589","DOI":"10.1016\/j.heliyon.2019.e02589","article-title":"Supersaturated proteins are enriched at synapses and underlie cell and tissue vulnerability in Alzheimer\u2019s disease","volume":"5","author":"Freer","year":"2019","journal-title":"Heliyon"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e1600947","DOI":"10.1126\/sciadv.1600947","article-title":"A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer\u2019s disease","volume":"2","author":"Freer","year":"2016","journal-title":"Sci. Adv."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1074\/jbc.M114.610527","article-title":"The H50Q mutation induces a 10-fold decrease in the solubility of \u03b1-synuclein","volume":"290","author":"Porcari","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/S1474-4422(21)00139-3","article-title":"Comparison of CSF biomarkers in down syndrome and autosomal dominant Alzheimer\u2019s disease: A cross-sectional study","volume":"20","author":"Fagan","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1136\/jnnp.2009.197483","article-title":"Differential levels of \u03b1-synuclein, \u03b2-amyloid42 and tau in CSF between patients with dementia with Lewy bodies and Alzheimer\u2019s disease","volume":"81","author":"Kasuga","year":"2010","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_74","first-page":"304","article-title":"Systemic amyloidosis: A contemporary overview","volume":"59","author":"Ralli","year":"2019","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1001\/jama.2020.5493","article-title":"Systemic amyloidosis recognition, prognosis, and therapy: A systematic review","volume":"324","author":"Gertz","year":"2020","journal-title":"JAMA"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1001\/archinte.166.17.1805","article-title":"Amyloidosis and the heart: A comprehensive review","volume":"166","author":"Shah","year":"2006","journal-title":"Arch. Intern. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1080\/19336896.2020.1776062","article-title":"Determination of amyloid core regions of insulin analogues fibrils","volume":"14","author":"Surin","year":"2020","journal-title":"Prion"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.amjmed.2013.10.029","article-title":"Insulin-derived amyloidosis and poor glycemic control: A case series","volume":"127","author":"Nagase","year":"2014","journal-title":"Am. J. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/nrc2723","article-title":"The first 30 years of p53: Growing ever more complex","volume":"9","author":"Levine","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.tibs.2014.04.001","article-title":"Prion-like aggregation of mutant p53 in cancer","volume":"39","author":"Silva","year":"2014","journal-title":"Trends Biochem. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1021\/acs.biochem.9b00796","article-title":"Prion-like p53 amyloids in cancer","volume":"59","author":"Navalkar","year":"2019","journal-title":"Biochemistry"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1534\/genetics.111.137760","article-title":"Prions in yeast","volume":"191","author":"Liebman","year":"2012","journal-title":"Genetics"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3707","DOI":"10.1016\/j.jmb.2018.04.022","article-title":"Yeast prions compared to functional prions and amyloids","volume":"430","author":"Wickner","year":"2018","journal-title":"J. Mol. Biol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"5337","DOI":"10.1073\/pnas.1102762108","article-title":"Suicidal [PSI+] is a lethal yeast prion","volume":"108","author":"McGlinchey","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"R57","DOI":"10.1530\/JME-17-0138","article-title":"IAPP and type 1 diabetes: Implications for immunity, metabolism and islet transplants","volume":"60","author":"Denroche","year":"2018","journal-title":"J. Mol. Endocrinol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.nicl.2013.02.006","article-title":"Amyloid imaging in cognitively normal individuals, at-risk populations and preclinical Alzheimer\u2019s disease","volume":"2","author":"Villain","year":"2013","journal-title":"NeuroImage Clin."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"100988","DOI":"10.1016\/j.eclinm.2021.100988","article-title":"High cerebrospinal amyloid-\u03b2 42 is associated with normal cognition in individuals with brain amyloidosis","volume":"38","author":"Sturchio","year":"2021","journal-title":"EClinicalMedicine"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41582-018-0116-6","article-title":"A critical appraisal of amyloid-\u03b2-targeting therapies for Alzheimer disease","volume":"15","author":"Panza","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_89","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_90","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.conb.2020.02.003","article-title":"Amyloid b-protein and beyond: The path forward in Alzheimer\u2019s disease","volume":"61","author":"Walsh","year":"2020","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"201922267","DOI":"10.1073\/pnas.1922267117","article-title":"Kinetic diversity of amyloid oligomers","volume":"117","author":"Dear","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"865","DOI":"10.3233\/JAD-2012-120211","article-title":"The load of amyloid-\u03b2 oligomers is decreased in the cerebrospinal fluid of Alzheimer\u2019s disease patients","volume":"31","author":"Sancesario","year":"2012","journal-title":"J. Alzheimers Dis."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"35","DOI":"10.3233\/JAD-142136","article-title":"Amyloid-\u03b2 oligomers relate to cognitive decline in alzheimer\u2019s disease","volume":"45","author":"Jongbloed","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1111\/j.1750-3639.2010.00374.x","article-title":"Higher soluble amyloid \u03b2 concentration in frontal cortex of young adults than in normal elderly or Alzheimer\u2019s disease","volume":"20","author":"Miners","year":"2010","journal-title":"Brain Pathol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/sj.embor.7400896","article-title":"When loss is gain: Reduced presenilin proteolytic function leads to increased A\u03b242\/A\u03b240. Talking Point on the role of presenilin mutations in Alzheimer disease","volume":"8","author":"Wolfe","year":"2007","journal-title":"EMBO Rep."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1007\/s11064-018-2512-0","article-title":"Knockout of amyloid \u03b2 protein precursor (APP) expression alters synaptogenesis, neurite branching and axonal morphology of hippocampal neurons","volume":"44","author":"Southam","year":"2019","journal-title":"Neurochem. Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1002\/ana.22313","article-title":"Endogenous amyloid-\u03b2 is necessary for hippocampal synaptic plasticity and memory","volume":"69","author":"Puzzo","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"36","DOI":"10.3389\/fnmol.2018.00036","article-title":"Silencing alpha synuclein in mature nigral neurons results in rapid neuroinflammation and subsequent toxicity","volume":"11","author":"Benskey","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1038\/mt.2010.115","article-title":"In vivo RNAi-mediated \u03b1-synuclein silencing induces nigrostriatal degeneration","volume":"18","author":"Gorbatyuk","year":"2010","journal-title":"Mol. Ther."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"12","DOI":"10.3389\/fnins.2016.00012","article-title":"Is alpha-synuclein loss-of-function a contributor to parkinsonian pathology? Evidence from non-human primates","volume":"10","author":"Collier","year":"2016","journal-title":"Front. Neurosci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"e12775","DOI":"10.1111\/acel.12775","article-title":"Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits","volume":"17","author":"Velazquez","year":"2018","journal-title":"Aging Cell"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/nn.2483","article-title":"Axonal prion protein is required for peripheral myelin maintenance","volume":"13","author":"Bremer","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2342","DOI":"10.1093\/brain\/awt097","article-title":"Is SOD1 loss of function involved in amyotrophic lateral sclerosis?","volume":"136","author":"Saccon","year":"2013","journal-title":"Brain"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1093\/hmg\/ddp534","article-title":"Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo","volume":"19","author":"Kabashi","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.3233\/JAD-210415","article-title":"Soluble Amyloid-\u03b2 Consumption in Alzheimer\u2019s Disease","volume":"82","author":"Espay","year":"2021","journal-title":"J. Alzheimers Dis."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/11\/4\/535\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:46:42Z","timestamp":1760136402000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/11\/4\/535"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,30]]},"references-count":105,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["biology11040535"],"URL":"https:\/\/doi.org\/10.3390\/biology11040535","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,30]]}}}