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The structure and phase of tau: from monomer to amyloid filament

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Abstract

Tau is a microtubule-associated protein involved in regulation of assembly and spatial organization of microtubule in neurons. However, in pathological conditions, tau monomers assemble into amyloid filaments characterized by the cross-β structures in a number of neurodegenerative diseases known as tauopathies. In this review, we summarize recent progression on the characterization of structures of tau monomer and filament, as well as the dynamic liquid droplet assembly. Our aim is to reveal how post-translational modifications, amino acid mutations, and interacting molecules modulate the conformational ensemble of tau monomer, and how they accelerate or inhibit tau assembly into aggregates. Structure-based aggregation inhibitor design is also discussed in the context of dynamics and heterogeneity of tau structures.

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References

  1. Goedert M, Spillantini MG, Potier MC, Ulrich J, Crowther RA (1989) Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J 8:393–399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Guo T, Noble W, Hanger DP (2017) Roles of tau protein in health and disease. Acta Neuropathol 133:665–704. https://doi.org/10.1007/s00401-017-1707-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sayas CL, Tortosa E, Bollati F, Ramirez-Rios S, Arnal I, Avila J (2015) Tau regulates the localization and function of End-binding proteins 1 and 3 in developing neuronal cells. J Neurochem 133:653–667. https://doi.org/10.1111/jnc.13091

    Article  CAS  PubMed  Google Scholar 

  4. Berriman J, Serpell LC, Oberg KA, Fink AL, Goedert M, Crowther RA (2003) Tau filaments from human brain and from in vitro assembly of recombinant protein show cross-beta structure. Proc Natl Acad Sci USA 100:9034–9038. https://doi.org/10.1073/pnas.1530287100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ballatore C, Lee VM, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 8:663–672. https://doi.org/10.1038/nrn2194

    Article  CAS  PubMed  Google Scholar 

  6. Iqbal K, Liu F, Gong CX (2016) Tau and neurodegenerative disease: the story so far. Nat Rev Neurol 12:15–27. https://doi.org/10.1038/nrneurol.2015.225

    Article  CAS  PubMed  Google Scholar 

  7. Lee G, Leugers CJ (2012) Tau and tauopathies. Prog Mol Biol Transl Sci 107:263–293. https://doi.org/10.1016/B978-0-12-385883-2.00004-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li C, Gotz J (2017) Tau-based therapies in neurodegeneration: opportunities and challenges. Nat Rev Drug Discov 16:863–883. https://doi.org/10.1038/nrd.2017.155

    Article  CAS  PubMed  Google Scholar 

  9. Medina M (2018) An overview on the clinical development of tau-based therapeutics. Int J Mol Sci 19:1160. https://doi.org/10.3390/ijms19041160

    Article  CAS  PubMed Central  Google Scholar 

  10. Long JM, Holtzman DM (2019) Alzheimer disease: an update on pathobiology and treatment strategies. Cell 179:312–339. https://doi.org/10.1016/j.cell.2019.09.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chong FP, Ng KY, Koh RY, Chye SM (2018) Tau proteins and tauopathies in Alzheimer’s disease. Cell Mol Neurobiol 38:965–980. https://doi.org/10.1007/s10571-017-0574-1

    Article  CAS  PubMed  Google Scholar 

  12. Morris M, Maeda S, Vossel K, Mucke L (2011) The many faces of tau. Neuron 70:410–426. https://doi.org/10.1016/j.neuron.2011.04.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sotiropoulos I, Galas MC, Silva JM, Skoulakis E, Wegmann S, Maina MB, Blum D, Sayas CL et al (2017) Atypical, non-standard functions of the microtubule associated Tau protein. Acta Neuropathol Commun 5:91. https://doi.org/10.1186/s40478-017-0489-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schweers O, Schönbrunn-Hanebeck E, Marx A, Mandelkow E (1994) Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for b-structure. J Biol Chem 269:24290–24297

    Article  CAS  PubMed  Google Scholar 

  15. Smet C, Leroy A, Sillen A, Wieruszeski JM, Landrieu I, Lippens G (2004) Accepting its random coil nature allows a partial NMR assignment of the neuronal Tau protein. ChemBioChem 5:1639–1646. https://doi.org/10.1002/cbic.200400145

    Article  CAS  PubMed  Google Scholar 

  16. Mylonas E, Hascher A, Bernado P, Blackledge M, Mandelkow E, Svergun DI (2008) Domain conformation of tau protein studied by solution small-angle X-ray scattering. Biochemistry 47:10345–10353. https://doi.org/10.1021/bi800900d

    Article  CAS  PubMed  Google Scholar 

  17. Nath A, Sammalkorpi M, DeWitt DC, Trexler AJ, Elbaum-Garfinkle S, O’Hern CS, Rhoades E (2012) The conformational ensembles of alpha-synuclein and tau: combining single-molecule FRET and simulations. Biophys J 103:1940–1949. https://doi.org/10.1016/j.bpj.2012.09.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schwalbe M, Ozenne V, Bibow S, Jaremko M, Jaremko L, Gajda M, Jensen MR, Biernat J et al (2014) Predictive atomic resolution descriptions of intrinsically disordered hTau40 and alpha-synuclein in solution from NMR and small angle scattering. Structure 22:238–249. https://doi.org/10.1016/j.str.2013.10.020

    Article  CAS  PubMed  Google Scholar 

  19. von Bergen M, Barghorn S, Li L, Marx A, Biernat J, Mandelkow EM, Mandelkow E (2001) Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure. J Biol Chem 276:48165–48174. https://doi.org/10.1074/jbc.M105196200

    Article  Google Scholar 

  20. von Bergen M, Friedhoff P, Biernat J, Heberle J, Mandelkow EM, Mandelkow E (2000) Assembly of t protein into Alzheimer paired helical filaments depends on a local sequence motif (306VQIVYK311) forming b structure. Proc Natl Acad Sci USA 97:5129–5134

    Article  Google Scholar 

  21. Mukrasch MD, Markwick P, Biernat J, Bergen M, Bernado P, Griesinger C, Mandelkow E, Zweckstetter M et al (2007) Highly populated turn conformations in natively unfolded tau protein identified from residual dipolar couplings and molecular simulation. J Am Chem Soc 129:5235–5243. https://doi.org/10.1021/ja0690159

    Article  CAS  PubMed  Google Scholar 

  22. Mukrasch MD, Bibow S, Korukottu J, Jeganathan S, Biernat J, Griesinger C, Mandelkow E, Zweckstetter M (2009) Structural polymorphism of 441-residue tau at single residue resolution. PLoS Biol 7:e34. https://doi.org/10.1371/journal.pbio.1000034

    Article  CAS  PubMed  Google Scholar 

  23. Mukrasch MD, Biernat J, von Bergen M, Griesinger C, Mandelkow E, Zweckstetter M (2005) Sites of tau important for aggregation populate {beta}-structure and bind to microtubules and polyanions. J Biol Chem 280:24978–24986. https://doi.org/10.1074/jbc.M501565200

    Article  CAS  PubMed  Google Scholar 

  24. Wegmann S, Scholer J, Bippes CA, Mandelkow E, Muller DJ (2011) Competing interactions stabilize pro- and anti-aggregant conformations of human tau. J Biol Chem 286:20512–20524. https://doi.org/10.1074/jbc.M111.237875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Luo Y, Ma BY, Nussinov R, Wei GH (2014) Structural insight into tau protein’s paradox of intrinsically disordered behavior, self-acetylation activity, and aggregation. J Phys Chem Lett 5:3026–3031. https://doi.org/10.1021/jz501457f

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jeganathan S, von Bergen M, Brutlach H, Steinhoff HJ, Mandelkow E (2006) Global hairpin folding of tau in solution. Biochemistry 45:2283–2293. https://doi.org/10.1021/bi0521543

    Article  CAS  PubMed  Google Scholar 

  27. Elbaum-Garfinkle S, Rhoades E (2012) Identification of an aggregation-prone structure of tau. J Am Chem Soc 134:16607–16613. https://doi.org/10.1021/ja305206m

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Popov KI, Makepeace KAT, Petrotchenko EV, Dokholyan NV, Borchers CH (2019) Insight into the structure of the “unstructured” tau protein. Structure 27:1710–1715. https://doi.org/10.1016/j.str.2019.09.003

    Article  CAS  PubMed  Google Scholar 

  29. Manger LH, Foote AK, Wood SL, Holden MR, Heylman KD, Margittai M, Goldsmith RH (2017) Revealing conformational variants of solution-phase intrinsically disordered tau protein at the single-molecule level. Angew Chem Int Ed Engl 56:15584–15588. https://doi.org/10.1002/anie.201708242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Foote AK, Manger LH, Holden MR, Margittai M, Goldsmith RH (2019) Time-resolved multirotational dynamics of single solution-phase tau proteins reveals details of conformational variation. Phys Chem Chem Phys 21:1863–1871. https://doi.org/10.1039/c8cp06971a

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mirbaha H, Chen D, Morazova OA, Ruff KM, Sharma AM, Liu X, Goodarzi M, Pappu RV et al (2018) Inert and seed-competent tau monomers suggest structural origins of aggregation. Elife 7:e36584. https://doi.org/10.7554/eLife.36584

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sharma AM, Thomas TL, Woodard DR, Kashmer OM, Diamond MI (2018) Tau monomer encodes strains. Elife 7:e37813. https://doi.org/10.7554/eLife.37813

    Article  PubMed  PubMed Central  Google Scholar 

  33. Carmel G, Mager EM, Binder LI, Kuret J (1996) The structural basis of monoclonal antibody Alz50’s selectivity for Alzheimer’s disease pathology. J Biol Chem 271:32789–32795. https://doi.org/10.1074/jbc.271.51.32789

    Article  CAS  PubMed  Google Scholar 

  34. Jicha GA, Bowser R, Kazam IG, Davies P (1997) Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau. J Neurosci Res 48:128–132. https://doi.org/10.1002/(sici)1097-4547(19970415)48:2%3c128::aid-jnr5%3e3.0.co;2-e

    Article  CAS  PubMed  Google Scholar 

  35. Ward SM, Himmelstein DS, Lancia JK, Binder LI (2012) Tau oligomers and tau toxicity in neurodegenerative disease. Biochem Soc Trans 40:667–671. https://doi.org/10.1042/BST20120134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Eschmann NA, Georgieva ER, Ganguly P, Borbat PP, Rappaport MD, Akdogan Y, Freed JH, Shea JE et al (2017) Signature of an aggregation-prone conformation of tau. Sci Rep 7:44739. https://doi.org/10.1038/srep44739

    Article  PubMed  PubMed Central  Google Scholar 

  37. Chen D, Drombosky KW, Hou Z, Sari L, Kashmer OM, Ryder BD, Perez VA, Woodard DR et al (2019) Tau local structure shields an amyloid-forming motif and controls aggregation propensity. Nat Commun 10:2493. https://doi.org/10.1038/s41467-019-10355-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhu S, Shala A, Bezginov A, Sljoka A, Audette G, Wilson DJ (2015) Hyperphosphorylation of intrinsically disordered tau protein induces an amyloidogenic shift in its conformational ensemble. PLoS ONE 10:e0120416. https://doi.org/10.1371/journal.pone.0120416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jeganathan S, Hascher A, Chinnathambi S, Biernat J, Mandelkow EM, Mandelkow E (2008) Proline-directed pseudo-phosphorylation at AT8 and PHF1 epitopes induces a compaction of the paperclip folding of tau and generates a pathological (MC-1) conformation. J Biol Chem 283:32066–32076. https://doi.org/10.1074/jbc.M805300200

    Article  CAS  PubMed  Google Scholar 

  40. Bibow S, Ozenne V, Biernat J, Blackledge M, Mandelkow E, Zweckstetter M (2011) Structural impact of proline-directed pseudophosphorylation at AT8, AT100, and PHF1 epitopes on 441-residue tau. J Am Chem Soc 133:15842–15845. https://doi.org/10.1021/ja205836j

    Article  CAS  PubMed  Google Scholar 

  41. Despres C, Byrne C, Qi H, Cantrelle FX, Huvent I, Chambraud B, Baulieu EE, Jacquot Y et al (2017) Identification of the tau phosphorylation pattern that drives its aggregation. Proc Natl Acad Sci USA 114:9080–9085. https://doi.org/10.1073/pnas.1708448114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wickramasinghe SP, Lempart J, Merens HE, Murphy J, Huettemann P, Jakob U, Rhoades E (2019) Polyphosphate initiates tau aggregation through intra- and intermolecular scaffolding. Biophys J 117:717–728. https://doi.org/10.1016/j.bpj.2019.07.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Akoury E, Mukrasch MD, Biernat J, Tepper K, Ozenne V, Mandelkow E, Blackledge M, Zweckstetter M (2016) Remodeling of the conformational ensemble of the repeat domain of tau by an aggregation enhancer. Protein Sci 25:1010–1020. https://doi.org/10.1002/pro.2911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Banani SF, Lee HO, Hyman AA, Rosen MK (2017) Biomolecular condensates: organizers of cellular biochemistry. Nat Rev Mol Cell Biol 18:285–298. https://doi.org/10.1038/nrm.2017.7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wu H, Fuxreiter M (2016) The Structure and dynamics of higher-order assemblies: amyloids, signalosomes, and granules. Cell 165:1055–1066. https://doi.org/10.1016/j.cell.2016.05.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Boeynaems S, Alberti S, Fawzi NL, Mittag T, Polymenidou M, Rousseau F, Schymkowitz J, Shorter J et al (2018) Protein phase separation: a new phase in cell biology. Trends Cell Biol 28:420–435. https://doi.org/10.1016/j.tcb.2018.02.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Feng Z, Chen X, Wu X, Zhang M (2019) Formation of biological condensates via phase separation: characteristics, analytical methods, and physiological implications. J Biol Chem 294:14823–14835. https://doi.org/10.1074/jbc.REV119.007895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Cramer P (2019) Organization and regulation of gene transcription. Nature 573:45–54. https://doi.org/10.1038/s41586-019-1517-4

    Article  CAS  PubMed  Google Scholar 

  49. Rhine K, Vidaurre V, Myong S (2020) RNA droplets. Annu Rev Biophys 49:247–265. https://doi.org/10.1146/annurev-biophys-052118-115508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Aguzzi A, Altmeyer M (2016) Phase separation: linking cellular compartmentalization to disease. Trends Cell Biol 26:547–558. https://doi.org/10.1016/j.tcb.2016.03.004

    Article  CAS  PubMed  Google Scholar 

  51. Shin Y, Brangwynne CP (2017) Liquid phase condensation in cell physiology and disease. Science 357:eaaf4382. https://doi.org/10.1126/science.aaf4382

    Article  CAS  PubMed  Google Scholar 

  52. Alberti S, Dormann D (2019) Liquid-liquid phase separation in disease. Annu Rev Genet 53:171–194. https://doi.org/10.1146/annurev-genet-112618-043527

    Article  CAS  PubMed  Google Scholar 

  53. de Oliveira GAP, Cordeiro Y, Silva JL, Vieira T (2019) Liquid-liquid phase transitions and amyloid aggregation in proteins related to cancer and neurodegenerative diseases. Adv Protein Chem Struct Biol 118:289–331. https://doi.org/10.1016/bs.apcsb.2019.08.002

    Article  PubMed  Google Scholar 

  54. Hernandez-Vega A, Braun M, Scharrel L, Jahnel M, Wegmann S, Hyman BT, Alberti S, Diez S et al (2017) Local nucleation of microtubule bundles through tubulin concentration into a condensed tau phase. Cell Rep 20:2304–2312. https://doi.org/10.1016/j.celrep.2017.08.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ambadipudi S, Biernat J, Riedel D, Mandelkow E, Zweckstetter M (2017) Liquid-liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein tau. Nat Commun 8:275. https://doi.org/10.1038/s41467-017-00480-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wegmann S, Eftekharzadeh B, Tepper K, Zoltowska KM, Bennett RE, Dujardin S, Laskowski PR, MacKenzie D et al (2018) Tau protein liquid-liquid phase separation can initiate tau aggregation. EMBO J 37:e98049. https://doi.org/10.15252/embj.201798049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Boyko S, Qi X, Chen TH, Surewicz K, Surewicz WK (2019) Liquid-liquid phase separation of tau protein: the crucial role of electrostatic interactions. J Biol Chem 294:11054–11059. https://doi.org/10.1074/jbc.AC119.009198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Vega IE, Umstead A, Kanaan NM (2019) EFhd2 affects tau liquid-liquid phase separation. Front Neurosci 13:845. https://doi.org/10.3389/fnins.2019.00845

    Article  PubMed  PubMed Central  Google Scholar 

  59. Ambadipudi S, Reddy JG, Biernat J, Mandelkow E, Zweckstetter M (2019) Residue-specific identification of phase separation hot spots of Alzheimer’s-related protein tau. Chem Sci 10:6503–6507. https://doi.org/10.1039/c9sc00531e

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lin Y, McCarty J, Rauch JN, Delaney KT, Kosik KS, Fredrickson GH, Shea JE, Han S (2019) Narrow equilibrium window for complex coacervation of tau and RNA under cellular conditions. Elife 8:e42571. https://doi.org/10.7554/eLife.42571

    Article  PubMed  PubMed Central  Google Scholar 

  61. Ukmar-Godec T, Hutten S, Grieshop MP, Rezaei-Ghaleh N, Cima-Omori MS, Biernat J, Mandelkow E, Soding J et al (2019) Lysine/RNA-interactions drive and regulate biomolecular condensation. Nat Commun 10:2909. https://doi.org/10.1038/s41467-019-10792-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhang X, Lin Y, Eschmann NA, Zhou H, Rauch JN, Hernandez I, Guzman E, Kosik KS et al (2017) RNA stores tau reversibly in complex coacervates. PLoS Biol 15:e2002183. https://doi.org/10.1371/journal.pbio.2002183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lin Y, Fichou Y, Zeng Z, Hu NY, Han S (2020) Electrostatically driven complex coacervation and amyloid aggregation of tau are independent processes with overlapping conditions. ACS Chem Neurosci 11:615–627. https://doi.org/10.1021/acschemneuro.9b00627

    Article  CAS  PubMed  Google Scholar 

  64. Ferreon JC, Jain A, Choi KJ, Tsoi PS, MacKenzie KR, Jung SY, Ferreon AC (2018) Acetylation disfavors tau phase separation. Int J Mol Sci 19:1360. https://doi.org/10.3390/ijms19051360

    Article  CAS  PubMed Central  Google Scholar 

  65. Rane JS, Kumari A, Panda D (2020) The acetyl mimicking mutation, K274Q in tau, enhances the metal binding affinity of tau and reduces the ability of tau to protect DNA. ACS Chem Neurosci 11:291–303. https://doi.org/10.1021/acschemneuro.9b00455

    Article  CAS  PubMed  Google Scholar 

  66. Singh V, Xu L, Boyko S, Surewicz K, Surewicz WK (2020) Zinc promotes liquid-liquid phase separation of tau protein. J Biol Chem 295:5850–5856. https://doi.org/10.1074/jbc.AC120.013166

    Article  PubMed  PubMed Central  Google Scholar 

  67. Majumdar A, Dogra P, Maity S, Mukhopadhyay S (2019) Liquid-liquid phase separation is driven by large-scale conformational unwinding and fluctuations of intrinsically disordered protein molecules. J Phys Chem Lett 10:3929–3936. https://doi.org/10.1021/acs.jpclett.9b01731

    Article  CAS  PubMed  Google Scholar 

  68. Rane JS, Kumari A, Panda D (2019) An acetylation mimicking mutation, K274Q, in tau imparts neurotoxicity by enhancing tau aggregation and inhibiting tubulin polymerization. Biochem J 476:1401–1417. https://doi.org/10.1042/BCJ20190042

    Article  CAS  PubMed  Google Scholar 

  69. Wang K, Liu JQ, Zhong T, Liu XL, Zeng Y, Qiao X, Xie T, Chen Y et al (2020) Phase separation and cytotoxicity of tau are modulated by protein disulfide isomerase and s-nitrosylation of this molecular chaperone. J Mol Biol 432:2141–2163. https://doi.org/10.1016/j.jmb.2020.02.013

    Article  CAS  PubMed  Google Scholar 

  70. Kanaan NM, Hamel C, Grabinski T, Combs B (2020) Liquid-liquid phase separation induces pathogenic tau conformations in vitro. Nat Commun 11:2809. https://doi.org/10.1038/s41467-020-16580-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wille H, Drewes G, Biernat J, Mandelkow EM, Mandelkow E (1992) Alzheimer-like paired helical filaments and antiparallel dimers formed from microtubule-associated protein tau in vitro. J Cell Biol 118:573–584. https://doi.org/10.1083/jcb.118.3.573

    Article  CAS  PubMed  Google Scholar 

  72. Sahara N, Maeda S, Murayama M, Suzuki T, Dohmae N, Yen SH, Takashima A (2007) Assembly of two distinct dimers and higher-order oligomers from full-length tau. Eur J Neurosci 25:3020–3029. https://doi.org/10.1111/j.1460-9568.2007.05555.x

    Article  PubMed  Google Scholar 

  73. Patterson KR, Remmers C, Fu Y, Brooker S, Kanaan NM, Vana L, Ward S, Reyes JF et al (2011) Characterization of prefibrillar tau oligomers in vitro and in Alzheimer disease. J Biol Chem 286:23063–23076. https://doi.org/10.1074/jbc.M111.237974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Makrides V, Shen TE, Bhatia R, Smith BL, Thimm J, Lal R, Feinstein SC (2003) Microtubule-dependent oligomerization of tau. Implications for physiological tau function and tauopathies. J Biol Chem 278:33298–33304. https://doi.org/10.1074/jbc.M305207200

    Article  CAS  PubMed  Google Scholar 

  75. Lasagna-Reeves CA, Castillo-Carranza DL, Guerrero-Muoz MJ, Jackson GR, Kayed R (2010) Preparation and characterization of neurotoxic tau oligomers. Biochemistry 49:10039–10041. https://doi.org/10.1021/bi1016233

    Article  CAS  PubMed  Google Scholar 

  76. Berger Z, Roder H, Hanna A, Carlson A, Rangachari V, Yue M, Wszolek Z, Ashe K et al (2007) Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J Neurosci 27:3650–3662. https://doi.org/10.1523/JNEUROSCI.0587-07.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Tian H, Davidowitz E, Lopez P, Emadi S, Moe J, Sierks M (2013) Trimeric tau is toxic to human neuronal cells at low nanomolar concentrations. Int J Cell Biol 2013:260787. https://doi.org/10.1155/2013/260787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ren Y, Sahara N (2013) Characteristics of tau oligomers Front Neurol 4:102. https://doi.org/10.3389/fneur.2013.00102

    Article  CAS  PubMed  Google Scholar 

  79. Ait-Bouziad N, Lv G, Mahul-Mellier AL, Xiao S, Zorludemir G, Eliezer D, Walz T, Lashuel HA (2017) Discovery and characterization of stable and toxic tau/phospholipid oligomeric complexes. Nat Commun 8:1678. https://doi.org/10.1038/s41467-017-01575-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Maeda S, Takashima A (2019) Tau oligomers. Adv Exp Med Biol 1184:373–380. https://doi.org/10.1007/978-981-32-9358-8_27

    Article  CAS  PubMed  Google Scholar 

  81. Kaniyappan S, Chandupatla RR, Mandelkow EM, Mandelkow E (2017) Extracellular low-n oligomers of tau cause selective synaptotoxicity without affecting cell viability. Alzheimers Dement 13:1270–1291. https://doi.org/10.1016/j.jalz.2017.04.002

    Article  PubMed  Google Scholar 

  82. Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Clos AL, Jackson GR, Kayed R (2011) Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice. Mol Neurodegener 6:39. https://doi.org/10.1186/1750-1326-6-39

    Article  PubMed  PubMed Central  Google Scholar 

  83. Tepper K, Biernat J, Kumar S, Wegmann S, Timm T, Hubschmann S, Redecke L, Mandelkow EM et al (2014) Oligomer formation of tau protein hyperphosphorylated in cells. J Biol Chem 289:34389–34407. https://doi.org/10.1074/jbc.M114.611368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kim D, Lim S, Haque MM, Ryoo N, Hong HS, Rhim H, Lee DE, Chang YT et al (2015) Identification of disulfide cross-linked tau dimer responsible for tau propagation. Sci Rep 5:15231. https://doi.org/10.1038/srep15231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Friedhoff P, von Bergen M, Mandelkow EM, Davies P, Mandelkow E (1998) A nucleated assembly mechanism of Alzheimer paired helical filaments. Proc Natl Acad Sci USA 95:15712–15717. https://doi.org/10.1073/pnas.95.26.15712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Cowan CM, Mudher A (2013) Are tau aggregates toxic or protective in tauopathies? Front Neurol 4:114. https://doi.org/10.3389/fneur.2013.00114

    Article  PubMed  PubMed Central  Google Scholar 

  87. Wegmann S, Nicholls S, Takeda S, Fan Z, Hyman BT (2016) Formation, release, and internalization of stable tau oligomers in cells. J Neurochem 139:1163–1174. https://doi.org/10.1111/jnc.13866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Castillo-Carranza DL, Sengupta U, Guerrero-Munoz MJ, Lasagna-Reeves CA, Gerson JE, Singh G, Estes DM, Barrett AD et al (2014) Passive immunization with Tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J Neurosci 34:4260–4272. https://doi.org/10.1523/JNEUROSCI.3192-13.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Sarmiento J, Troncoso J, Jackson GR, Kayed R (2012) Identification of oligomers at early stages of tau aggregation in Alzheimer’s disease. FASEB J 26:1946–1959. https://doi.org/10.1096/fj.11-199851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Maeda S, Sahara N, Saito Y, Murayama M, Yoshiike Y, Kim H, Miyasaka T, Murayama S et al (2007) Granular tau oligomers as intermediates of tau filaments. Biochemistry 46:3856–3861. https://doi.org/10.1021/bi061359o

    Article  CAS  PubMed  Google Scholar 

  91. Rosenberg KJ, Ross JL, Feinstein HE, Feinstein SC, Israelachvili J (2008) Complementary dimerization of microtubule-associated tau protein: Implications for microtubule bundling and tau-mediated pathogenesis. Proc Natl Acad Sci USA 105:7445–7450. https://doi.org/10.1073/pnas.0802036105

    Article  PubMed  PubMed Central  Google Scholar 

  92. Watanabe A, Hong WK, Dohmae N, Takio K, Morishima-Kawashima M, Ihara Y (2004) Molecular aging of tau: disulfide-independent aggregation and non-enzymatic degradation in vitro and in vivo. J Neurochem 90:1302–1311. https://doi.org/10.1111/j.1471-4159.2004.02611.x

    Article  CAS  PubMed  Google Scholar 

  93. Feinstein HE, Benbow SJ, LaPointe NE, Patel N, Ramachandran S, Do TD, Gaylord MR, Huskey NE et al (2016) Oligomerization of the microtubule-associated protein tau is mediated by its N-terminal sequences: implications for normal and pathological tau action. J Neurochem 137:939–954. https://doi.org/10.1111/jnc.13604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ramachandran G, Udgaonkar JB (2011) Understanding the kinetic roles of the inducer heparin and of rod-like protofibrils during amyloid fibril formation by Tau protein. J Biol Chem 286:38948–38959. https://doi.org/10.1074/jbc.M111.271874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Fichou Y, Oberholtzer ZR, Ngo H, Cheng CY, Keller TJ, Eschmann NA, Han S (2019) Tau-cofactor complexes as building blocks of tau fibrils. Front Neurosci 13:1339. https://doi.org/10.3389/fnins.2019.01339

    Article  PubMed  PubMed Central  Google Scholar 

  96. von Bergen M, Barghorn S, Jeganathan S, Mandelkow EM, Mandelkow E (2006) Spectroscopic approaches to the conformation of tau protein in solution and in paired helical filaments. Neurodegener Dis 3:197–206. https://doi.org/10.1159/000095257

    Article  CAS  Google Scholar 

  97. Jakes R, Novak M, Davison M, Wischik CM (1991) Identification of 3- and 4-repeat tau isoforms within the PHF in Alzheimer’s disease. EMBO J 10:2725–2729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Andronesi OC, von Bergen M, Biernat J, Seidel K, Griesinger C, Mandelkow E, Baldus M (2008) Characterization of Alzheimer’s-like paired helical filaments from the core domain of tau protein using solid-state NMR spectroscopy. J Am Chem Soc 130:5922–5928. https://doi.org/10.1021/ja7100517

    Article  CAS  PubMed  Google Scholar 

  99. Daebel V, Chinnathambi S, Biernat J, Schwalbe M, Habenstein B, Loquet A, Akoury E, Tepper K et al (2012) beta-Sheet core of tau paired helical filaments revealed by solid-state NMR. J Am Chem Soc 134:13982–13989. https://doi.org/10.1021/ja305470p

    Article  CAS  PubMed  Google Scholar 

  100. Margittai M, Langen R (2004) Template-assisted filament growth by parallel stacking of tau. Proc Natl Acad Sci USA 101:10278–10283. https://doi.org/10.1073/pnas.0401911101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kirschner DA, Abraham C, Selkoe DJ (1986) X-ray diffraction from intraneuronal paired helical filaments and extraneuronal amyloid fibers in Alzheimer disease indicates cross-beta conformation. Proc Natl Acad Sci USA 83:503–507. https://doi.org/10.1073/pnas.83.2.503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Barghorn S, Davies P, Mandelkow E (2004) Tau paired helical filaments from Alzheimer’s disease brain and assembled in vitro are based on beta-structure in the core domain. Biochemistry 43:1694–1703. https://doi.org/10.1021/bi0357006

    Article  CAS  PubMed  Google Scholar 

  103. Bibow S, Mukrasch MD, Chinnathambi S, Biernat J, Griesinger C, Mandelkow E, Zweckstetter M (2011) The dynamic structure of filamentous tau. Angew Chem Int Ed Engl 50:11520–11524. https://doi.org/10.1002/anie.201105493

    Article  CAS  PubMed  Google Scholar 

  104. Goedert M, Eisenberg DS, Crowther RA (2017) Propagation of tau aggregates and neurodegeneration. Annu Rev Neurosci 40:189–210. https://doi.org/10.1146/annurev-neuro-072116-031153

    Article  CAS  PubMed  Google Scholar 

  105. Goedert M, Spillantini MG (2019) Ordered assembly of tau protein and neurodegeneration. Adv Exp Med Biol 1184:3–21. https://doi.org/10.1007/978-981-32-9358-8_1

    Article  CAS  PubMed  Google Scholar 

  106. Taniguchi-Watanabe S, Arai T, Kametani F, Nonaka T, Masuda-Suzukake M, Tarutani A, Murayama S, Saito Y et al (2016) Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau. Acta Neuropathol 131:267–280. https://doi.org/10.1007/s00401-015-1503-3

    Article  CAS  PubMed  Google Scholar 

  107. Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B et al (2017) Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547:185–190. https://doi.org/10.1038/nature23002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Falcon B, Zhang W, Schweighauser M, Murzin AG, Vidal R, Garringer HJ, Ghetti B, Scheres SHW et al (2018) Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold. Acta Neuropathol 136:699–708. https://doi.org/10.1007/s00401-018-1914-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Falcon B, Zhang W, Murzin AG, Murshudov G, Garringer HJ, Vidal R, Crowther RA, Ghetti B et al (2018) Structures of filaments from Pick’s disease reveal a novel tau protein fold. Nature 561:137–140. https://doi.org/10.1038/s41586-018-0454-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Falcon B, Zivanov J, Zhang W, Murzin AG, Garringer HJ, Vidal R, Crowther RA, Newell KL et al (2019) Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature 568:420–423. https://doi.org/10.1038/s41586-019-1026-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhang W, Tarutani A, Newell KL, Murzin AG, Matsubara T, Falcon B, Vidal R, Garringer HJ et al (2020) Novel tau filament fold in corticobasal degeneration. Nature 580:283–287. https://doi.org/10.1038/s41586-020-2043-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Crowther RA (1991) Straight and paired helical filaments in Alzheimer disease have a common structural unit. Proc Natl Acad Sci USA 88:2288–2292. https://doi.org/10.1073/pnas.88.6.2288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Crowther RA, Wischik CM (1985) Image reconstruction of the Alzheimer paired helical filament. EMBO J 4:3661–3665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Zhang W, Falcon B, Murzin AG, Fan J, Crowther RA, Goedert M, Scheres SH (2019) Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer’s and Pick’s diseases. Elife 8:e43584. https://doi.org/10.7554/eLife.43584

    Article  PubMed  PubMed Central  Google Scholar 

  115. Dregni AJ, Mandala VS, Wu H, Elkins MR, Wang HK, Hung I, DeGrado WF, Hong M (2019) In vitro 0N4R tau fibrils contain a monomorphic beta-sheet core enclosed by dynamically heterogeneous fuzzy coat segments. Proc Natl Acad Sci USA 116:16357–16366. https://doi.org/10.1073/pnas.1906839116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Nizynski B, Dzwolak W, Nieznanski K (2017) Amyloidogenesis of tau protein. Protein Sci 26:2126–2150. https://doi.org/10.1002/pro.3275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Nizynski B, Nieznanska H, Dec R, Boyko S, Dzwolak W, Nieznanski K (2018) Amyloidogenic cross-seeding of tau protein: transient emergence of structural variants of fibrils. PLoS ONE 13:e0201182. https://doi.org/10.1371/journal.pone.0201182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Scheres SH, Zhang W, Falcon B, Goedert M (2020) Cryo-EM structures of tau filaments. Curr Opin Struct Biol 64:17–25. https://doi.org/10.1016/j.sbi.2020.05.011

    Article  CAS  PubMed  Google Scholar 

  119. Chirita CN, Congdon EE, Yin H, Kuret J (2005) Triggers of full-length tau aggregation: a role for partially folded intermediates. Biochemistry 44:5862–5872. https://doi.org/10.1021/bi0500123

    Article  CAS  PubMed  Google Scholar 

  120. Barghorn S, Zheng-Fischhofer Q, Ackmann M, Biernat J, von Bergen M, Mandelkow EM, Mandelkow E (2000) Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry 39:11714–11721. https://doi.org/10.1021/bi000850r

    Article  CAS  PubMed  Google Scholar 

  121. Eckermann K, Mocanu MM, Khlistunova I, Biernat J, Nissen A, Hofmann A, Schonig K, Bujard H et al (2007) The beta-propensity of tau determines aggregation and synaptic loss in inducible mouse models of tauopathy. J Biol Chem 282:31755–31765. https://doi.org/10.1074/jbc.M705282200

    Article  CAS  PubMed  Google Scholar 

  122. Rossi G, Bastone A, Piccoli E, Mazzoleni G, Morbin M, Uggetti A, Giaccone G, Sperber S et al (2012) New mutations in MAPT gene causing frontotemporal lobar degeneration: biochemical and structural characterization. Neurobiol Aging 33:834. https://doi.org/10.1016/j.neurobiolaging.2011.08.008

    Article  CAS  PubMed  Google Scholar 

  123. Strang KH, Croft CL, Sorrentino ZA, Chakrabarty P, Golde TE, Giasson BI (2018) Distinct differences in prion-like seeding and aggregation between tau protein variants provide mechanistic insights into tauopathies. J Biol Chem 293:2408–2421. https://doi.org/10.1074/jbc.M117.815357

    Article  CAS  PubMed  Google Scholar 

  124. Margittai M, Langen R (2006) Side chain-dependent stacking modulates tau filament structure. J Biol Chem 281:37820–37827. https://doi.org/10.1074/jbc.M605336200

    Article  CAS  PubMed  Google Scholar 

  125. Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K (2001) Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci USA 98:6923–6928. https://doi.org/10.1073/pnas.121119298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Liu F, Li B, Tung EJ, Grundke-Iqbal I, Iqbal K, Gong CX (2007) Site-specific effects of tau phosphorylation on its microtubule assembly activity and self-aggregation. Eur J Neurosci 26:3429–3436. https://doi.org/10.1111/j.1460-9568.2007.05955.x

    Article  PubMed  PubMed Central  Google Scholar 

  127. Alonso AD, Di Clerico J, Li B, Corbo CP, Alaniz ME, Grundke-Iqbal I, Iqbal K (2010) Phosphorylation of tau at Thr212, Thr231, and Ser262 combined causes neurodegeneration. J Biol Chem 285:30851–30860. https://doi.org/10.1074/jbc.M110.110957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Qi H, Prabakaran S, Cantrelle FX, Chambraud B, Gunawardena J, Lippens G, Landrieu I (2016) Characterization of neuronal tau protein as a target of extracellular signal-regulated kinase. J Biol Chem 291:7742–7753. https://doi.org/10.1074/jbc.M115.700914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Schneider A, Biernat J, von Bergen M, Mandelkow E, Mandelkow EM (1999) Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. Biochemistry 38:3549–3558. https://doi.org/10.1021/bi981874p

    Article  CAS  PubMed  Google Scholar 

  130. Haj-Yahya M, Gopinath P, Rajasekhar K, Mirbaha H, Diamond MI, Lashuel HA (2020) Site-specific hyperphosphorylation inhibits, rather than promotes, tau fibrillization, seeding capacity, and its microtubule binding. Angew Chem Int Ed Engl 59:4059–4067. https://doi.org/10.1002/anie.201913001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Necula M, Kuret J (2004) Pseudophosphorylation and glycation of tau protein enhance but do not trigger fibrillization in vitro. J Biol Chem 279:49694–49703. https://doi.org/10.1074/jbc.M405527200

    Article  CAS  PubMed  Google Scholar 

  132. Chang E, Kim S, Schafer KN, Kuret J (2011) Pseudophosphorylation of tau protein directly modulates its aggregation kinetics. Biochim Biophys Acta 1814:388–395. https://doi.org/10.1016/j.bbapap.2010.10.005

    Article  CAS  PubMed  Google Scholar 

  133. Tetz G, Pinho M, Pritzkow S, Mendez N, Soto C, Tetz V (2020) Bacterial DNA promotes tau aggregation. Sci Rep 10:2369. https://doi.org/10.1038/s41598-020-59364-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Maiza A, Chantepie S, Vera C, Fifre A, Huynh MB, Stettler O, Ouidja MO, Papy-Garcia D (2018) The role of heparan sulfates in protein aggregation and their potential impact on neurodegeneration. FEBS Lett 592:3806–3818. https://doi.org/10.1002/1873-3468.13082

    Article  CAS  PubMed  Google Scholar 

  135. Roman AY, Devred F, Byrne D, La Rocca R, Ninkina NN, Peyrot V, Tsvetkov PO (2019) Zinc induces temperature-dependent reversible self-assembly of tau. J Mol Biol 431:687–695. https://doi.org/10.1016/j.jmb.2018.12.008

    Article  CAS  PubMed  Google Scholar 

  136. Ahmadi S, Zhu S, Sharma R, Wu B, Soong R, Dutta Majumdar R, Wilson DJ, Simpson AJ et al (2019) Aggregation of microtubule binding repeats of tau protein is promoted by Cu(2). ACS Omega 4:5356–5366. https://doi.org/10.1021/acsomega.8b03595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Moreira GG, Cristóvão JS, Torres VM, Carapeto AP, Rodrigues MS, Landrieu I, Cordeiro C, Gomes CM (2019) Zinc binding to tau influences aggregation kinetics and oligomer distribution. Int J Mol Sci 20:5979. https://doi.org/10.3390/ijms20235979

    Article  CAS  PubMed Central  Google Scholar 

  138. Zhou Z, Fan JB, Zhu HL, Shewmaker F, Yan X, Chen X, Chen J, Xiao GF et al (2009) Crowded cell-like environment accelerates the nucleation step of amyloidogenic protein misfolding. J Biol Chem 284:30148–30158. https://doi.org/10.1074/jbc.M109.002832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Ma Q, Fan JB, Zhou Z, Zhou BR, Meng SR, Hu JY, Chen J, Liang Y (2012) The contrasting effect of macromolecular crowding on amyloid fibril formation. PLoS ONE 7:e36288. https://doi.org/10.1371/journal.pone.0036288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Wu Y, Teng N, Li S (2016) Effects of macromolecular crowding and osmolyte on human tau fibrillation. Int J Biol Macromol 90:27–36. https://doi.org/10.1016/j.ijbiomac.2015.11.091

    Article  CAS  PubMed  Google Scholar 

  141. Kundel F, De S, Flagmeier P, Horrocks MH, Kjaergaard M, Shammas SL, Jackson SE, Dobson CM et al (2018) Hsp70 inhibits the nucleation and elongation of tau and sequesters tau aggregates with high Affinity. ACS Chem Biol 13:636–646. https://doi.org/10.1021/acschembio.7b01039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Baughman HER, Clouser AF, Klevit RE, Nath A (2018) HspB1 and Hsc70 chaperones engage distinct tau species and have different inhibitory effects on amyloid formation. J Biol Chem 293:2687–2700. https://doi.org/10.1074/jbc.M117.803411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Thompson AD, Scaglione KM, Prensner J, Gillies AT, Chinnaiyan A, Paulson HL, Jinwal UK, Dickey CA et al (2012) Analysis of the tau-associated proteome reveals that exchange of Hsp70 for Hsp90 is involved in tau degradation. ACS Chem Biol 7:1677–1686. https://doi.org/10.1021/cb3002599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Mok SA, Condello C, Freilich R, Gillies A, Arhar T, Oroz J, Kadavath H, Julien O et al (2018) Mapping interactions with the chaperone network reveals factors that protect against tau aggregation. Nat Struct Mol Biol 25:384–393. https://doi.org/10.1038/s41594-018-0057-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Weickert S, Wawrzyniuk M, John LH, Rudiger SGD, Drescher M (2020) The mechanism of Hsp90-induced oligomerization of tau. Sci Adv 6:eaax6999. https://doi.org/10.1126/sciadv.aax6999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. McEwan WA, Falcon B, Vaysburd M, Clift D, Oblak AL, Ghetti B, Goedert M, James LC (2017) Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation. Proc Natl Acad Sci USA 114:574–579. https://doi.org/10.1073/pnas.1607215114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Cisek K, Cooper GL, Huseby CJ, Kuret J (2014) Structure and mechanism of action of tau aggregation inhibitors. Curr Alzheimer Res 11:918–927. https://doi.org/10.2174/1567205011666141107150331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Brunden KR, Ballatore C, Crowe A, Smith AB 3rd, Lee VM, Trojanowski JQ (2010) Tau-directed drug discovery for Alzheimer’s disease and related tauopathies: a focus on tau assembly inhibitors. Exp Neurol 223:304–310. https://doi.org/10.1016/j.expneurol.2009.08.031

    Article  CAS  PubMed  Google Scholar 

  149. Brunden KR, Trojanowski JQ, Lee VM (2009) Advances in tau-focused drug discovery for Alzheimer’s disease and related tauopathies. Nat Rev Drug Discov 8:783–793. https://doi.org/10.1038/nrd2959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Calcul L, Zhang B, Jinwal UK, Dickey CA, Baker BJ (2012) Natural products as a rich source of tau-targeting drugs for Alzheimer’s disease. Future Med Chem 4:1751–1761. https://doi.org/10.4155/fmc.12.124

    Article  CAS  PubMed  Google Scholar 

  151. Schafer KN, Cisek K, Huseby CJ, Chang E, Kuret J (2013) Structural determinants of tau aggregation inhibitor potency. J Biol Chem 288:32599–32611. https://doi.org/10.1074/jbc.M113.503474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Rauch JN, Olson SH, Gestwicki JE (2017) Interactions between microtubule-associated protein tau (MAPT) and small molecules. Cold Spring Harb Perspect Med 7:a024034. https://doi.org/10.1101/cshperspect.a024034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Mouchlis VD, Melagraki G, Zacharia LC, Afantitis A (2020) Computer-aided drug design of beta-secretase, gamma-secretase and anti-tau inhibitors for the discovery of novel Alzheimer’s therapeutics. Int J Mol Sci. https://doi.org/10.3390/ijms21030703

    Article  PubMed  PubMed Central  Google Scholar 

  154. Pickhardt M, Neumann T, Schwizer D, Callaway K, Vendruscolo M, Schenk D, St George-Hyslop P, Mandelkow EM et al (2015) Identification of small molecule inhibitors of tau aggregation by targeting monomeric tau as a potential therapeutic approach for tauopathies. Curr Alzheimer Res 12:814–828. https://doi.org/10.2174/156720501209151019104951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Wobst HJ, Sharma A, Diamond MI, Wanker EE, Bieschke J (2015) The green tea polyphenol (−)-epigallocatechin gallate prevents the aggregation of tau protein into toxic oligomers at substoichiometric ratios. FEBS Lett 589:77–83. https://doi.org/10.1016/j.febslet.2014.11.026

    Article  CAS  PubMed  Google Scholar 

  156. Dubey T, Gorantla NV, Chandrashekara KT, Chinnathambi S (2019) Photoexcited toluidine blue inhibits tau aggregation in Alzheimer’s disease. ACS Omega 4:18793–18802. https://doi.org/10.1021/acsomega.9b02792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Lo CH, Lim CK, Ding Z, Wickramasinghe SP, Braun AR, Ashe KH, Rhoades E, Thomas DD et al (2019) Targeting the ensemble of heterogeneous tau oligomers in cells: a novel small molecule screening platform for tauopathies. Alzheimers Dement 15:1489–1502. https://doi.org/10.1016/j.jalz.2019.06.4954

    Article  PubMed  PubMed Central  Google Scholar 

  158. Wischik CM, Edwards PC, Lai RY, Roth M, Harrington CR (1996) Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc Natl Acad Sci USA 93:11213–11218. https://doi.org/10.1073/pnas.93.20.11213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Kiss R, Csizmadia G, Solti K, Keresztes A, Zhu M, Pickhardt M, Mandelkow E, Toth G (2018) Structural basis of small molecule targetability of monomeric tau protein. ACS Chem Neurosci 9:2997–3006. https://doi.org/10.1021/acschemneuro.8b00182

    Article  CAS  PubMed  Google Scholar 

  160. Chong B, Li M, Li T, Yu M, Zhang Y, Liu Z (2018) Conservation of potentially druggable cavities in intrinsically disordered proteins. ACS Omega 3:15643–15652. https://doi.org/10.1021/acsomega.8b02092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Despres C, Di J, Cantrelle FX, Li Z, Huvent I, Chambraud B, Zhao J, Chen J et al (2019) Major differences between the self-assembly and seeding behavior of heparin-induced and in vitro phosphorylated tau and their modulation by potential inhibitors. ACS Chem Biol 14:1363–1379. https://doi.org/10.1021/acschembio.9b00325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Baggett DW, Nath A (2018) The rational discovery of a tau aggregation inhibitor. Biochemistry 57:6099–6107. https://doi.org/10.1021/acs.biochem.8b00581

    Article  CAS  PubMed  Google Scholar 

  163. Ruan H, Sun Q, Zhang W, Liu Y, Lai L (2019) Targeting intrinsically disordered proteins at the edge of chaos. Drug Discov Today 24:217–227. https://doi.org/10.1016/j.drudis.2018.09.017

    Article  CAS  PubMed  Google Scholar 

  164. Jin F, Yu C, Lai L, Liu Z (2013) Ligand clouds around protein clouds: a scenario of ligand binding with intrinsically disordered proteins. PLoS Comput Biol 9:e1003249. https://doi.org/10.1371/journal.pcbi.1003249

    Article  PubMed  PubMed Central  Google Scholar 

  165. Falcon B, Cavallini A, Angers R, Glover S, Murray TK, Barnham L, Jackson S, O’Neill MJ et al (2015) Conformation determines the seeding potencies of native and recombinant Tau aggregates. J Biol Chem 290:1049–1065. https://doi.org/10.1074/jbc.M114.589309

    Article  CAS  PubMed  Google Scholar 

  166. Zheng J, Liu C, Sawaya MR, Vadla B, Khan S, Woods RJ, Eisenberg D, Goux WJ et al (2011) Macrocyclic beta-sheet peptides that inhibit the aggregation of a tau-protein-derived hexapeptide. J Am Chem Soc 133:3144–3157. https://doi.org/10.1021/ja110545h

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Sievers SA, Karanicolas J, Chang HW, Zhao A, Jiang L, Zirafi O, Stevens JT, Munch J et al (2011) Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation. Nature 475:96–100. https://doi.org/10.1038/nature10154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Seidler PM, Boyer DR, Rodriguez JA, Sawaya MR, Cascio D, Murray K, Gonen T, Eisenberg DS (2018) Structure-based inhibitors of tau aggregation. Nat Chem 10:170–176. https://doi.org/10.1038/nchem.2889

    Article  CAS  PubMed  Google Scholar 

  169. Seidler PM, Boyer DR, Murray KA, Yang TP, Bentzel M, Sawaya MR, Rosenberg G, Cascio D et al (2019) Structure-based inhibitors halt prion-like seeding by Alzheimer’s disease-and tauopathy-derived brain tissue samples. J Biol Chem 294:16451–16464. https://doi.org/10.1074/jbc.RA119.009688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Berhanu WM, Masunov AE (2015) Atomistic mechanism of polyphenol amyloid aggregation inhibitors: molecular dynamics study of Curcumin, Exifone, and Myricetin interaction with the segment of tau peptide oligomer. J Biomol Struct Dyn 33:1399–1411. https://doi.org/10.1080/07391102.2014.951689

    Article  CAS  PubMed  Google Scholar 

  171. Gauthier S, Feldman HH, Schneider LS, Wilcock GK, Frisoni GB, Hardlund JH, Moebius HJ, Bentham P et al (2016) Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer’s disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet 388:2873–2884. https://doi.org/10.1016/S0140-6736(16)31275-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Wilcock GK, Gauthier S, Frisoni GB, Jia J, Hardlund JH, Moebius HJ, Bentham P, Kook KA et al (2018) Potential of low dose leuco-methylthioninium bis(hydromethanesulphonate) (LMTM) monotherapy for treatment of mild Alzheimer’s disease: cohort analysis as modified primary outcome in a phase III clinical trial. J Alzheimers Dis 61:435–457. https://doi.org/10.3233/JAD-170560

    Article  CAS  PubMed  Google Scholar 

  173. Schelter BO, Shiells H, Baddeley TC, Rubino CM, Ganesan H, Hammel J, Vuksanovic V, Staff RT et al (2019) Concentration-dependent activity of hydromethylthionine on cognitive decline and brain atrophy in mild to moderate Alzheimer’s disease. J Alzheimers Dis 72:931–946. https://doi.org/10.3233/JAD-190772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Holehouse AS, Das RK, Ahad JN, Richardson MO, Pappu RV (2017) CIDER: resources to analyze sequence-ensemble relationships of intrinsically disordered proteins. Biophys J 112:16–21. https://doi.org/10.1016/j.bpj.2016.11.3200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Romero P, Obradovic Z, Dunker AK (1997) Sequence data analysis for long disordered regions prediction in the calcineurin family. Genome Inform 8:110–124

    CAS  Google Scholar 

  176. Li X, Romero P, Rani M, Dunker AK, Obradovic Z (1999) Predicting protein disorder for N-, C-, and internal regions. Genome Inform 10:30–40

    CAS  Google Scholar 

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Acknowledgements

This work was supported by the Natural Science Foundation of Hubei Province (2019CFB713) and funding from Hubei University of Technology (BSQD2017022).

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Authors and Affiliations

  1. Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei University of Technology, Wuhan, China

    Yifan Zeng, Jing Yang, Bailing Zhang, Meng Gao, Zhengding Su & Yongqi Huang

  2. Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China

    Yifan Zeng, Jing Yang, Bailing Zhang, Meng Gao, Zhengding Su & Yongqi Huang

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  1. Yifan Zeng
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  2. Jing Yang
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Contributions

Y. H. and Z. S. had the idea for the article; Y. Z., J. Y., and B. Z. performed the literature search and data analysis; Y. Z., J. Y., and M. G. drafted the work; Y. Z., B. Z., M. G., Y. H., and Z. S. critically revised the work.

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Correspondence to Yongqi Huang.

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Zeng, Y., Yang, J., Zhang, B. et al. The structure and phase of tau: from monomer to amyloid filament. Cell. Mol. Life Sci. 78, 1873–1886 (2021). https://doi.org/10.1007/s00018-020-03681-x

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  • DOI: https://doi.org/10.1007/s00018-020-03681-x

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