Recent studies of atomic-resolution structures of tau protein and structure-based inhibitors

Abstract

Background: Alzheimer’s disease (AD) is one of the most popular tauopathies. Neurofibrillary tangles and senile plaques are widely recognized as the pathological hallmarks of AD, which are mainly composed of tau and β-amyloid (Aβ) respectively. Recent failures of drugs targeting Aβ have led scientists to scrutinize the crucial impact of tau in neurodegenerative diseases. Mutated or abnormal phosphorylated tau protein loses affinity with microtubules and assembles into pathological accumulations. The aggregation process closely correlates to two amyloidogenic core of PHF6 (³⁰⁶VQIVYK³¹¹) and PHF6* (²⁷⁵VQIINK²⁸⁰) fragments. Moreover, tau accumulations display diverse morphological characteristics in different diseases, which increases the difficulty of providing a unifying neuropathological criterion for early diagnosis.

Results: This review mainly summarizes atomic-resolution structures of tau protein in the monomeric, oligomeric and fibrillar states, as well as the promising inhibitors designed to prevent tau aggregation or disaggregate tau accumulations, recently revealed by experimental and computational studies. We also systematically sort tau functions, their relationship with tau structures and the potential pathological processes of tau protein.

Conclusion: The current progress on tau structures at atomic level of detail expands our understanding of tau aggregation and related pathology. We discuss the difficulties in determining the source of neurotoxicity and screening effective inhibitors. We hope this review will inspire new clues for designing medicines against tau aggregation and shed light on AD diagnosis and therapies.

Author summary

The accumulation of tau protein is closely related to the pathological process of Alzheimer’s disease (AD). At present, the source of tau neurotoxicity has not been fully clarified. It may come from the misfolding of tau in the early stage, oligomeric intermediates, or the aggregation process itself. Therefore, probing the atomic structures of tau, exploring key interactions, and screening potential inhibitors are crucial to the proposal of effective treatments. We hope this review can expand our understanding of tau pathology to accelerate medicine development for AD therapies.

Graphical abstract

Keywords

tau / paired helical filaments / inhibitor / cryo-electron microscopy / molecular dynamics simulation

References

[1] ChenQ., DuY., ZhangK., LiangZ., LiJ., YuH., RenR., FengJ., JinZ., LiF. . (2018). A tau-targeted multifunctional nanocomposite for combinational therapy of Alzheimer’s disease. ACS Nano, 12 : 1321–1338

[2] ZeiselJ., BennettK. (2020). World Alzheimer report 2020: Design, dignity, dementia: dementia-related design and the built environment. Accessed: February 1, 2021

[3] Alzheimer’sAssociation (2021). 2021 Alzheimer’s disease facts and figures. Alzheimers Dement., 17 : 327–406

[4] GrandyJ. (2013). Melatonin: Therapeutic intervention in mild cognitive impairment and Alzheimer disease. J. Neurol. Neurophysiol., 4 : 148

[5] UddinM. S., KabirM. T., Al MamunA., Abdel-DaimM. M., BarretoG. E. AshrafG. (2019). APOE and Alzheimer’s disease: Evidence mounts that targeting APOE4 may combat Alzheimer’s pathogenesis. Mol. Neurobiol., 56 : 2450–2465

[6] HardyJ. A. HigginsG. (1992). Alzheimer’s disease: the amyloid cascade hypothesis. Science, 256 : 184–185

[7] RajasekharK., ChakrabartiM. (2015). Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer’s disease. Chem. Commun. (Camb.), 51 : 13434–13450

[8] RajasekharK. (2018). Current progress, challenges and future prospects of diagnostic and therapeutic interventions in Alzheimer’s disease. RSC Advances, 8 : 23780–23804

[9] van der KantR., GoldsteinL. S. B. (2020). Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat. Rev. Neurosci., 21 : 21–35

[10] CongdonE. E. SigurdssonE. (2018). Tau-targeting therapies for Alzheimer disease. Nat. Rev. Neurol., 14 : 399–415

[11] Alavi NainiS. M. (2015). Tau hyperphosphorylation and oxidative stress, a critical vicious circle in neurodegenerative tauopathies? Oxid. Med. Cell. Longev., 2015 : 151979

[12] KerrJ. S., AdriaanseB. A., GreigN. H., MattsonM. P., CaderM. Z., BohrV. A. FangE. (2017). Mitophagy and Alzheimer’s disease: Cellular and molecular mechanisms. Trends Neurosci., 40 : 151–166

[13] BuscheM. A. HymanB. (2020). Synergy between amyloid-β and tau in Alzheimer’s disease. Nat. Neurosci., 23 : 1183–1193

[14] MullardA. (2021). Failure of first anti-tau antibody in Alzheimer disease highlights risks of history repeating. Nat. Rev. Drug Discov., 20 : 3–5

[15] DehmeltL. (2005). The MAP2/Tau family of microtubule-associated proteins. Genome Biol., 6 : 204

[16] JamesonL., FreyT., ZeebergB., DalldorfF. (1980). Inhibition of microtubule assembly by phosphorylation of microtubule-associated proteins. Biochemistry, 19 : 2472–2479

[17] GuY., OyamaF. (1996). Tau is widely expressed in rat tissues. J. Neurochem., 67 : 1235–1244

[18] BakotaL. (2016). Tau biology and tau-directed therapies for Alzheimer’s disease. Drugs, 76 : 301–313

[19] GuoT., NobleW. HangerD. (2017). Roles of tau protein in health and disease. Acta Neuropathol., 133 : 665–704

[20] GoedertM., SpillantiniM. G., JakesR., RutherfordD. CrowtherR. (1989). Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron, 3 : 519–526

[21] MandelkowE. (2012). Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb. Perspect. Med., 2 : a006247

[22] CondeC. (2009). Microtubule assembly, organization and dynamics in axons and dendrites. Nat. Rev. Neurosci., 10 : 319–332

[23] WeingartenM. D., LockwoodA. H., HwoS. Y. KirschnerM. (1975). A protein factor essential for microtubule assembly. Proc. Natl. Acad. Sci. USA, 72 : 1858–1862

[24] CastroT. G., MunteanuF. D. (2019). Electrostatics of tau protein by molecular dynamics. Biomolecules, 9 : 116

[25] KelloggE. H., HejabN. M. A., PoepselS., DowningK. H., DiMaioF. (2018). Near-atomic model of microtubule-tau interactions. Science, 360 : 1242–1246

[26] Qiang, L., Sun, X., Austin, T. O., Muralidharan, H., Jean, D. C., Liu, M., Yu, W., and Baas, P. W. (2018) Tau does not stabilize axonal microtubules but rather enables them to have long labile domains. Curr. Biol., 28, 2181−2189. e4

[27] BaasP. W. (2019). Tau: It’s not what you think. Trends Cell Biol., 29 : 452–461

[28] WitmanG. B., ClevelandD. W., WeingartenM. D. KirschnerM. (1976). Tubulin requires tau for growth onto microtubule initiating sites. Proc. Natl. Acad. Sci. USA, 73 : 4070–4074

[29] ZhangB., CarrollJ., TrojanowskiJ. Q., YaoY., IbaM., PotuzakJ. S., HoganA. M., XieS. X., BallatoreC., Smith IIIA. B. . (2012). The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. J. Neurosci., 32 : 3601–3611

[30] Mietelska-PorowskaA., WasikU., GorasM., FilipekA. (2014). Tau protein modifications and interactions: their role in function and dysfunction. Int. J. Mol. Sci., 15 : 4671–4713

[31] MedinaM. (2014). The role of extracellular tau in the spreading of neurofibrillary pathology. Front. Cell. Neurosci., 8 : 113

[32] ElieA., PrezelE., rinC., DenarierE., Ramirez-RiosS., SerreL., AndrieuxA., Fourest-LieuvinA., BlanchoinL. (2015). Tau co-organizes dynamic microtubule and actin networks. Sci. Rep., 5 : 9964

[33] VioletM., DelattreL., TardivelM., SultanA., ChauderlierA., CaillierezR., TalahariS., NesslanyF., LefebvreB., BonnefoyE. . (2014). A major role for tau in neuronal DNA and RNA protection in vivo under physiological and hyperthermic conditions. Front. Cell. Neurosci., 8 : 84

[34] SultanA., NesslanyF., VioletM., gardS., LoyensA., TalahariS., MansurogluZ., MarzinD., SergeantN., HumezS. . (2011). Nuclear tau, a key player in neuronal DNA protection. J. Biol. Chem., 286 : 4566–4575

[35] BulicB., PickhardtM., MandelkowE. M. (2010). Tau protein and tau aggregation inhibitors. Neuropharmacology, 59 : 276–289

[36] SeidlerP. M., BoyerD. R., RodriguezJ. A., SawayaM. R., CascioD., MurrayK., GonenT. EisenbergD. (2018). Structure-based inhibitors of tau aggregation. Nat. Chem., 10 : 170–176

[37] NizynskiB., DzwolakW. (2017). Amyloidogenesis of tau protein. Protein Sci., 26 : 2126–2150

[38] LiuY., NguyenM., RobertA. (2019). Metal ions in Alzheimer’s disease: A key role or not? Acc. Chem. Res., 52 : 2026–2035

[39] FanniA. M., Vander ZandenC. M., MajewskaP. V., MajewskiJ. ChiE. (2019). Membrane-mediated fibrillation and toxicity of the tau hexapeptide PHF6. J. Biol. Chem., 294 : 15304–15317

[40] ZhuH. L., ndezC., FanJ. B., ShewmakerF., ChenJ., MintonA. P. (2010). Quantitative characterization of heparin binding to tau protein: implication for inducer-mediated tau filament formation. J. Biol. Chem., 285 : 3592–3599

[41] KfouryN., HolmesB. B., JiangH., HoltzmanD. M. DiamondM. (2012). Trans-cellular propagation of tau aggregation by fibrillar species. J. Biol. Chem., 287 : 19440–19451

[42] La JoieR., VisaniA. V., BakerS. L., BrownJ. A., BourakovaV., ChaJ., ChaudharyK., EdwardsL., IaccarinoL., JanabiM. . (2020). Prospective longitudinal atrophy in Alzheimer’s disease correlates with the intensity and topography of baseline tau-PET. Sci. Transl. Med., 12 : eaau5732

[43] LeeC. C., NayakA., SethuramanA., BelfortG. McRaeG. (2007). A three-stage kinetic model of amyloid fibrillation. Biophys. J., 92 : 3448–3458

[44] IannuzziC., BorrielloM., IraceG., CammarotaM., Di MaroA. (2017). Vanillin affects amyloid aggregation and non-enzymatic glycation in human insulin. Sci. Rep., 7 : 15086

[45] MirbahaH., ChenD., MorazovaO. A., RuffK. M., SharmaA. M., LiuX., GoodarziM., PappuR. V., ColbyD. W., MirzaeiH. . (2018). Inert and seed-competent tau monomers suggest structural origins of aggregation. eLife, 7 : e36584

[46] ShammasS. L., GarciaG. A., KumarS., KjaergaardM., HorrocksM. H., ShivjiN., MandelkowE., KnowlesT. P., MandelkowE. (2015). A mechanistic model of tau amyloid aggregation based on direct observation of oligomers. Nat. Commun., 6 : 7025

[47] KjaergaardM., DearA. J., KundelF., QamarS., MeislG., KnowlesT. P. J. (2018). Oligomer diversity during the aggregation of the repeat region of tau. ACS Chem. Neurosci., 9 : 3060–3071

[48] RomanA. Y., DevredF., ByrneD., La RoccaR., NinkinaN. N., PeyrotV. TsvetkovP. (2019). Zinc induces temperature-dependent reversible self-assembly of tau. J. Mol. Biol., 431 : 687–695

[49] SonawaneS. K., ChidambaramH., BoralD., GorantlaN. V., BalmikA. A., DangiA., RamasamyS., MarelliU. K. (2020). EGCG impedes human tau aggregation and interacts with Tau. Sci. Rep., 10 : 12579

[50] RamachandranG. UdgaonkarJ. (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

[51] ChiritaC. N., CongdonE. E., YinH. (2005). Triggers of full-length tau aggregation: a role for partially folded intermediates. Biochemistry, 44 : 5862–5872

[52] LuoY., DinkelP., YuX., MargittaiM., ZhengJ., NussinovR., WeiG. (2013). Molecular insights into the reversible formation of tau protein fibrils. Chem. Commun. (Camb.), 49 : 3582–3584

[53] GoedertM., EisenbergD. S. CrowtherR. (2017). Propagation of tau aggregates and neurodegeneration. Annu. Rev. Neurosci., 40 : 189–210

[54] FitzpatrickA. W. P., FalconB., HeS., MurzinA. G., MurshudovG., GarringerH. J., CrowtherR. A., GhettiB., GoedertM. ScheresS. H. (2017). Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature, 547 : 185–190

[55] FalconB., ZhangW., SchweighauserM., MurzinA. G., VidalR., GarringerH. J., GhettiB., ScheresS. H. W. (2018). Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold. Acta Neuropathol., 136 : 699–708

[56] GoedertM., FalconB., ZhangW., GhettiB. ScheresS. H. (2018). Distinct conformers of assembled tau in Alzheimer’s and Pick’s diseases. Cold Spring Harb. Symp. Quant. Biol., 83 : 163–171

[57] FalconB., ZhangW., MurzinA. G., MurshudovG., GarringerH. J., VidalR., CrowtherR. A., GhettiB., ScheresS. H. W. (2018). Structures of filaments from Pick’s disease reveal a novel tau protein fold. Nature, 561 : 137–140

[58] QiB., JinS., QianH. (2020). Bibliometric analysis of chronic traumatic encephalopathy research from 1999 to 2019. Int. J. Environ. Res. Public Health, 17 : 5411

[59] FalconB., ZivanovJ., ZhangW., MurzinA. G., GarringerH. J., VidalR., CrowtherR. A., NewellK. L., GhettiB., GoedertM. . (2019). Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature, 568 : 420–423

[60] SergeantN., WattezA. (1999). Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration: tau pathologies with exclusively “exon 10” isoforms. J. Neurochem., 72 : 1243–1249

[61] ZhangW., TarutaniA., NewellK. L., MurzinA. G., MatsubaraT., FalconB., VidalR., GarringerH. J., ShiY., IkeuchiT. . (2020). Novel tau filament fold in corticobasal degeneration. Nature, 580 : 283–287

[62] MukraschM. D., von BergenM., BiernatJ., FischerD., GriesingerC., MandelkowE. (2007). The “jaws” of the tau-microtubule interaction. J. Biol. Chem., 282 : 12230–12239

[63] MukraschM. D., BibowS., KorukottuJ., JeganathanS., BiernatJ., GriesingerC., MandelkowE. (2009). Structural polymorphism of 441-residue tau at single residue resolution. PLoS Biol., 7 : e34

[64] ChenD., DromboskyK. W., HouZ., SariL., KashmerO. M., RyderB. D., PerezV. A., WoodardD. R., LinM. M., DiamondM. I. . (2019). Tau local structure shields an amyloid-forming motif and controls aggregation propensity. Nat. Commun., 10 : 2493

[65] NelsonR., SawayaM. R., BalbirnieM., MadsenA. O., RiekelC., GrotheR. (2005). Structure of the cross-beta spine of amyloid-like fibrils. Nature, 435 : 773–778

[66] SawayaM. R., SambashivanS., NelsonR., IvanovaM. I., SieversS. A., ApostolM. I., ThompsonM. J., BalbirnieM., WiltziusJ. J., McFarlaneH. T. . (2007). Atomic structures of amyloid cross-beta spines reveal varied steric zippers. Nature, 447 : 453–457

[67] KrishnaKumarV. G., PaulA., GazitE. (2018). Mechanistic insights into remodeled tau-derived PHF6 peptide fibrils by Naphthoquinone-Tryptophan hybrids. Sci. Rep., 8 : 71

[68] SieversS. A., KaranicolasJ., ChangH. W., ZhaoA., JiangL., ZirafiO., StevensJ. T., nchJ., BakerD. (2011). Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation. Nature, 475 : 96–100

[69] Chemerovski-GlikmanM., Frenkel-PinterM., MdahR., Abu-MokhA., GazitE. (2017). Inhibition of the aggregation and toxicity of the minimal amyloidogenic fragment of tau by its pro-substituted analogues. Chemistry, 23 : 9618–9624

[70] PickhardtM., NeumannT., SchwizerD., CallawayK., VendruscoloM., SchenkD., St George-HyslopP., MandelkowE. M., DobsonC. M., McConlogueL. . (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

[71] DavidowitzE. J., KrishnamurthyP. K., LopezP., JimenezH., AdrienL., DaviesP. MoeJ. (2020). In vivo validation of a small molecule inhibitor of tau self-association in htau mice. J. Alzheimers Dis., 73 : 147–161

[72] KundelF., DeS., FlagmeierP., HorrocksM. H., KjaergaardM., ShammasS. L., JacksonS. E., DobsonC. M. (2018). Hsp70 inhibits the nucleation and elongation of tau and sequesters tau aggregates with high affinity. ACS Chem. Biol., 13 : 636–646

[73] SeidlerP. M., BoyerD. R., MurrayK. A., YangT. P., BentzelM., SawayaM. R., RosenbergG., CascioD., WilliamsC. K., NewellK. L. . (2019). Structure-based inhibitors halt prion-like seeding by Alzheimer’s disease-and tauopathy-derived brain tissue samples. J. Biol. Chem., 294 : 16451–16464

[74] LarbigG., PickhardtM., LloydD. G., SchmidtB. (2007). Screening for inhibitors of tau protein aggregation into Alzheimer paired helical filaments: a ligand based approach results in successful scaffold hopping. Curr. Alzheimer Res., 4 : 315–323

[75] ViswanathanG. K., ShwartzD., LosevY., AradE., ShemeshC., PichinukE., EngelH., RavehA., JelinekR., CooperI. . (2020). Purpurin modulates tau-derived VQIVYK fibrillization and ameliorates Alzheimer’s disease-like symptoms in animal model. Cell. Mol. Life Sci., 77 : 2795–2813

[76] PoratY., AbramowitzA. (2006). Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism. Chem. Biol. Drug Des., 67 : 27–37

[77] BijariN., BalalaieS., AkbariV., GolmohammadiF., MoradiS., AdibiH. (2018). Effective suppression of the modified PHF6 peptide/1N4R Tau amyloid aggregation by intact curcumin, not its degradation products: Another evidence for the pigment as preventive/therapeutic “functional food”. Int. J. Biol. Macromol., 120 : 1009–1022

[78] RaneJ. S., BhaumikP. (2017). Curcumin inhibits tau aggregation and disintegrates preformed tau filaments in vitro. J. Alzheimers Dis., 60 : 999–1014

[79] AnandP., KunnumakkaraA. B., NewmanR. A. AggarwalB. (2007). Bioavailability of curcumin: problems and promises. Mol. Pharm., 4 : 807–818

[80] Lo CascioF., PuangmalaiN., EllsworthA., BucchieriF., PaceA., Palumbo PiccionelloA. (2019). Toxic tau oligomers modulated by novel curcumin derivatives. Sci. Rep., 9 : 19011

[81] SatoR., VohraS., YamamotoS., SuzukiK., PavelK., ShulgaS., BlumeY. (2020). Specific interactions between tau protein and curcumin derivatives: Molecular docking and ab initio molecular orbital simulations. J. Mol. Graph. Model., 98 : 107611

[82] OkudaM., HijikuroI., FujitaY., WuX., NakayamaS., SakataY., NoguchiY., OgoM., AkasofuS., ItoY. . (2015). PE859, a novel tau aggregation inhibitor, reduces aggregated tau and prevents onset and progression of neural dysfunction in vivo. PLoS One, 10 : e0117511

[83] OkudaM., HijikuroI., FujitaY., TeruyaT., KawakamiH., TakahashiT. (2016). Design and synthesis of curcumin derivatives as tau and amyloid β dual aggregation inhibitors. Bioorg. Med. Chem. Lett., 26 : 5024–5028

[84] LiuW., HuX., ZhouL., TuY., ShiS. (2020). Orientation-inspired perspective on molecular inhibitor of tau aggregation by curcumin conjugated with ruthenium(ii) complex scaffold. J. Phys. Chem. B, 124 : 2343–2353

[85] YuK. C., KwanP., CheungS. K. K., HoA. (2018). Effects of resveratrol and morin on insoluble tau in tau transgenic mice. Transl. Neurosci., 9 : 54–60

[86] SunX. Y., DongQ. X., ZhuJ., SunX., ZhangL. F., QiuM., YuX. L. LiuR. (2019). Resveratrol rescues tau-induced cognitive deficits and neuropathology in a mouse model of tauopathy. Curr. Alzheimer Res., 16 : 710–722

[87] PasinettiG. M., WangJ., HoL., ZhaoW. (2015). Roles of resveratrol and other grape-derived polyphenols in Alzheimer’s disease prevention and treatment. Biochim. Biophys. Acta, 1852 : 1202–1208

[88] CornejoA., Aguilar SandovalF., CaballeroL., MachucaL., ozP., CaballeroJ., PerryG., ArdilesA., ArecheC. (2017). Rosmarinic acid prevents fibrillization and diminishes vibrational modes associated to β sheet in tau protein linked to Alzheimer’s disease. J. Enzyme Inhib. Med. Chem., 32 : 945–953

[89] GuoY., ZhaoY., NanY., WangX., ChenY. (2017). (‒)-Epigallocatechin-3-gallate ameliorates memory impairment and rescues the abnormal synaptic protein levels in the frontal cortex and hippocampus in a mouse model of Alzheimer’s disease. Neuroreport, 28 : 590–597

[90] KumarS., KrishnakumarV. G., MoryaV., GuptaS. (2019). Nanobiocatalyst facilitated aglycosidic quercetin as a potent inhibitor of tau protein aggregation. Int. J. Biol. Macromol., 138 : 168–180

[91] SonawaneS. K., BalmikA. A., BoralD., RamasamyS. (2019). Baicalein suppresses repeat tau fibrillization by sequestering oligomers. Arch. Biochem. Biophys., 675 : 108119

[92] ZhangM., WuQ., YaoX., ZhaoJ., ZhongW., LiuQ. (2019). Xanthohumol inhibits tau protein aggregation and protects cells against tau aggregates. Food Funct., 10 : 7865–7874

[93] PickhardtM., GazovaZ., von BergenM., KhlistunovaI., WangY., HascherA., MandelkowE. BiernatJ. (2005). Anthraquinones inhibit tau aggregation and dissolve Alzheimer’s paired helical filaments in vitro and in cells. J. Biol. Chem., 280 : 3628–3635

[94] NepovimovaE., UliassiE., KorabecnyJ., a-AltamiraL. E., SamezS., PesaresiA., GarciaG. E., BartoliniM., AndrisanoV., BergaminiC. . (2014). Multitarget drug design strategy: quinone-tacrine hybrids designed to block amyloid-β aggregation and to exert anticholinesterase and antioxidant effects. J. Med. Chem., 57 : 8576–8589

[95] CornejoA., SalgadoF., CaballeroJ., VargasR., SimirgiotisM. (2016). Secondary metabolites in ramalina terebrata detected by UHPLC/ESI/MS/MS and identification of parietin as tau protein inhibitor. Int. J. Mol. Sci., 17 : 1303

[96] Frenkel-PinterM., TalS., Scherzer-AttaliR., Abu-HussienM., AlyagorI., EisenbaumT., GazitE., SegalD. (2016). Naphthoquinone-tryptophan hybrid inhibits aggregation of the tau-derived peptide PHF6 and reduces neurotoxicity. J. Alzheimers Dis., 51 : 165–178

[97] SalgadoF., CaballeroJ., VargasR., CornejoA. (2020). Continental and antarctic lichens: isolation, identification and molecular modeling of the depside tenuiorin from the Antarctic lichen Umbilicaria antarctica as tau protein inhibitor. Nat. Prod. Res., 34 : 646–650

[98] ShiC. J., PengW., ZhaoJ. H., YangH. L., QuL. L., WangC., KongL. Y. WangX. (2020). Usnic acid derivatives as tau-aggregation and neuroinflammation inhibitors. Eur. J. Med. Chem., 187 : 111961

[99] GorantlaN. V., DasR., MulaniF. A., ThulasiramH. V. (2019). Neem derivatives inhibits tau aggregation. J. Alzheimers Dis. Rep., 3 : 169–178

[100] XiaoS., WuQ., YaoX., ZhangJ., ZhongW., ZhaoJ., LiuQ. (2021). Inhibitory effects of isobavachalcone on tau protein aggregation, tau phosphorylation, and oligomeric tau-induced apoptosis. ACS Chem. Neurosci., 12 : 123–132

[101] RafieeS., AsadollahiK., RiaziG., AhmadianS. SabouryA. (2017). Vitamin B12 inhibits tau fibrillization via binding to cysteine residues of tau. ACS Chem. Neurosci., 8 : 2676–2682

[102] GhasemzadehS. RiaziG. (2020). Inhibition of tau amyloid fibril formation by folic acid: In-vitro and theoretical studies. Int. J. Biol. Macromol., 154 : 1505–1516

[103] KifleL., OrtizD. SheaT. (2009). Deprivation of folate and B12 increases neurodegeneration beyond that accompanying deprivation of either vitamin alone. J. Alzheimers Dis., 16 : 533–540

[104] DubeyT., GorantlaN. V., ChandrashekaraK. T. (2019). Photoexcited toluidine blue inhibits tau aggregation in Alzheimer’s disease. ACS Omega, 4 : 18793–18802

[105] HajE.,, Losev Y., Guru KrishnaKumarV.,, PichinukE.,, Engel H.,, RavehA.,, GazitE.. (2018) Integrating in vitro and in silico approaches to evaluate the “dual functionality” of palmatine chloride in inhibiting and disassembling tau-derived VQIVYK peptide fibrils. Biochim. Biophys. Acta Gen. Subj., 1862, 1565−1575

[106] LoC. H., LimC. K., DingZ., WickramasingheS. P., BraunA. R., AsheK. H., RhoadesE., ThomasD. D. SachsJ. (2019). Targeting the ensemble of heterogeneous tau oligomers in cells: A novel small molecule screening platform for tauopathies. Alzheimers Dement., 15 : 1489–1502

[107] HallidayM., RadfordH., ZentsK. A. M., MolloyC., MorenoJ. A., VerityN. C., SmithE., OrtoriC. A., BarrettD. A., BushellM. . (2017). Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain, 140 : 1768–1783

[108] LaA. L., WalshC. M., NeylanT. C., VosselK. A., YaffeK., KrystalA. D., MillerB. L. (2019). Long-term trazodone use and cognition: A potential therapeutic role for slow-wave sleep enhancers. J. Alzheimers Dis., 67 : 911–921

[109] KumarP., KaloniaH. (2011). Novel protective mechanisms of antidepressants against 3-nitropropionic acid induced Huntington’s-like symptoms: a comparative study. J. Psychopharmacol., 25 : 1399–1411

[110] GrippeT. C., alvesB. S. B., LouzadaL. L., QuintasJ. L., NavesJ. O. S., CamargosE. F. bregaO. (2015). Circadian rhythm in Alzheimer disease after trazodone use. Chronobiol. Int., 32 : 1311–1314

[111] AkbariV., GhobadiS., MohammadiS. (2020). The antidepressant drug; trazodone inhibits tau amyloidogenesis: Prospects for prophylaxis and treatment of AD. Arch. Biochem. Biophys., 679 : 108218

[112] CorpasR., valosV., PorquetD., a de FrutosP., Franciscato CozzolinoS. M., SanfeliuC. CardosoB. (2018). Melatonin induces mechanisms of brain resilience against neurodegeneration. J. Pineal Res., 65 : e12515

[113] BalmikA. A.,, DasR.,, DangiA.,, GorantlaN. V.,, MarelliU. K.. (2020) Melatonin interacts with repeat domain of tau to mediate disaggregation of paired helical filaments. Biochim. Biophys. Acta, Gen. Subj., 1864, 129467

[114] DasR., BalmikA. A. (2020). Effect of melatonin on tau aggregation and tau-mediated cell surface morphology. Int. J. Biol. Macromol., 152 : 30–39

[115] RenS. C.,, Suo Q. F.,, DuW. T.,, PanH.,, YangM. M.,, WangR. H.. (2010) Quercetin permeability across blood-brain barrier and its effect on the viability of U251 cells. Sichuan Da Xue Xue Bao Yi Xue Ban (in Chinese), 41, 751–754, 759

[116] HabtemariamS. (2018). Molecular pharmacology of rosmarinic and salvianolic acids: Potential seeds for Alzheimer’s and vascular dementia drugs. Int. J. Mol. Sci., 19 : 458

[117] WangJ., TangC., FerruzziM. G., GongB., SongB. J., JanleE. M., ChenT. Y., CooperB., VargheseM., ChengA. . (2013). Role of standardized grape polyphenol preparation as a novel treatment to improve synaptic plasticity through attenuation of features of metabolic syndrome in a mouse model. Mol. Nutr. Food Res., 57 : 2091–2102

[118] RahmaniS., MogharizadehL., AttarF., RezayatS. M., MousaviS. E. (2018). Probing the interaction of silver nanoparticles with tau protein and neuroblastoma cell line as nervous system models. J. Biomol. Struct. Dyn., 36 : 4057–4071

[119] ZamanM., AhmadE., QadeerA., RabbaniG. KhanR. (2014). Nanoparticles in relation to peptide and protein aggregation. Int J Nanomedicine, 9 : 899–912

[120] NiuL., ZouY., LinY., ZhengY., YangY. (2019). Regulation mechanism of nanobiointerfaces in amyloid peptide assembly and aggregation structures. Sci. Sin. Chim., 49 : 500–515

[121] HajsalimiG., TaheriS., ShahiF., AttarF., AhmadiH. (2018). Interaction of iron nanoparticles with nervous system: an in vitro study. J. Biomol. Struct. Dyn., 36 : 928–937

[122] VakilinezhadM. A., AminiA., Akbari JavarH., addini Beigi ZarandiB. F., MontaseriH. (2018). Nicotinamide loaded functionalized solid lipid nanoparticles improves cognition in Alzheimer’s disease animal model by reducing Tau hyperphosphorylation. Daru, 26 : 165–177

[123] VimalS. K., ZuoH., WangZ., WangH., LongZ. (2020). Self-therapeutic nanoparticle that alters tau protein and ameliorates tauopathy toward a functional nanomedicine to tackle Alzheimer’s. Small, 16 : e1906861

[124] SonawaneS. K., AhmadA. (2019). Protein-capped metal nanoparticles inhibit tau aggregation in Alzheimer’s disease. ACS Omega, 4 : 12833–12840

[125] SoedaY., SaitoM., MaedaS., IshidaK., NakamuraA., KojimaS. (2019). Methylene blue inhibits formation of tau fibrils but not of granular tau oligomers: A plausible key to understanding failure of a clinical trial for Alzheimer’s disease. J. Alzheimers Dis., 68 : 1677–1686

[126] ZhaoJ., YinF., JiL., WangC., ShiC., LiuX., YangH., WangX. (2020). Development of a tau-targeted drug delivery system using a multifunctional nanoscale metal-organic framework for Alzheimer’s disease therapy. ACS Appl. Mater. Interfaces, 12 : 44447–44458

[127] ManjuS. (2011). Hollow microcapsules built by layer by layer assembly for the encapsulation and sustained release of curcumin. Colloids Surf. B Biointerfaces, 82 : 588–593

[128] ChenX., ZouL. Q., NiuJ., LiuW., PengS. F. LiuC. (2015). The stability, sustained release and cellular antioxidant activity of curcumin nanoliposomes. Molecules, 20 : 14293–14311

[129] FanS., ZhengY., LiuX., FangW., ChenX., LiaoW., JingX., LeiM., TaoE., MaQ. . (2018). Curcumin-loaded PLGA-PEG nanoparticles conjugated with B6 peptide for potential use in Alzheimer’s disease. Drug Deliv., 25 : 1091–1102

[130] GaoC., ChuX., GongW., ZhengJ., XieX., WangY., YangM., LiZ., GaoC. (2020). Neuron tau-targeting biomimetic nanoparticles for curcumin delivery to delay progression of Alzheimer’s disease. J. Nanobiotechnology, 18 : 71

[131] HuY., HuX., LuY., ShiS., YangD. (2020). New strategy for reducing tau aggregation cytologically by a hairpinlike molecular inhibitor, tannic acid encapsulated in liposome. ACS Chem. Neurosci., 11 : 3623–3634

[132] SinghN. A., BhardwajV., RaviC., RameshN., MandalA. K. A. KhanZ. (2018). EGCG nanoparticles attenuate aluminum chloride induced neurobehavioral deficits, beta amyloid and tau pathology in a rat model of Alzheimer’s disease. Front. Aging Neurosci., 10 : 244

[133] ArmientoV., SpanopoulouA. (2020). Peptide-based molecular strategies to interfere with protein misfolding, aggregation, and cell degeneration. Angew. Chem. Int. Ed. Engl., 59 : 3372–3384

[134] RauscherS., BaudS., MiaoM., KeeleyF. W. (2006). Proline and glycine control protein self-organization into elastomeric or amyloid fibrils. Structure, 14 : 1667–1676

[135] LiS. C., GotoN. K., WilliamsK. A. DeberC. (1996). Alpha-helical, but not β-sheet, propensity of proline is determined by peptide environment. Proc. Natl. Acad. Sci. USA., 93 : 6676–6681

[136] PandeyG.,, Morla S.,, KumarS.. (2020) Modulation of tau protein aggregation using ‘Trojan’ sequences. Biochim. Biophys. Acta, Gen. Subj., 1864, 129569

[137] ChengI. H., Scearce-LevieK., LegleiterJ., PalopJ. J., GersteinH., Bien-LyN., liJ., AsheK. H., MuchowskiP. J. . (2007). Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J. Biol. Chem., 282 : 23818–23828

[138] DammersC., YolcuD., KukukL., WillboldD., PickhardtM., MandelkowE., HornA. H., StichtH., MalhisM. N., WillN. . (2016). Selection and characterization of tau binding D-enantiomeric peptides with potential for therapy of Alzheimer disease. PLoS One, 11 : e0167432

[139] GorantlaN. V., SunnyL. P., RajasekharK., NagarajuP. G., CgP. P., GovindarajuT. (2021). Amyloid-β-derived peptidomimetics inhibits tau aggregation. ACS Omega, 6 : 11131–11138

[140] BestR. (2017). Computational and theoretical advances in studies of intrinsically disordered proteins. Curr. Opin. Struct. Biol., 42 : 147–154

[141] Meneksedag-ErolD. (2019). Atomistic simulation tools to study protein self-aggregation. Methods Mol. Biol., 2039 : 243–262

[142] PopovK. I., MakepeaceK. A. T., PetrotchenkoE. V., DokholyanN. V. BorchersC. (2019). Insight into the structure of the “unstructured” tau protein. Structure, 27 : 1710–1715.e4

[143] LariniL., GesselM. M., LaPointeN. E., DoT. D., BowersM. T., FeinsteinS. C. SheaJ. (2013). Initiation of assembly of tau (273‒284) and its ΔK280 mutant: an experimental and computational study. Phys. Chem. Chem. Phys., 15 : 8916–8928

[144] DaebelV., ChinnathambiS., BiernatJ., SchwalbeM., HabensteinB., LoquetA., AkouryE., TepperK., llerH., BaldusM. . (2012). β-Sheet core of tau paired helical filaments revealed by solid-state NMR. J. Am. Chem. Soc., 134 : 13982–13989

[145] AdamcikJ., nchez-FerrerA., Ait-BouziadN., ReynoldsN. P., LashuelH. A. (2016). Microtubule-binding R3 fragment from tau self-assembles into giant multistranded amyloid ribbons. Angew. Chem. Int. Ed. Engl., 55 : 618–622

[146] LiuH., ZhongH., XuZ., ZhangQ., ShahS. J. A., LiuH. (2020). The misfolding mechanism of the key fragment R3 of tau protein: a combined molecular dynamics simulation and Markov state model study. Phys. Chem. Chem. Phys., 22 : 10968–10980

[147] LiX., DongX., WeiG., MargittaiM., NussinovR. (2018). The distinct structural preferences of tau protein repeat domains. Chem. Commun. (Camb.), 54 : 5700–5703

[148] SmitF. X., LuikenJ. A. BolhuisP. (2017). Primary fibril nucleation of aggregation prone tau fragments PHF6 and PHF6*. J. Phys. Chem. B, 121 : 3250–3261

[149] LiuH., ZhongH., LiuX., ZhouS., TanS., LiuH. (2019). Disclosing the mechanism of spontaneous aggregation and template-induced misfolding of the key hexapeptide (PHF6) of tau protein based on molecular dynamics simulation. ACS Chem. Neurosci., 10 : 4810–4823

[150] EschmannN. A., GeorgievaE. R., GangulyP., BorbatP. P., RappaportM. D., AkdoganY., FreedJ. H., SheaJ. E. (2017). Signature of an aggregation-prone conformation of tau. Sci. Rep., 7 : 44739

[151] GuoJ. P., AraiT., MiklossyJ. McGeerP. (2006). Abeta and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA, 103 : 1953–1958

[152] RojasA. V., MaisuradzeG. G. ScheragaH. (2018). Dependence of the formation of tau and Aβ peptide mixed aggregates on the secondary structure of the N-terminal region of Aβ. J. Phys. Chem. B, 122 : 7049–7056

[153] MillerY., MaB. (2011). Synergistic interactions between repeats in tau protein and Aβ amyloids may be responsible for accelerated aggregation via polymorphic states. Biochemistry, 50 : 5172–5181

[154] DoT. D., EconomouN. J., ChamasA., BurattoS. K., SheaJ. E. BowersM. (2014). Interactions between amyloid-β and Tau fragments promote aberrant aggregates: implications for amyloid toxicity. J. Phys. Chem. B, 118 : 11220–11230

[155] ShinW. S., DiJ., MurrayK. A., SunC., LiB., BitanG. (2019). Different amyloid-beta self-assemblies have distinct effects on intracellular tau aggregation. Front. Mol. Neurosci., 12 : 268

ACKNOWLEDGEMENTS

We thank Prof. Guanghong Wei for helpful discussion. This work was supported by the National Natural Science Foundation of China (Nos. 11704256 and 11932013).

COMPLIANCE WITH ETHICS GUIDELINES

The authors Lili Zhu and Zhenyu Qian declare that they have no conflict of interest or financial conflicts to disclose.

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