Tauopathies, including Alzheimer's disease (AD), are the most troublesome of all age-related chronic conditions, as there are no well-established disease-modifying therapies for their prevention and treatment. Spatio-temporal distribution of tau protein pathology correlates with cognitive decline and severity of the disease, therefore, tau protein has become an appealing target for therapy. Current knowledge of the pathological effects and significance of specific species in the tau aggregation pathway is incomplete although more and more structural and mechanistic insights are being gained using biophysical techniques. Here, we review the application of NMR to structural studies of various tau forms that appear in its aggregation process, focusing on results obtained from solid-state NMR. Furthermore, we discuss implications from these studies and their prospective contribution to the development of new tauopathy therapies.

AXON Neuroscience R and D Services SE Bratislava Slovakia

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Chemistry Faculty of Science Masaryk University Brno Czech Republic

Faculty of Chemistry University of Latvia Riga Latvia

Faculty of Science National Centre for Biomolecular Research Masaryk University Brno Czech Republic

Institute of Neuroimmunology Slovak Academy of Sciences Bratislava Slovakia

Laboratory of Physical Organic Chemistry Latvian Institute of Organic Synthesis Riga Latvia

Zobrazit více v PubMed

Ahmadi S., Zhu S., Sharma R., Wu B., Soong R., Dutta Majumdar R., et al. (2019). Aggregation of Microtubule Binding Repeats of Tau Protein Is Promoted by Cu2+ . ACS Omega 4, 5356–5366. 10.1021/acsomega.8b03595 PubMed DOI PMC

Ahuja P., Cantrelle F.-X., Huvent I., Hanoulle X., Lopez J., Smet C., et al. (2016). Proline Conformation in a Functional Tau Fragment. J. Mol. Biol. 428, 79–91. 10.1016/j.jmb.2015.11.023 PubMed DOI

Ait-Bouziad N., Chiki A., Limorenko G., Xiao S., Eliezer D., Lashuel H. A. (2020). Phosphorylation of the Overlooked Tyrosine 310 Regulates the Structure, Aggregation, and Microtubule- and Lipid-Binding Properties of Tau. J. Biol. Chem. 295, 7905–7922. 10.1074/jbc.RA119.012517 PubMed DOI PMC

Akoury E., Gajda M., Pickhardt M., Biernat J., Soraya P., Griesinger C., et al. (2013). Inhibition of Tau Filament Formation by Conformational Modulation. J. Am. Chem. Soc. 135, 2853–2862. 10.1021/ja312471h PubMed DOI

Akoury E., Mukrasch M. D., Biernat J., Tepper K., Ozenne V., Mandelkow E., et al. (2016). Remodeling of the Conformational Ensemble of the Repeat Domain of Tau by an Aggregation Enhancer. Protein Sci. 25, 1010–1020. 10.1002/pro.2911 PubMed DOI PMC

Al‐Hilaly Y. K., Foster B. E., Biasetti L., Lutter L., Pollack S. J., Rickard J. E., et al. (2019). Tau (297‐391) Forms Filaments that Structurally Mimic the Core of Paired Helical Filaments in Alzheimer's Disease Brain. FEBS Lett. 594, 944–950. 10.1002/1873-3468.13675 PubMed DOI PMC

Al-Hilaly Y. K., Pollack S. J., Vadukul D. M., Citossi F., Rickard J. E., Simpson M., et al. (2017). Alzheimer's Disease-like Paired Helical Filament Assembly from Truncated Tau Protein Is Independent of Disulfide Crosslinking. J. Mol. Biol. 429, 3650–3665. 10.1016/j.jmb.2017.09.007 PubMed DOI

Alonso A. d. C., Zaidi T., Novak M., Grundke-Iqbal I., Iqbal K. (2001). Hyperphosphorylation Induces Self-Assembly of into Tangles of Paired Helical Filaments/straight Filaments. Proc. Natl. Acad. Sci. 98, 6923–6928. 10.1073/pnas.121119298 PubMed DOI PMC

Amniai L., Barbier P., Sillen A., Wieruszeski J.-M., Peyrot V., Lippens G., et al. (2009). Alzheimer Disease Specific Phosphoepitopes of Tau Interfere with Assembly of Tubulin but Not Binding to Microtubules. FASEB j. 23, 1146–1152. 10.1096/fj.08-121590 PubMed DOI

Amniai L., Lippens G., Landrieu I. (2011). Characterization of the AT180 Epitope of Phosphorylated Tau Protein by a Combined Nuclear Magnetic Resonance and Fluorescence Spectroscopy Approach. Biochem. Biophysical Res. Commun. 412, 743–746. 10.1016/j.bbrc.2011.08.046 PubMed DOI

Andrei S. A., Meijer F. A., Neves J. F., Brunsveld L., Landrieu I., Ottmann C., et al. (2018). Inhibition of 14-3-3/Tau by Hybrid Small-Molecule Peptides Operating via Two Different Binding Modes. ACS Chem. Neurosci. 9, 2639–2654. 10.1021/acschemneuro.8b00118 PubMed DOI PMC

Andronesi O. C., Bergen M. v., Biernat J., Seidel K., Griesinger C., Mandelkow E., et al. (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. 10.1021/ja7100517 PubMed DOI

Berger Z., Roder H., Hanna A., Carlson A., Rangachari V., Yue M., et al. (2007). Accumulation of Pathological Tau Species and Memory Loss in a Conditional Model of Tauopathy. J. Neurosci. 27, 3650–3662. 10.1523/jneurosci.0587-07.2007 PubMed DOI PMC

Bibow S., Mukrasch M. D., Chinnathambi S., Biernat J., Griesinger C., Mandelkow E., et al. (2011). The Dynamic Structure of Filamentous Tau. Angew. Chem. Int. Ed. 50, 11520–11524. 10.1002/anie.201105493 PubMed DOI

Bielska A. A., Zondlo N. J. (2006). Hyperphosphorylation of Tau Induces Local Polyproline II helix. Biochemistry 45, 5527–5537. 10.1021/bi052662c PubMed DOI

Biernat J., Gustke N., Drewes G., Mandelkow E., Mandelkow E. (1993). Phosphorylation of Ser262 Strongly Reduces Binding of Tau to Microtubules: Distinction between PHF-like Immunoreactivity and Microtubule Binding. Neuron 11, 153–163. 10.1016/0896-6273(93)90279-z PubMed DOI

Braak H., Braak E. (1991). Neuropathological Stageing of Alzheimer-Related Changes. Acta Neuropathol. 82, 239–259. 10.1007/bf00308809 PubMed DOI

Braak H., Thal D. R., Ghebremedhin E., Del Tredici K. (2011). Stages of the Pathologic Process in Alzheimer Disease: Age Categories from 1 to 100 Years. J. Neuropathol. Exp. Neurol. 70, 960–969. 10.1097/nen.0b013e318232a379 PubMed DOI

Carlomagno Y., Manne S., DeTure M., Prudencio M., Zhang Y.-J., Hanna Al-Shaikh R., et al. (2021). The AD Tau Core Spontaneously Self-Assembles and Recruits Full-Length Tau to Filaments. Cel Rep. 34, 108843. 10.1016/j.celrep.2021.108843 PubMed DOI PMC

Cavazzoni P. (2021). FDA’s Decision to Approve New Treatment for Alzheimer’s Disease. FDA. Available at: https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease (Accessed July 12, 2021).

Chakraborty P., Rivière G., Liu S., de Opakua A. I., Dervişoğlu R., Hebestreit A., et al. (2021). Co-factor-free Aggregation of Tau into Seeding-Competent RNA-Sequestering Amyloid Fibrils. Nat. Commun. 12, 4231. 10.1038/s41467-021-24362-8 PubMed DOI PMC

Chen Y., Chen X., Yao Z., Shi Y., Xiong J., Zhou J., et al. (2019). 14-3-3/Tau Interaction and Tau Amyloidogenesis. J. Mol. Neurosci. 68, 620–630. 10.1007/s12031-019-01325-9 PubMed DOI

Congdon E. E., Sigurdsson E. M. (2018). Tau-targeting Therapies for Alzheimer Disease. Nat. Rev. Neurol. 14, 399–415. 10.1038/s41582-018-0013-z PubMed DOI PMC

Cummings J. L., Morstorf T., Zhong K. (2014). Alzheimer's Disease Drug-Development Pipeline: Few Candidates, Frequent Failures. Alzheimers Res. Ther. 6, 37. 10.1186/alzrt269 PubMed DOI PMC

Daebel V., Chinnathambi S., Biernat J., Schwalbe M., Habenstein B., Loquet A., et al. (2012). β-Sheet Core of Tau Paired Helical Filaments Revealed by Solid-State NMR. J. Am. Chem. Soc. 134, 13982–13989. 10.1021/ja305470p PubMed DOI

Daly N. L., Hoffmann R., Otvos L., Craik D. J. (2000). Role of Phosphorylation in the Conformation of τ Peptides Implicated in Alzheimer's Disease. Biochemistry 39, 9039–9046. 10.1021/bi0004807 PubMed DOI

de Calignon A., Fox L. M., Pitstick R., Carlson G. A., Bacskai B. J., Spires-Jones T. L., et al. (2010). Caspase Activation Precedes and Leads to Tangles. Nature 464, 1201–1204. 10.1038/nature08890 PubMed DOI PMC

Despres C., Byrne C., Qi H., Cantrelle F.-X., Huvent I., Chambraud B., et al. (2017). Identification of the Tau Phosphorylation Pattern that Drives its Aggregation. Proc. Natl. Acad. Sci. USA. 114, 9080–9085. 10.1073/pnas.1708448114 PubMed DOI PMC

Despres C., Di J., Cantrelle F.-X., Li Z., Huvent I., Chambraud B., 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. 10.1021/acschembio.9b00325 PubMed DOI PMC

Ding F., Borreguero J. M., Buldyrey S. V., Stanley H. E., Dokholyan N. V. (2003). Mechanism for the α-helix to β-hairpin Transition. Proteins 53, 220–228. 10.1002/prot.10468 PubMed DOI

Dregni A. J., Duan P., Hong M. (2020). Hydration and Dynamics of Full-Length Tau Amyloid Fibrils Investigated by Solid-State Nuclear Magnetic Resonance. Biochemistry 59, 2237–2248. 10.1021/acs.biochem.0c00342 PubMed DOI PMC

Dregni A. J., Mandala V. S., Wu H., Elkins M. R., Wang H. K., Hung I., et al. (2019). In Vitro 0N4R Tau Fibrils Contain a Monomorphic β-sheet Core Enclosed by Dynamically Heterogeneous Fuzzy Coat Segments. Proc. Natl. Acad. Sci. USA. 116, 16357–16366. 10.1073/pnas.1906839116 PubMed DOI PMC

Dregni A. J., Wang H. K., Wu H., Duan P., Jin J., DeGrado W. F., et al. (2021). Inclusion of the C-Terminal Domain in the β-Sheet Core of Heparin-Fibrillized Three-Repeat Tau Protein Revealed by Solid-State Nuclear Magnetic Resonance Spectroscopy. J. Am. Chem. Soc. 143, 7839–7851. 10.1021/jacs.1c03314 PubMed DOI PMC

Eliezer D., Barré P., Kobaslija M., Chan D., Li X., Heend L. (2005). Residual Structure in the Repeat Domain of Tau: Echoes of Microtubule Binding and Paired Helical Filament Formation. Biochemistry 44, 1026–1036. 10.1021/bi048953n PubMed DOI

Falcon B., Zhang W., Murzin A. G., Murshudov G., Garringer H. J., Vidal R., et al. (2018). Structures of Filaments from Pick's Disease Reveal a Novel Tau Protein Fold. Nature 561, 137–140. 10.1038/s41586-018-0454-y PubMed DOI PMC

Fichou Y., Vigers M., Goring A. K., Eschmann N. A., Han S. (2018). Heparin-induced Tau Filaments Are Structurally Heterogeneous and Differ from Alzheimer's Disease Filaments. Chem. Commun. 54, 4573–4576. 10.1039/c8cc01355a PubMed DOI

Fischer D., Mukrasch M. D., Biernat J., Bibow S., Blackledge M., Griesinger C., et al. (2009). Conformational Changes Specific for Pseudophosphorylation at Serine 262 Selectively Impair Binding of Tau to Microtubules. Biochemistry 48, 10047–10055. 10.1021/bi901090m PubMed DOI

Fischer D., Mukrasch M. D., von Bergen M., Klos-Witkowska A., Biernat J., Griesinger C., et al. (2007). Structural and Microtubule Binding Properties of Tau Mutants of Frontotemporal Dementias. Biochemistry 46, 2574–2582. 10.1021/bi061318s PubMed DOI

Fitzpatrick A. W. P., Falcon B., He S., Murzin A. G., Murshudov G., Garringer H. J., et al. (2017). Cryo-EM Structures of Tau Filaments from Alzheimer's Disease. Nature 547, 185–190. 10.1038/nature23002 PubMed DOI PMC

Gandhi N. S., Landrieu I., Byrne C., Kukic P., Amniai L., Cantrelle F.-X., et al. (2015). A Phosphorylation-Induced Turn Defines the Alzheimer's Disease AT8 Antibody Epitope on the Tau Protein. Angew. Chem. Int. Ed. 54, 6819–6823. 10.1002/anie.201501898 PubMed DOI

Ghag G., Bhatt N., Cantu D. V., Guerrero-Munoz M. J., Ellsworth A., Sengupta U., et al. (2018). Soluble Tau Aggregates, Not Large Fibrils, Are the Toxic Species that Display Seeding and Cross-Seeding Behavior. Protein Sci. 27, 1901–1909. 10.1002/pro.3499 PubMed DOI PMC

Goedert M., Jakes R., Spillantini M. G., Hasegawa M., Smith M. J., Crowther R. A. (1996). Assembly of Microtubule-Associated Protein Tau into Alzheimer-like Filaments Induced by Sulphated Glycosaminoglycans. Nature 383, 550–553. 10.1038/383550a0 PubMed DOI

Goedert M., Wischik C. M., Crowther R. A., Walker J. E., Klug A. (1988). Cloning and Sequencing of the cDNA Encoding a Core Protein of the Paired Helical Filament of Alzheimer Disease: Identification as the Microtubule-Associated Protein Tau. Proc. Natl. Acad. Sci. 85, 4051–4055. 10.1073/pnas.85.11.4051 PubMed DOI PMC

Gogl G., Tugaeva K. V., Eberling P., Kostmann C., Trave G., Sluchanko N. N. (2021). Hierarchized Phosphotarget Binding by the Seven Human 14-3-3 Isoforms. Nat. Commun. 12, 1677. 10.1038/s41467-021-21908-8 PubMed DOI PMC

Guo J.-P., Arai T., Miklossy J., McGeer P. L. (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. 103, 1953–1958. 10.1073/pnas.0509386103 PubMed DOI PMC

Habchi J., Tompa P., Longhi S., Uversky V. N. (2014). Introducing Protein Intrinsic Disorder. Chem. Rev. 114, 6561–6588. 10.1021/cr400514h PubMed DOI

Haj‐Yahya M., Gopinath P., Rajasekhar K., Mirbaha H., Diamond M. I., Lashuel H. A. (2020). Site‐Specific Hyperphosphorylation Inhibits, rather Than Promotes, Tau Fibrillization, Seeding Capacity, and its Microtubule Binding. Angew. Chem. Int. Ed. 59, 4059–4067. 10.1002/anie.201913001 PubMed DOI PMC

Harbison N. W., Bhattacharya S., Eliezer D. (2012). Assigning Backbone NMR Resonances for Full Length Tau Isoforms: Efficient Compromise between Manual Assignments and Reduced Dimensionality. PLoS ONE 7, e34679. 10.1371/journal.pone.0034679 PubMed DOI PMC

Hashiguchi M., Sobue K., Paudel H. K. (2000). 14-3-3ζ Is an Effector of Tau Protein Phosphorylation. J. Biol. Chem. 275, 25247–25254. 10.1074/jbc.m003738200 PubMed DOI

Hernández F., Cuadros R., Avila J. (2004). Zeta 14-3-3 Protein Favours the Formation of Human Tau Fibrillar Polymers. Neurosci. Lett. 357, 143–146. 10.1016/j.neulet.2003.12.049 PubMed DOI

Hojjatian A., Dasari A. K. R., Sengupta U., Taylor D., Daneshparvar N., Yeganeh F. A., et al. (2021). Tau Induces Formation of α-synuclein Filaments with Distinct Molecular Conformations. Biochem. Biophysical Res. Commun. 554, 145–150. 10.1016/j.bbrc.2021.03.091 PubMed DOI PMC

Hou G., Yan S., Trébosc J., Amoureux J.-P., Polenova T. (2013). Broadband Homonuclear Correlation Spectroscopy Driven by Combined R2nv Sequences under Fast Magic Angle Spinning for NMR Structural Analysis of Organic and Biological Solids. J. Magn. Reson. 232, 18–30. 10.1016/j.jmr.2013.04.009 PubMed DOI PMC

Huvent I., Kamah A., Cantrelle F.-X., Barois N., Slomianny C., Smet-Nocca C., et al. (2014). A Functional Fragment of Tau Forms Fibers without the Need for an Intermolecular Cysteine Bridge. Biochem. Biophysical Res. Commun. 445, 299–303. 10.1016/j.bbrc.2014.01.161 PubMed DOI

Jadhav S., Avila J., Schöll M., Kovacs G. G., Kövari E., Skrabana R., et al. (2019). A Walk through Tau Therapeutic Strategies. Acta Neuropathol. Commun. 7, 22. 10.1186/s40478-019-0664-z PubMed DOI PMC

Jayan P., Vahid A. A., Kizhakkeduth S. T., Muhammed S. O. H., Shibina A. B., Vijayan V. (2021). Direct Observation of the Self‐Aggregation of R3R4 Bi‐repeat of Tau Protein. ChemBioChem 22, 2093–2097. 10.1002/cbic.202100013 PubMed DOI

Jiji A. C., Arshad A., Dhanya S. R., Shabana P. S., Mehjubin C. K., Vijayan V. (2017). Zn2+ Interrupts R4-R3 Association Leading to Accelerated Aggregation of Tau Protein. Chem. Eur. J. 23, 16976–16979. 10.1002/chem.201704555 PubMed DOI

Jin M., Shepardson N., Yang T., Chen G., Walsh D., Selkoe D. J. (2011). Soluble Amyloid -protein Dimers Isolated from Alzheimer Cortex Directly Induce Tau Hyperphosphorylation and Neuritic Degeneration. Proc. Natl. Acad. Sci. 108, 5819–5824. 10.1073/pnas.1017033108 PubMed DOI PMC

Joo Y., Schumacher B., Landrieu I., Bartel M., Smet‐Nocca C., Jang A., et al. (2015). Involvement of 14‐3‐3 in Tubulin Instability and Impaired Axon Development Is Mediated by Tau. FASEB j. 29, 4133–4144. 10.1096/fj.14-265009 PubMed DOI

Kadavath H., Cabrales Fontela Y., Jaremko M., Jaremko Ł., Overkamp K., Biernat J., et al. (2018). The Binding Mode of a Tau Peptide with Tubulin. Angew. Chem. Int. Ed. 57, 3246–3250. 10.1002/anie.201712089 PubMed DOI

Kadavath H., Hofele R. V., Biernat J., Kumar S., Tepper K., Urlaub H., et al. (2015a). Tau Stabilizes Microtubules by Binding at the Interface between Tubulin Heterodimers. Proc. Natl. Acad. Sci. USA. 112, 7501–7506. 10.1073/pnas.1504081112 PubMed DOI PMC

Kadavath H., Jaremko M., Jaremko Ł., Biernat J., Mandelkow E., Zweckstetter M. (2015b). Folding of the Tau Protein on Microtubules. Angew. Chem. Int. Ed. 54, 10347–10351. 10.1002/anie.201501714 PubMed DOI

Kellogg E. H., Hejab N. M. A., Poepsel S., Downing K. H., DiMaio F., Nogales E. (2018). Near-atomic Model of Microtubule-Tau Interactions. Science 360, 1242–1246. 10.1126/science.aat1780 PubMed DOI PMC

Kovacs G. G. (2015). Invited Review: Neuropathology of Tauopathies: Principles and Practice. Neuropathol. Appl. Neurobiol. 41, 3–23. 10.1111/nan.12208 PubMed DOI

Landrieu I., Lacosse L., Leroy A., Wieruszeski J.-M., Trivelli X., Sillen A., et al. (2006). NMR Analysis of a Tau Phosphorylation Pattern. J. Am. Chem. Soc. 128, 3575–3583. 10.1021/ja054656+ PubMed DOI

Lasagna‐Reeves C. A., Castillo‐Carranza D. L., Sengupta U., Sarmiento J., Troncoso J., Jackson G. R., et al. (2012). Identification of Oligomers at Early Stages of Tau Aggregation in Alzheimer's Disease. FASEB j. 26, 1946–1959. 10.1096/fj.11-199851 PubMed DOI PMC

Layfield R., Fergusson J., Aitken A., Lowe J., Landon M., Mayer R. J. (1996). Neurofibrillary Tangles of Alzheimer's Disease Brains Contain 14-3-3 Proteins. Neurosci. Lett. 209, 57–60. 10.1016/0304-3940(96)12598-2 PubMed DOI

Li C., Götz J. (2017). Somatodendritic Accumulation of Tau in Alzheimer's Disease Is Promoted by Fyn‐mediated Local Protein Translation. EMBO J. 36, 3120–3138. 10.15252/embj.201797724 PubMed DOI PMC

Li T., Paudel H. K. (2016). 14-3-3ζ Mediates Tau Aggregation in Human Neuroblastoma M17 Cells. PLoS ONE 11, e0160635. 10.1371/journal.pone.0160635 PubMed DOI PMC

Lindwall G., Cole R. D. (1984). Phosphorylation Affects the Ability of Tau Protein to Promote Microtubule Assembly. J. Biol. Chem. 259, 5301–5305. Available at: https://pubmed.ncbi.nlm.nih.gov/6425287/ (Accessed August 18, 2021). 10.1016/s0021-9258(17)42989-9 PubMed DOI

Lippens G., Sillen A., Smet C., Wieruszeski J.-M., Leroy A., Buée L., et al. (2006). Studying the Natively Unfolded Neuronal Tau Protein by Solution NMR Spectroscopy. Ppl 13, 235–246. 10.2174/092986606775338461 PubMed DOI

Lippens G., Wieruszeski J.-M., Leroy A., Smet C., Sillen A., Buée L., et al. (2003). Proline-directed Random-Coil Chemical Shift Values as a Tool for the NMR Assignment of the Tau Phosphorylation Sites. ChemBioChem. 5, 73–78. 10.1002/cbic.200300763 PubMed DOI

Louša P., Nedozrálová H., Župa E., Nováček J., Hritz J. (2017). Phosphorylation of the Regulatory Domain of Human Tyrosine Hydroxylase 1 Monitored Using Non-uniformly Sampled NMR. Biophysical Chem. 223, 25–29. 10.1016/j.bpc.2017.01.003 PubMed DOI

Lu J., Zhang S., Ma X., Jia C., Liu Z., Huang C., et al. (2020). Structural Basis of the Interplay between α-synuclein and Tau in Regulating Pathological Amyloid Aggregation. J. Biol. Chem. 295, 7470–7480. 10.1074/jbc.RA119.012284 PubMed DOI PMC

Luchinat E., Banci L. (2018). In-cell NMR in Human Cells: Direct Protein Expression Allows Structural Studies of Protein Folding and Maturation. Acc. Chem. Res. 51, 1550–1557. 10.1021/acs.accounts.8b00147 PubMed DOI

Marsh J. A., Singh V. K., Jia Z., Forman-Kay J. D. (2006). Sensitivity of Secondary Structure Propensities to Sequence Differences between α- and γ-synuclein: Implications for Fibrillation. Protein Sci. 15, 2795–2804. 10.1110/ps.062465306 PubMed DOI PMC

Mayzel M., Rosenlöw J., Isaksson L., Orekhov V. Y. (2014). Time-resolved Multidimensional NMR with Non-uniform Sampling. J. Biomol. NMR 58, 129–139. 10.1007/s10858-013-9811-1 PubMed DOI PMC

Melková K., Narasimhan S., Jansen S., Hritz J., Škrabana R., Zweckstetter M., et al. (2019). Structure and Functions of Microtubule Associated Proteins Tau and MAP2c: Similarities and Differences. Biomolecules 9, 105. 10.3390/biom9030105 PubMed DOI PMC

Minoura K., Tomoo K., Ishida T., Hasegawa H., Sasaki M., Taniguchi T. (2002). Amphipathic Helical Behavior of the Third Repeat Fragment in the Tau Microtubule-Binding Domain, Studied by 1H NMR Spectroscopy. Biochem. Biophysical Res. Commun. 294, 210–214. 10.1016/S0006-291X(02)00457-6 PubMed DOI

Minoura K., Tomoo K., Ishida T., Hasegawa H., Sasaki M., Taniguchi T. (2003). Solvent-Dependent Conformation of the Third Repeat Fragment in the Microtubule-Binding Domain of Tau Protein, Analyzed by1H-NMR Spectroscopy and Molecular Modeling Calculation. Bcsj 76, 1617–1624. 10.1246/bcsj.76.1617 DOI

Minoura K., Yao T.-M., Tomoo K., Sumida M., Sasaki M., Taniguchi T., et al. (2004). Different Associational and Conformational Behaviors between the Second and Third Repeat Fragments in the Tau Microtubule-Binding Domain. Eur. J. Biochem. 271, 545–552. 10.1046/j.1432-1033.2003.03956.x PubMed DOI

Monteith W. B., Pielak G. J. (2014). Residue Level Quantification of Protein Stability in Living Cells. Proc. Natl. Acad. Sci. 111, 11335–11340. 10.1073/pnas.1406845111 PubMed DOI PMC

Mukrasch M. D., Bibow S., Korukottu J., Jeganathan S., Biernat J., Griesinger C., et al. (2009). Structural Polymorphism of 441-residue Tau at Single Residue Resolution. Plos Biol. 7, e1000034. 10.1371/journal.pbio.1000034 PubMed DOI PMC

Mukrasch M. D., Biernat J., von Bergen M., Griesinger C., Mandelkow E., Zweckstetter M. (2005). Sites of Tau Important for Aggregation Populate β-Structure and Bind to Microtubules and Polyanions. J. Biol. Chem. 280, 24978–24986. 10.1074/jbc.M501565200 PubMed DOI

Mukrasch M. D., von Bergen M., Biernat J., Fischer D., Griesinger C., Mandelkow E., et al. (2007). The "Jaws" of the Tau-Microtubule Interaction. J. Biol. Chem. 282, 12230–12239. 10.1074/jbc.M607159200 PubMed DOI

Narayanan R. L., Dürr U. H. N., Bibow S., Biernat J., Mandelkow E., Zweckstetter M. (2010). Automatic Assignment of the Intrinsically Disordered Protein Tau with 441-residues. J. Am. Chem. Soc. 132, 11906–11907. 10.1021/ja105657f PubMed DOI

Naruto K., Minoura K., Okuda R., Taniguchi T., In Y., Ishida T., et al. (2010). Interplay between I308 and Y310 Residues in the Third Repeat of Microtubule-Binding Domain Is Essential for Tau Filament Formation. FEBS Lett. 584, 4233–4236. 10.1016/j.febslet.2010.09.012 PubMed DOI

Novak P., Cehlar O., Skrabana R., Novak M. (2018a). Tau Conformation as a Target for Disease-Modifying Therapy: The Role of Truncation. Jad 64, S535–S546. 10.3233/JAD-179942 PubMed DOI

Novak P., Kontsekova E., Zilka N., Novak M. (2018b). Ten Years of Tau-Targeted Immunotherapy: The Path Walked and the Roads Ahead. Front. Neurosci. 12, 798. 10.3389/fnins.2018.00798 PubMed DOI PMC

Novak P., Kovacech B., Katina S., Schmidt R., Scheltens P., Kontsekova E., et al. (2021). ADAMANT: a Placebo-Controlled Randomized Phase 2 Study of AADvac1, an Active Immunotherapy against Pathological Tau in Alzheimer's Disease. Nat. Aging 1, 521–534. 10.1038/s43587-021-00070-2 PubMed DOI

Paudel H. K., Li W. (1999). Heparin-induced Conformational Change in Microtubule-Associated Protein Tau as Detected by Chemical Cross-Linking and Phosphopeptide Mapping. J. Biol. Chem. 274, 8029–8038. 10.1074/jbc.274.12.8029 PubMed DOI

Peterson D. W., Zhou H., Dahlquist F. W., Lew J. (2008). A Soluble Oligomer of Tau Associated with Fiber Formation Analyzed by NMR. Biochemistry 47, 7393–7404. 10.1021/bi702466a PubMed DOI

Qi H., Prabakaran S., Cantrelle F.-X., Chambraud B., Gunawardena J., Lippens G., et al. (2016). Characterization of Neuronal Tau Protein as a Target of Extracellular Signal-Regulated Kinase. J. Biol. Chem. 291, 7742–7753. 10.1074/jbc.M115.700914 PubMed DOI PMC

Qureshi H. Y., Li T., MacDonald R., Cho C. M., Leclerc N., Paudel H. K. (2013). Interaction of 14-3-3ζ with Microtubule-Associated Protein Tau within Alzheimer's Disease Neurofibrillary Tangles. Biochemistry 52, 6445–6455. 10.1021/bi400442d PubMed DOI

Raz Y., Adler J., Vogel A., Scheidt H. A., Häupl T., Abel B., et al. (2014). The Influence of the ΔK280 Mutation and N- or C-Terminal Extensions on the Structure, Dynamics, and Fibril Morphology of the Tau R2 Repeat. Phys. Chem. Chem. Phys. 16, 7710–7717. 10.1039/C3CP54890B PubMed DOI

Reitz C., Brayne C., Mayeux R. (2011). Epidemiology of Alzheimer Disease. Nat. Rev. Neurol. 7, 137–152. 10.1038/nrneurol.2011.2 PubMed DOI PMC

Sadik G., Tanaka T., Kato K., Yanagi K., Kudo T., Takeda M. (2009). Differential Interaction and Aggregation of 3-repeat and 4-repeat Tau Isoforms with 14-3-3ζ Protein. Biochem. Biophysical Res. Commun. 383, 37–41. 10.1016/j.bbrc.2009.03.107 PubMed DOI

Savastano A., Jaipuria G., Andreas L., Mandelkow E., Zweckstetter M. (2020). Solid-state NMR Investigation of the Involvement of the P2 Region in Tau Amyloid Fibrils. Sci. Rep. 10, 21210. 10.1038/s41598-020-78161-0 PubMed DOI PMC

Schneider A., Biernat J., von Bergen M., Mandelkow E., Mandelkow E.-M. (1999). Phosphorylation that Detaches Tau Protein from Microtubules (Ser262, Ser214) Also Protects it against Aggregation into Alzheimer Paired Helical Filaments. Biochemistry 38, 3549–3558. 10.1021/bi981874p PubMed DOI

Schwalbe M., Kadavath H., Biernat J., Ozenne V., Blackledge M., Mandelkow E., et al. (2015). Structural Impact of Tau Phosphorylation at Threonine 231. Structure 23, 1448–1458. 10.1016/j.str.2015.06.002 PubMed DOI

Schweers O., Mandelkow E. M., Biernat J., Mandelkow E. (1995). Oxidation of Cysteine-322 in the Repeat Domain of Microtubule-Associated Protein Tau Controls the In Vitro Assembly of Paired Helical Filaments. Proc. Natl. Acad. Sci. 92, 8463–8467. 10.1073/pnas.92.18.8463 PubMed DOI PMC

Scott C. W., Spreen R. C., Herman J. L., Chow F. P., Davison M. D., Young J., et al. (1993). Phosphorylation of Recombinant Tau by cAMP-dependent Protein Kinase. Identification of Phosphorylation Sites and Effect on Microtubule Assembly. J. Biol. Chem. 268, 1166–1173. 10.1016/S0021-9258(18)54055-2 PubMed DOI

Serber Z., Dötsch V. (2001). In-cell NMR Spectroscopy. Biochemistry 40, 14317–14323. 10.1021/bi011751w PubMed DOI

Sevigny J., Chiao P., Bussière T., Weinreb P. H., Williams L., Maier M., et al. (2016). The Antibody Aducanumab Reduces Aβ Plaques in Alzheimer's Disease. Nature 537, 50–56. 10.1038/nature19323 PubMed DOI

Shiraki K., Nishikawa K., Goto Y. (1995). Trifluoroethanol-induced Stabilization of the α-Helical Structure of β-Lactoglobulin: Implication for Non-hierarchical Protein Folding. J. Mol. Biol. 245, 180–194. 10.1006/jmbi.1994.0015 PubMed DOI

Sibille N., Huvent I., Fauquant C., Verdegem D., Amniai L., Leroy A., et al. (2012). Structural Characterization by Nuclear Magnetic Resonance of the Impact of Phosphorylation in the Proline-Rich Region of the Disordered Tau Protein. Proteins 80, 454–462. 10.1002/prot.23210 PubMed DOI

Sibille N., Sillen A., Leroy A., Wieruszeski J.-M., Mulloy B., Landrieu I., et al. (2006). Structural Impact of Heparin Binding to Full-Length Tau as Studied by NMR Spectroscopy. Biochemistry 45, 12560–12572. 10.1021/bi060964o PubMed DOI

Sillen A., Barbier P., Landrieu I., Lefebvre S., Wieruszeski J.-M., Leroy A., et al. (2007). NMR Investigation of the Interaction between the Neuronal Protein Tau and the Microtubules. Biochemistry 46, 3055–3064. 10.1021/bi061920i PubMed DOI

Sillen A., Leroy A., Wieruszeski J.-M., Loyens A., Beauvillain J.-C., Buée L., et al. (2005a). Regions of Tau Implicated in the Paired Helical Fragment Core as Defined by NMR. Chembiochem 6, 1849–1856. 10.1002/cbic.200400452 PubMed DOI

Sillen A., Wieruszeski J.-M., Leroy A., Younes A. B., Landrieu I., Lippens G. (2005b). High-Resolution Magic Angle Spinning NMR of the Neuronal Tau Protein Integrated in Alzheimer's-like Paired Helical Fragments. J. Am. Chem. Soc. 127, 10138–10139. 10.1021/ja0516211 PubMed DOI

Sluchanko N. N., Bustos D. M. (2019). Intrinsic Disorder Associated with 14-3-3 Proteins and Their Partners. Prog. Mol. Biol. Transl. Sci. 166, 19–61. 10.1016/bs.pmbts.2019.03.007 PubMed DOI

Sluchanko N. N., Seit-Nebi A. S., Gusev N. B. (2009). Phosphorylation of More Than One Site Is Required for Tight Interaction of Human Tau Protein with 14-3-3ζ. FEBS Lett. 583, 2739–2742. 10.1016/j.febslet.2009.07.043 PubMed DOI

Smet C., Leroy A., Sillen A., Wieruszeski J.-M., Landrieu I., Lippens G. (2004). Accepting its Random Coil Nature Allows a Partial NMR Assignment of the Neuronal Tau Protein. ChemBioChem. 5, 1639–1646. 10.1002/cbic.200400145 PubMed DOI

Sogawa K., Minoura K., In Y., Ishida T., Taniguchi T., Tomoo K. (2014). CH-π Interaction in VQIVYK Sequence Elucidated by NMR Spectroscopy Is Essential for PHF Formation of Tau. Biopolymers 102, 288–295. 10.1002/bip.22489 PubMed DOI

Soragni A., Zambelli B., Mukrasch M. D., Biernat J., Jeganathan S., Griesinger C., et al. (2008). Structural Characterization of Binding of Cu(II) to Tau Protein. Biochemistry 47, 10841–10851. 10.1021/bi8008856 PubMed DOI

Sotiropoulos I., Galas M.-C., Silva J. M., Skoulakis E., Wegmann S., Maina M. B., et al. (2017). Atypical, Non-standard Functions of the Microtubule Associated Tau Protein. Acta Neuropathol. Commun. 5, 91. 10.1186/s40478-017-0489-6 PubMed DOI PMC

Stöhr J., Wu H., Nick M., Wu Y., Bhate M., Condello C., et al. (2017). A 31-residue Peptide Induces Aggregation of Tau's Microtubule-Binding Region in Cells. Nat. Chem 9, 874–881. 10.1038/nchem.2754 PubMed DOI PMC

Theillet F.-X., Binolfi A., Bekei B., Martorana A., Rose H. M., Stuiver M., et al. (2016). Structural Disorder of Monomeric α-synuclein Persists in Mammalian Cells. Nature 530, 45–50. 10.1038/nature16531 PubMed DOI

Tomoo K., Yao T.-M., Minoura K., Hiraoka S., Sumida M., Taniguchi T., et al. (2005). Possible Role of Each Repeat Structure of the Microtubule-Binding Domain of the Tau Protein in In Vitro Aggregation. J. Biochem. 138, 413–423. 10.1093/jb/mvi142 PubMed DOI

Umahara T., Uchihara T., Tsuchiya K., Nakamura A., Iwamoto T., Ikeda K., et al. (2004). 14-3-3 Proteins and Zeta Isoform Containing Neurofibrillary Tangles in Patients with Alzheimer’s Disease. Acta Neuropathol. 108, 279–286. 10.1007/s00401-004-0885-4 PubMed DOI

von Bergen M., Barghorn S., Biernat J., Mandelkow E.-M., Mandelkow E. (2005). Tau Aggregation Is Driven by a Transition from Random Coil to Beta Sheet Structure. Biochim. Biophys. Acta (Bba) - Mol. Basis Dis. 1739, 158–166. 10.1016/j.bbadis.2004.09.010 PubMed DOI

von Bergen M., Friedhoff P., Biernat J., Heberle J., Mandelkow E.-M., Mandelkow E. (2000). Assembly of Tau Protein into Alzheimer Paired Helical Filaments Depends on a Local Sequence Motif (306VQIVYK311) Forming Beta Structure. Proc. Natl. Acad. Sci. 97, 5129–5134. 10.1073/pnas.97.10.5129 PubMed DOI PMC

Wallin C., Hiruma Y., Wärmländer S. K. T. S., Huvent I., Jarvet J., Abrahams J. P., et al. (2018). The Neuronal Tau Protein Blocks In Vitro Fibrillation of the Amyloid-β (Aβ) Peptide at the Oligomeric Stage. J. Am. Chem. Soc. 140, 8138–8146. 10.1021/jacs.7b13623 PubMed DOI

Wegmann S., Biernat J., Mandelkow E. (2021). A Current View on Tau Protein Phosphorylation in Alzheimer's Disease. Curr. Opin. Neurobiol. 69, 131–138. 10.1016/j.conb.2021.03.003 PubMed DOI

Wegmann S., Schöler J., Bippes C. A., Mandelkow E., Muller D. J. (2011). Competing Interactions Stabilize Pro- and Anti-aggregant Conformations of Human Tau. J. Biol. Chem. 286, 20512–20524. 10.1074/jbc.m111.237875 PubMed DOI PMC

Wimo A., Jönsson L., Gustavsson A., McDaid D., Ersek K., Georges J., et al. (2010). The Economic Impact of Dementia in Europe in 2008-cost Estimates from the Eurocode Project. Int. J. Geriat. Psychiatry 26, 825–832. 10.1002/gps.2610 PubMed DOI

Wischik C. M., Novak M., Edwards P. C., Klug A., Tichelaar W., Crowther R. A. (1988). Structural Characterization of the Core of the Paired Helical Filament of Alzheimer Disease. Proc. Natl. Acad. Sci. 85, 4884–4888. 10.1073/pnas.85.13.4884 PubMed DOI PMC

World Health Organisation (2020). Dementia. Who.int. Available at: https://www.who.int/news-room/fact-sheets/detail/dementia (Accessed July 1, 2021).

Xiang S., Kulminskaya N., Habenstein B., Biernat J., Tepper K., Paulat M., et al. (2017). A Two-Component Adhesive: Tau Fibrils Arise from a Combination of a Well-Defined Motif and Conformationally Flexible Interactions. J. Am. Chem. Soc. 139, 2639–2646. 10.1021/jacs.6b09619 PubMed DOI

Zhang S., Wang C., Lu J., Ma X., Liu Z., Li D., et al. (2018). In-cell NMR Study of Tau and MARK2 Phosphorylated Tau. Ijms 20, 90. 10.3390/ijms20010090 PubMed DOI PMC

Zhang W., Falcon B., Murzin A. G., Fan J., Crowther R. A., Goedert M., et al. (2019). Heparin-induced Tau Filaments Are Polymorphic and Differ from Those in Alzheimer's and Pick's Diseases. eLife 8, e43584. 10.7554/elife.43584 PubMed DOI PMC

Zhang W., Tarutani A., Newell K. L., Murzin A. G., Matsubara T., Falcon B., et al. (2020). Novel Tau Filament Fold in Corticobasal Degeneration. Nature 580, 283–287. 10.1038/s41586-020-2043-0 PubMed DOI PMC

Zhao J., Zhu Y., Song X., Xiao Y., Su G., Liu X., et al. (2020). 3‐ O ‐Sulfation of Heparan Sulfate Enhances Tau Interaction and Cellular Uptake. Angew. Chem. Int. Ed. 59, 1818–1827. 10.1002/anie.201913029 PubMed DOI PMC

Zhou L.-X., Zeng Z.-Y., Du J.-T., Zhao Y.-F., Li Y.-M. (2006). The Self-Assembly Ability of the First Microtubule-Binding Repeat from Tau and its Modulation by Phosphorylation. Biochem. Biophysical Res. Commun. 348, 637–642. 10.1016/j.bbrc.2006.07.099 PubMed DOI

Zilka N., Kazmerova Z., Jadhav S., Neradil P., Madari A., Obetkova D., et al. (2012). Who Fans the Flames of Alzheimer's Disease Brains? Misfolded Tau on the Crossroad of Neurodegenerative and Inflammatory Pathways. J. Neuroinflammation 9, 47. 10.1186/1742-2094-9-47 PubMed DOI PMC

dGAE(297-391) Tau Fragment Promotes Formation of Chronic Traumatic Encephalopathy-Like Tau Filaments