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Amyloid β structural polymorphism, associated toxicity and therapeutic strategies

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Abstract

A review of the multidisciplinary scientific literature reveals a large variety of amyloid-β (Aβ) oligomeric species, differing in molecular weight, conformation and morphology. These species, which may assemble via either on‐ or off-aggregation pathways, exhibit differences in stability, function and neurotoxicity, according to different experimental settings. The conformations of the different Aβ species are stabilized by intra- and inter-molecular hydrogen bonds and by electrostatic and hydrophobic interactions, all depending on the chemical and physical environment (e.g., solvent, ions, pH) and interactions with other molecules, such as lipids and proteins. This complexity and the lack of a complete understanding of the relationship between the different Aβ species and their toxicity is currently dictating the nature of the inhibitor (or inducer)-based approaches that are under development for interfering with (or inducing) the formation of specific species and Aβ oligomerization, and for interfering with the associated downstream neurotoxic effects. Here, we review the principles that underlie the involvement of different Aβ oligomeric species in neurodegeneration, both in vitro and in preclinical studies. In addition, we provide an overview of the existing inhibitors (or inducers) of Aβ oligomerization that serve as potential therapeutics for neurodegenerative diseases. The review, which covers the exciting studies that have been published in the past few years, comprises three main parts: 1) on- and off‐fibrillar assembly mechanisms and Aβ structural polymorphism; 2) interactions of Aβ with other molecules and cell components that dictate the Aβ aggregation pathway; and 3) targeting the on‐fibrillar Aβ assembly pathway as a therapeutic approach.

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References

  1. Chiti F, Dobson CM (2006) Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 75:333–366

    Article  CAS  PubMed  Google Scholar 

  2. Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10:698–712

    Article  CAS  PubMed  Google Scholar 

  3. Klein WL, Krafft GA, Finch CE (2001) Targeting small Amyloid beta oligomers: the solution to an Alzheimer’s disease conundrum? Trends Neurosci 24:219–224

    Article  CAS  PubMed  Google Scholar 

  4. Jankowsky JL, Slunt HH, Gonzales V, Savonenko AV, Wen JC, Jenkins NA, Copeland NG, Younkin LH, Lester HA, Younkin SG, and Borchelt DR (2005) Persistent amyloidosis following suppression of Amyloid beta production in a transgenic model of Alzheimer disease. PLoS Med 2, e355

  5. Yan P, Bero AW, Cirrito JR, Xiao Q, Hu X, Wang Y, Gonzales E, Holtzman DM, Lee JM (2009) Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice. J Neurosci 29:10706–10714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580

    Article  CAS  PubMed  Google Scholar 

  7. Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, Kholodenko D, Malenka RC, Nicoll RA, Mucke L (1999) Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc Natl Acad Sci U S A 96:3228–3233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hayden EY, Teplow DB (2013) Amyloid beta-protein oligomers and Alzheimer’s disease. Alzheimers Res Ther 5:60

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ono K, Condron MM, Teplow DB (2009) Structure-neurotoxicity relationships of amyloid beta-protein oligomers. Proc Natl Acad Sci U S A 106:14745–14750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bitan G, Kirkitadze MD, Lomakin A, Vollers SS, Benedek GB, Teplow DB (2003) Amyloid beta -protein (Amyloid beta) assembly: Amyloid beta 40 and Amyloid beta 42 oligomerize through distinct pathways. Proc Natl Acad Sci U S A 100:330–335

    Article  CAS  PubMed  Google Scholar 

  11. Arosio P, Michaels TC, Linse S, Mansson C, Emanuelsson C, Presto J, Johansson J, Vendruscolo M, Dobson CM, Knowles TP (2016) Kinetic analysis reveals the diversity of microscopic mechanisms through which molecular chaperones suppress amyloid formation. Nat Commun 7:10948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cohen SI, Linse S, Luheshi LM, Hellstrand E, White DA, Rajah L, Otzen DE, Vendruscolo M, Dobson CM, Knowles TP (2013) Proliferation of amyloid-beta42 aggregates occurs through a secondary nucleation mechanism. Proc Natl Acad Sci U S A 110:9758–9763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Knowles TP, Vendruscolo M, Dobson CM (2014) The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol 15:384–396

    Article  CAS  PubMed  Google Scholar 

  14. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440:352–357

    Article  CAS  PubMed  Google Scholar 

  15. Miller Y, Ma B, Nussinov R (2010) Polymorphism in Alzheimer Amyloid beta amyloid organization reflects conformational selection in a rugged energy landscape. Chem Rev 110:4820–4838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Misra P, Kodali R, Chemuru S, Kar K, Wetzel R (2016) Rapid alpha-oligomer formation mediated by the Amyloid beta C terminus initiates an amyloid assembly pathway. Nat Commun 7:12419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Orte A, Birkett NR, Clarke RW, Devlin GL, Dobson CM, Klenerman D (2008) Direct characterization of amyloidogenic oligomers by single-molecule fluorescence. Proc Natl Acad Sci U S A 105:14424–14429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pitschke M, Prior R, Haupt M, Riesner D (1998) Detection of single amyloid beta-protein aggregates in the cerebrospinal fluid of Alzheimer’s patients by fluorescence correlation spectroscopy. Nat Med 4:832–834

    Article  CAS  PubMed  Google Scholar 

  20. Klaips CL, Jayaraj GG, Hartl FU (2018) Pathways of cellular proteostasis in aging and disease. J Cell Biol 217:51–63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen GF, Xu TH, Yan Y, Zhou YR, Jiang Y, Melcher K, Xu HE (2017) Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin 38:1205–1235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tran L, Ha-Duong T (2015) Exploring the Alzheimer amyloid-beta peptide conformational ensemble: A review of molecular dynamics approaches. Peptides 69:86–91

    Article  CAS  PubMed  Google Scholar 

  23. Bernstein SL, Dupuis NF, Lazo ND, Wyttenbach T, Condron MM, Bitan G, Teplow DB, Shea JE, Ruotolo BT, Robinson CV, Bowers MT (2009) Amyloid-beta protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer’s disease. Nat Chem 1:326–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Economou NJ, Giammona MJ, Do TD, Zheng X, Teplow DB, Buratto SK, Bowers MT (2016) Amyloid beta-Protein Assembly and Alzheimer’s Disease: Dodecamers of Amyloid beta42, but Not of Amyloid beta40, Seed Fibril Formation. J Am Chem Soc 138:1772–1775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jan A, Gokce O, Luthi-Carter R, Lashuel HA (2008) The ratio of monomeric to aggregated forms of Amyloid beta40 and Amyloid beta42 is an important determinant of amyloid-beta aggregation, fibrillogenesis, and toxicity. J Biol Chem 283:28176–28189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tran J, Chang D, Hsu F, Wang H, Guo Z (2017) Cross-seeding between Amyloid beta40 and Amyloid beta42 in Alzheimer’s disease. FEBS Lett 591:177–185

    Article  CAS  PubMed  Google Scholar 

  27. Chang YJ, Chen YR (2014) The coexistence of an equal amount of Alzheimer’s amyloid-beta 40 and 42 forms structurally stable and toxic oligomers through a distinct pathway. FEBS J 281:2674–2687

    Article  CAS  PubMed  Google Scholar 

  28. Vendruscolo M, Paci E, Karplus M, Dobson CM (2003) Structures and relative free energies of partially folded states of proteins. Proc Natl Acad Sci U S A 100:14817–14821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kad NM, Myers SL, Smith DP, Smith DA, Radford SE, Thomson NH (2003) Hierarchical assembly of beta2-microglobulin amyloid in vitro revealed by atomic force microscopy. J Mol Biol 330:785–797

    Article  CAS  PubMed  Google Scholar 

  30. Wetzel R (2006) Kinetics and thermodynamics of amyloid fibril assembly. Acc Chem Res 39:671–679

    Article  CAS  PubMed  Google Scholar 

  31. Garai K, Frieden C (2013) Quantitative analysis of the time course of Amyloid beta oligomerization and subsequent growth steps using tetramethylrhodamine-labeled Amyloid beta. Proc Natl Acad Sci U S A 110:3321–3326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ehrnhoefer DE, Bieschke J, Boeddrich A, Herbst M, Masino L, Lurz R, Engemann S, Pastore A, Wanker EE (2008) EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat Struct Mol Biol 15:558–566

    Article  CAS  PubMed  Google Scholar 

  33. Cremades N, Dobson CM (2018) The contribution of biophysical and structural studies of protein self-assembly to the design of therapeutic strategies for amyloid diseases. Neurobiol Dis 109:178–190

    Article  CAS  PubMed  Google Scholar 

  34. Bieschke J, Russ J, Friedrich RP, Ehrnhoefer DE, Wobst H, Neugebauer K, Wanker EE (2010) EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity. Proc Natl Acad Sci U S A 107:7710–7715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Karamanos, T. K., Jackson, M. P., Calabrese, A. N., Goodchild, S. C., Cawood, E. E., Thompson, G. S., Kalverda, A. P., Hewitt, E. W., and Radford, S. E. (2019) Structural mapping of oligomeric intermediates in an amyloid assembly pathway. Elife 8

  36. Wu JW, Breydo L, Isas JM, Lee J, Kuznetsov YG, Langen R, Glabe C (2010) Fibrillar oligomers nucleate the oligomerization of monomeric amyloid beta but do not seed fibril formation. J Biol Chem 285:6071–6079

    Article  CAS  PubMed  Google Scholar 

  37. Liang C, Ni R, Smith JE, Childers WS, Mehta AK, Lynn DG (2014) Kinetic intermediates in amyloid assembly. J Am Chem Soc 136:15146–15149

    Article  CAS  PubMed  Google Scholar 

  38. De Benedictis, C. A., Vilella, A., and Grabrucker, A. M. (2019) The Role of Trace Metals in Alzheimer’s Disease. Exon Publications, 85–106.

  39. Lovell M, Robertson J, Teesdale W, Campbell J, Markesbery W (1998) Copper, iron and zinc in Alzheimer’s disease senile plaques. J Neurol Sci 158:47–52

    Article  CAS  PubMed  Google Scholar 

  40. Frederickson CJ, Koh JY, Bush AI (2005) The neurobiology of zinc in health and disease. Nat Rev Neurosci 6:449–462

    Article  CAS  PubMed  Google Scholar 

  41. Bush AI (2003) The metallobiology of Alzheimer’s disease. Trends Neurosci 26:207–214

    Article  CAS  PubMed  Google Scholar 

  42. Garai K, Sahoo B, Kaushalya S, Desai R, Maiti S (2007) Zinc lowers amyloid-β toxicity by selectively precipitating aggregation intermediates. Biochemistry 46:10655–10663

    Article  CAS  PubMed  Google Scholar 

  43. Lovell MA, Xie C, Markesbery WR (1999) Protection against amyloid beta peptide toxicity by zinc. Brain Res 823:88–95

    Article  CAS  PubMed  Google Scholar 

  44. Bishop GM, Robinson SR (2004) The Amyloid Paradox: Amyloid-β-Metal Complexes can be Neurotoxic and Neuroprotective. Brain Pathol 14:448–452

    Article  CAS  PubMed  Google Scholar 

  45. Lee MC, Yu WC, Shih YH, Chen CY, Guo ZH, Huang SJ, Chan JC, Chen YR (2018) Zinc ion rapidly induces toxic, off-pathway amyloid-β oligomers distinct from amyloid-β derived diffusible ligands in Alzheimer’s disease. Sci Rep 8:1–16

    Google Scholar 

  46. Lucas MJ, Keitz BK (2018) Influence of zeolites on amyloid-β aggregation. Langmuir 34:9789–9797

    Article  CAS  PubMed  Google Scholar 

  47. Borghesani V, Alies B, Hureau C (2018) Cu(II) binding to various forms of amyloid-β peptides: are they friends or foes? Eur J Inorg Chem 2018:7–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Boopathi S, Kolandaivel P (2016) Fe2+ binding on amyloid β-peptide promotes aggregation. Proteins: Structure. Function, and Bioinformatics 84:1257–1274

    Article  CAS  Google Scholar 

  49. Vahed, M., Sweeney, A., Shirasawa, H., and Vahed, M. (2019) The initial stage of structural transformation of Aβ42 peptides from the human and mole rat in the presence of Fe2+ and Fe3+: Related to Alzheimer's disease. Computational biology and chemistry 83, 107128

  50. Grasso G, Rebella M, Muscat S, Morbiducci U, Tuszynski J, Danani A, and Deriu MA (2018) Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid beta Assemblies. Int J Mol Sci 19

  51. Matsuzaki K (2014) How do membranes initiate Alzheimer’s disease? Formation of toxic amyloid fibrils by the amyloid β-protein on ganglioside clusters. Acc Chem Res 47:2397–2404

    Article  CAS  PubMed  Google Scholar 

  52. Qian Z, Zhang Q, Liu Y, Chen P (2017) Assemblies of amyloid-β30–36 hexamer and its G33V/L34T mutants by replica-exchange molecular dynamics simulation. PLoS ONE 12:e0188794

    Article  PubMed  PubMed Central  Google Scholar 

  53. Henry S, Vignaud H, l. n., Bobo, C., Decossas, M., Lambert, O., Harte, E., Alves, I. D., Cullin, C., and Lecomte, S. (2015) Interaction of Aβ1–42 amyloids with lipids promotes “off-pathway” oligomerization and membrane damage. Biomacromol 16:944–950

    Article  CAS  Google Scholar 

  54. Cheng, Q., Hu, Z.-W., Doherty, K. E., Tobin-Miyaji, Y. J., and Qiang, W. (2018) The on-fibrillation-pathway membrane content leakage and off-fibrillation-pathway lipid mixing induced by 40-residue β-amyloid peptides in biologically relevant model liposomes. Biochim Biophy Acta (BBA)-Biomembr. 1860, 1670–1680

  55. Itoh N, Takada E, Okubo K, Yano Y, Hoshino M, Sasaki A, Kinjo M, Matsuzaki K (2018) Not Oligomers but Amyloids are Cytotoxic in the Membrane-Mediated Amyloidogenesis of Amyloid-β Peptides. ChemBioChem 19:430–433

    Article  CAS  PubMed  Google Scholar 

  56. Takada E, Okubo K, Yano Y, Iida K, Someda M, Hirasawa A, Yonehara S, Matsuzaki K (2020) Molecular Mechanism of Apoptosis by Amyloid β-Protein Fibrils Formed on Neuronal Cells. ACS Chem Neurosci 11:796–805

    Article  CAS  PubMed  Google Scholar 

  57. Cheng Q, Hu ZW, Doherty KE, Tobin-Miyaji YJ, Qiang W (2018) The on-fibrillation-pathway membrane content leakage and off-fibrillation-pathway lipid mixing induced by 40-residue beta-amyloid peptides in biologically relevant model liposomes. Biochim Biophys Acta Biomembranes 1860:1670–1680

    Article  CAS  PubMed  Google Scholar 

  58. Matsuzaki K (2014) How do membranes initiate Alzheimer’s Disease? Formation of toxic amyloid fibrils by the amyloid beta-protein on ganglioside clusters. Acc Chem Res 47:2397–2404

    Article  CAS  PubMed  Google Scholar 

  59. Henry S, Vignaud H, Bobo C, Decossas M, Lambert O, Harte E, Alves ID, Cullin C, Lecomte S (2015) Interaction of Amyloid beta(1–42) amyloids with lipids promotes “off-pathway” oligomerization and membrane damage. Biomacromol 16:944–950

    Article  CAS  Google Scholar 

  60. Kedia N, Almisry M, Bieschke J (2017) Glucose directs amyloid-beta into membrane-active oligomers. Phys Chem Chem Phys 19:18036–18046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Malishev R, Shaham-Niv S, Nandi S, Kolusheva S, Gazit E, Jelinek R (2017) Bacoside-A, an Indian traditional-medicine substance, inhibits β-amyloid cytotoxicity, fibrillation, and membrane interactions. ACS Chem Neurosci 8:884–891

    Article  CAS  PubMed  Google Scholar 

  62. Malishev R, Nandi S, Kolusheva S, Levi-Kalisman Y, Klärner F-G, Schrader T, Bitan G, Jelinek R (2015) Toxicity inhibitors protect lipid membranes from disruption by Aβ42. ACS Chem Neurosci 6:1860–1869

    Article  CAS  PubMed  Google Scholar 

  63. Oren O, Ben Zichri S, Taube R, Jelinek R, Papo N (2020) An Aβ42 double mutant inhibits Aβ42-induced plasma and mitochondrial membrane disruption in artificial membranes, isolated organs and intact cells. ACS Chem Neurosci 11(7):1027

    Article  CAS  PubMed  Google Scholar 

  64. Lee SJC, Nam E, Lee HJ, Savelieff MG, Lim MH (2017) Towards an understanding of amyloid-β oligomers: characterization, toxicity mechanisms, and inhibitors. Chem Soc Rev 46:310–323

    Article  CAS  PubMed  Google Scholar 

  65. Chainoglou E, Hadjipavlou-Litina D (2020) Curcumin in Health and Diseases: Alzheimer’s Disease and Curcumin Analogues, Derivatives, and Hybrids. Int J Mol Sci 21:1975

    Article  CAS  PubMed Central  Google Scholar 

  66. Reddy PH, Manczak M, Yin X, Grady MC, Mitchell A, Tonk S, Kuruva CS, Bhatti JS, Kandimalla R, Vijayan M (2018) Protective effects of Indian spice curcumin against amyloid-β in Alzheimer’s disease. J Alzheimers Dis 61:843–866

    Article  PubMed  PubMed Central  Google Scholar 

  67. Thapa A, Jett SD, Chi EY (2016) Curcumin attenuates amyloid-β aggregate toxicity and modulates amyloid-β aggregation pathway. ACS Chem Neurosci 7:56–68

    Article  CAS  PubMed  Google Scholar 

  68. Ahmed R, VanSchouwen B, Jafari N, Ni X, Ortega J, Melacini G (2017) Molecular mechanism for the (−)-epigallocatechin gallate-induced toxic to nontoxic remodeling of Aβ oligomers. J Am Chem Soc 139:13720–13734

    Article  CAS  PubMed  Google Scholar 

  69. Kurisaki I, Tanaka S (2019) ATP converts Aβ42 oligomer into off-pathway species by making contact with its backbone atoms using hydrophobic adenosine. J Phys Chem B 123:9922–9933

    Article  CAS  PubMed  Google Scholar 

  70. Patel A, Malinovska L, Saha S, Wang J, Alberti S, Krishnan Y, Hyman AA (2017) ATP as a biological hydrotrope. Science 356:753–756

    Article  CAS  PubMed  Google Scholar 

  71. Wiglenda T, Groenke N, Hoffmann W, Manz C, Diez L, Buntru A, Brusendorf L, Neuendorf N, Schnoegl S, Haenig C (2020) Sclerotiorin stabilizes the assembly of nonfibrillar amyloid beta42 oligomers with low toxicity, seeding activity, and beta-sheet content. J Mol Biol 432:2080–2098

    Article  CAS  PubMed  Google Scholar 

  72. Derrick JS, Kerr RA, Nam Y, Oh SB, Lee HJ, Earnest KG, Suh N, Peck KL, Ozbil M, Korshavn KJ (2015) A redox-active, compact molecule for cross-linking amyloidogenic peptides into nontoxic, off-pathway aggregates: in vitro and in vivo efficacy and molecular mechanisms. J Am Chem Soc 137:14785–14797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Beck MW, Oh SB, Kerr RA, Lee HJ, Kim SH, Kim S, Jang M, Ruotolo BT, Lee J-Y, Lim MH (2015) A rationally designed small molecule for identifying an in vivo link between metal–amyloid-β complexes and the pathogenesis of Alzheimer’s disease. Chem Sci 6:1879–1886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Rammes G, Gravius A, Ruitenberg M, Wegener N, Chambon C, Sroka-Saidi K, Jeggo R, Staniaszek L, Spanswick D, O’Hare E (2015) MRZ-99030–A novel modulator of Aβ aggregation: II–Reversal of Aβ oligomer-induced deficits in long-term potentiation (LTP) and cognitive performance in rats and mice. Neuropharmacology 92:170–182

    Article  CAS  PubMed  Google Scholar 

  75. Frydman-Marom A, Rechter M, Shefler I, Bram Y, Shalev DE, Gazit E (2009) Cognitive-performance recovery of Alzheimer’s disease model mice by modulation of early soluble amyloidal assemblies. Angew Chem Int Ed 48:1981–1986

    Article  CAS  Google Scholar 

  76. Parsons CG, Ruitenberg M, Freitag CE, Sroka-Saidi K, Russ H, Rammes G (2015) MRZ-99030–A novel modulator of Aβ aggregation: I-Mechanism of action (MoA) underlying the potential neuroprotective treatment of Alzheimer’s disease, glaucoma and age-related macular degeneration (AMD). Neuropharmacology 92:158–169

    Article  CAS  PubMed  Google Scholar 

  77. Guichard G, Huc I (2011) Synthetic foldamers. Chem Commun 47:5933–5941

    Article  CAS  Google Scholar 

  78. Kumar S, Henning-Knechtel A, Chehade I, Magzoub M, Hamilton AD (2017) Foldamer-mediated structural rearrangement attenuates Aβ oligomerization and cytotoxicity. J Am Chem Soc 139:17098–17108

    Article  CAS  PubMed  Google Scholar 

  79. Oren O, Banerjee V, Taube R, Papo N (2018) An Aβ42 variant that inhibits intra-and extracellular amyloid aggregation and enhances cell viability. Biochemical Journal 475:3087–3103

    Article  CAS  Google Scholar 

  80. Banerjee V, Oren O, Dagan B, Taube R, Engel S, Papo N (2018) An engineered variant of the B1 domain of protein G suppresses the aggregation and toxicity of intra-and extracellular Aβ42. ACS Chem Neurosci 10:1488–1496

    Article  PubMed  Google Scholar 

  81. Gray VE, Sitko K, Kameni FZN, Williamson M, Stephany JJ, Hasle N, and Fowler DM (2019) Elucidating the Molecular Determinants of Amyloid beta Aggregation with Deep Mutational Scanning. G3 (Bethesda). 9(11):3683–3689

  82. Fowler DM, Fields S (2014) Deep mutational scanning: a new style of protein science. Nat Methods 11:801–807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Fowler DM, Stephany JJ, Fields S (2014) Measuring the activity of protein variants on a large scale using deep mutational scanning. Nat Protoc 9:2267–2284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Radbakhsh S, Barreto GE, Bland AR, Sahebkar A (2021) Curcumin: A small molecule with big functionality against amyloid aggregation in neurodegenerative diseases and type 2 diabetes. BioFactors 47:570–586

    Article  CAS  PubMed  Google Scholar 

  85. Ide K, Yamada H, Takuma N, Harada S, Nakase J, Ukawa Y, Sagesaka YM (2015) Effects of green tea consumption on cognitive dysfunction in an elderly population: a randomized placebo-controlled study. Nutr J 15:49–58

    Article  Google Scholar 

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Funding

This work was supported by the European Research Council “Ideas program” ERC-2013-StG (contract grant number: 336041) and the Israel Science Foundation (grant number 615/14) to Niv Papo.

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  1. The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, 84105, Beer-Sheva, Israel

    Ofek Oren & Ran Taube

  2. Department of Biotechnology Engineering, Avram and Stella Goldstein-Goren, National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, P.O. Box 653, 84105, Beer-Sheva, Israel

    Ofek Oren & Niv Papo

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  1. Ofek Oren
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  2. Ran Taube
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O.O. and N.P. wrote the paper. All authors edited the manuscript and approved the final version.

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Oren, O., Taube, R. & Papo, N. Amyloid β structural polymorphism, associated toxicity and therapeutic strategies. Cell. Mol. Life Sci. 78, 7185–7198 (2021). https://doi.org/10.1007/s00018-021-03954-z

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