Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Structure-based inhibitors of tau aggregation

Abstract

Aggregated tau protein is associated with over 20 neurological disorders, which include Alzheimer's disease. Previous work has shown that tau's sequence segments VQIINK and VQIVYK drive its aggregation, but inhibitors based on the structure of the VQIVYK segment only partially inhibit full-length tau aggregation and are ineffective at inhibiting seeding by full-length fibrils. Here we show that the VQIINK segment is the more powerful driver of tau aggregation. Two structures of this segment determined by the cryo-electron microscopy method micro-electron diffraction explain its dominant influence on tau aggregation. Of practical significance, the structures lead to the design of inhibitors that not only inhibit tau aggregation but also inhibit the ability of exogenous full-length tau fibrils to seed intracellular tau in HEK293 biosensor cells into amyloid. We also raise the possibility that the two VQIINK structures represent amyloid polymorphs of tau that may account for a subset of prion-like strains of tau.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Atomic structures of amyloid fibrils formed by segments of tau, viewed down the fibril axes.
Figure 2: Time dependence of fibrillization and oligomerization for the WT K18 construct and the 2xIN and 2xVY K18 mutant constructs.
Figure 3: Structure-based design of Phase 1 inhibitors of VQIINK aggregation.
Figure 4: The inhibition of tau aggregation by Phase 2 designed inhibitors.

Accession codes

Primary accessions

Protein Data Bank

References

  1. 1

    Margittai, M. & Langen, R. Side chain-dependent stacking modulates tau filament structure. J. Biol. Chem. 281, 37820–37827 (2006).

    CAS  Article  Google Scholar 

  2. 2

    von Bergen, M. et al. Assembly of τ protein into Alzheimer paired helical filaments depends on a local sequence motif (306VQIVYK311) forming β structure. Proc. Natl Acad. Sci. USA 97, 5129–5134 (2000).

    CAS  Article  Google Scholar 

  3. 3

    Goedert, M., Eisenberg, D. S. & Crowther, R. A. Propagation of tau aggregates and neurodegeneration. Annu. Rev. Neurosci. 40, 189–210 (2017).

    CAS  Article  Google Scholar 

  4. 4

    Schwarz, A. J. et al. Regional profiles of the candidate tau PET ligand recapitulate key features of Braak histopathological stages. Brain 139, 1539–1550 (2016).

    Article  Google Scholar 

  5. 5

    Manczak, M. & Reddy, P. H. Abnormal interaction of oligomeric amyloid-β with phosphorylated tau: implications to synaptic dysfunction and neuronal damage. J. Alzheimers Dis. 36, 285–295 (2013).

    CAS  Article  Google Scholar 

  6. 6

    Seward, M. E. et al. Amyloid-β signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer's disease. J. Cell Sci. 126, 1278–1286 (2013).

    CAS  Article  Google Scholar 

  7. 7

    Brier, M. R. et al. Tau and Aβ imaging, CSF measures, and cognition in Alzheimer's disease. Sci. Transl. Med. 8, 338ra366 (2016).

    Article  Google Scholar 

  8. 8

    Kfoury, N., Holmes, B. B., Jiang, H., Holtzman, D. M. & Diamond, M. I. Trans-cellular propagation of tau aggregation by fibrillar species. J. Biol. Chem. 287, 19440–19451 (2012).

    CAS  Article  Google Scholar 

  9. 9

    von Bergen, M. et al. Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure. J. Biol. Chem., 276, 48165–48174 (2001).

    CAS  Article  Google Scholar 

  10. 10

    Sawaya, M. R. et al. Atomic structures of amyloid cross-[bgr] spines reveal varied steric zippers. Nature 447, 453–457 (2007).

    CAS  Article  Google Scholar 

  11. 11

    Sievers, S. A. et al. Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation. Nature 475, 96–100 (2011).

    CAS  Article  Google Scholar 

  12. 12

    Zheng, J. et al. Macrocyclic β-sheet peptides that inhibit the aggregation of a tau-protein-derived hexapeptide. J. Am. Chem. Soc. 133, 3144–3157 (2011).

    CAS  Article  Google Scholar 

  13. 13

    Shi, D., Nannenga, B. L., Iadanza, M. G. & Gonen, T. Three-dimensional electron crystallography of protein microcrystals. eLife 2, e01345 (2013).

    Article  Google Scholar 

  14. 14

    Rodriguez, J. A. et al. Structure of the toxic core of [agr]-synuclein from invisible crystals. Nature 525, 486–490 (2015).

    CAS  Article  Google Scholar 

  15. 15

    Rodriguez, J. A. & Gonen, T. in Methods in Enzymology Vol. 579 (ed. Crowther, R. A.) 369–392 (Academic, 2016).

    Google Scholar 

  16. 16

    Eisenberg, D. S. & Sawaya, M. R. Structural studies of amyloid proteins at the molecular level. Annu. Rev. Biochem. 86, 3.1–3.27 (2017).

    Article  Google Scholar 

  17. 17

    Wood, S. J., Wetzel, R., Martin, J. D. & Hurle, M. R. Prolines and amyloidogenicity in fragments of the Alzheimer's peptide β/A4. Biochemistry 34, 724–730 (1995).

    CAS  Article  Google Scholar 

  18. 18

    Moore, C. L. et al. Secondary nucleating sequences affect kinetics and thermodynamics of tau aggregation. Biochemistry 50, 10876–10886 (2011).

    CAS  Article  Google Scholar 

  19. 19

    von Bergen, M. et al. Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local β-structure. J. Biol. Chem. 276, 48165–48174 (2001).

    CAS  Article  Google Scholar 

  20. 20

    Margittai, M. & Langen, R. Fibrils with parallel in-register structure constitute a major class of amyloid fibrils: molecular insights from electron paramagnetic resonance spectroscopy. Q. Rev. Biophys. 41, 265–297 (2008).

    CAS  Article  Google Scholar 

  21. 21

    Mirbaha, H., Holmes, B. B., Sanders, D. W., Bieschke, J. & Diamond, M. I. Tau trimers are the minimal propagation unit spontaneously internalized to seed intracellular aggregation. J. Biol. Chem., 290 14893–14903 (2015).

    CAS  Article  Google Scholar 

  22. 22

    Sanders, D. W . et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82, 1271–1288 (2014).

    CAS  Article  Google Scholar 

  23. 23

    Siddiqua, A. et al. Conformational basis for asymmetric seeding barrier in filaments of three- and four-repeat tau. J. Am. Chem. Soc. 134, 10271–10278 (2012).

    CAS  Article  Google Scholar 

  24. 24

    Margittai, M. & Langen, R. Template-assisted filament growth by parallel stacking of tau. Proc. Natl Acad. Sci. USA 101, 10278–10283 (2004).

    CAS  Article  Google Scholar 

  25. 25

    Fitzpatrick, A. W. P. et al. Cryo-EM structures of tau filaments from Alzheimer's disease. Nature 547, 185–190 (2017).

    CAS  Article  Google Scholar 

  26. 26

    Kaufman, S. K. et al. Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo. Neuron 92, 796–812 (2016).

    CAS  Article  Google Scholar 

  27. 27

    Wiltzius, J. J. W. et al. Molecular mechanisms for protein-encoded inheritance. Nat. Struct. Mol. Biol. 16, 973–978 (2009).

    CAS  Article  Google Scholar 

  28. 28

    Kabsch, W. XDS. Acta Crystallogr. D 66, 125–132 (2010).

    CAS  Article  Google Scholar 

  29. 29

    McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007).

    CAS  Article  Google Scholar 

  30. 30

    Murshudov, G. N., Vagin, A. A. & Dodson, E. J. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr. D 53, 240–255 (1997).

    CAS  Article  Google Scholar 

  31. 31

    Bricogne, G., B. E. et al. BUSTER 2.10.0 (Global Phasing Ltd, 2016).

    Google Scholar 

  32. 32

    Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr D 66, 486–501 (2010).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank M. Diamond for discussion and for gifting the monoclonal biosensor HEK293 cell-line that expressed tau 4R1N P301S-EYFP for our inhibitor assay, and H. Mirbaha for assistance and advice on conducting the biosensor seeding experiments and purifying K18 tau oligomers by gel filtration chromatography. We also thank awards 1R01 AG029430 and RF1 AG054022 from the National Institute on Aging, 1F32 NS095661 from the National Institute of Neurological Disorders and Stroke, A2016588F from the BrightFocus Foundation and HHMI and the Janelia Visiting Scientist Program for support.

Author information

Affiliations

Authors

Contributions

P.M.S. conceived and designed the experiments; P.M.S., D.R.B., J.A.R. and K.M. performed the experiments; P.M.S., D.R.B., M.R.S. and D.C. analysed data; and P.M.S., D.S.E. and T.G. co-wrote the paper.

Corresponding author

Correspondence to D. S. Eisenberg.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Seidler, P., Boyer, D., Rodriguez, J. et al. Structure-based inhibitors of tau aggregation. Nature Chem 10, 170–176 (2018). https://doi.org/10.1038/nchem.2889

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing