Structure-based inhibitors halt prion-like seeding by Alzheimer's disease-and tauopathy-derived brain tissue samples

Paul Matthew Seidler, David R. Boyer, Kevin A. Murray, Tianxiao P. Yang, Megan Bentzel, Michael R. Sawaya, Gregory Rosenberg, Duilio Cascio, Christopher Kazu Williams, Kathy L. Newell, Bernardino Ghetti, Michael A. DeTure, Dennis W. Dickson, Harry V. Vinters, David S. Eisenberg

Research output: Contribution to journalArticle

Abstract

In Alzheimer's disease (AD) and tauopathies, tau aggregation accompanies progressive neurodegeneration. Aggregated tau appears to spread between adjacent neurons and adjacent brain regions by prion-like seeding. Hence, inhibitors of this seeding offer a possible route to managing tauopathies. Here, we report the 1.0 Å resolution micro-electron diffraction structure of an aggregation-prone segment of tau with the sequence SVQIVY, present in the cores of patient-derived fibrils from AD and tauopathies. This structure illuminates how distinct interfaces of the parent segment, containing the sequence VQIVYK, foster the formation of distinct structures. Peptide-based fibril-capping inhibitors designed to target the two VQIVYK interfaces blocked proteopathic seeding by patient-derived fibrils. These VQIVYK inhibitors add to a panel of tau-capping inhibitors that targets specific polymorphs of recombinant and patient-derived tau fibrils. Inhibition of seeding initiated by brain tissue extracts differed among donors with different tauopathies, suggesting that particular fibril polymorphs of tau are associated with certain tauopathies. Donors with progressive supranuclear palsy exhibited more variation in inhibitor sensitivity, suggesting that fibrils from these donors were more polymorphic and potentially vary within individual donor brains. Our results suggest that a subset of inhibitors from our panel could be specific for particular disease-associated polymorphs, whereas inhibitors that blocked seeding by extracts from all of the tauopathies tested could be used to broadly inhibit seeding by multiple disease-specific tau polymorphs. Moreover, we show that tau-capping inhibitors can be transiently expressed in HEK293 tau biosensor cells, indicating that nucleic acid- based vectors can be used for inhibitor delivery.

Original languageEnglish (US)
Pages (from-to)16451-16464
Number of pages14
JournalJournal of Biological Chemistry
Volume294
Issue number44
DOIs
StatePublished - Jan 1 2019

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Tauopathies
Prions
Polymorphism
Brain
Alzheimer Disease
Tissue
Tissue Donors
Agglomeration
Tissue Extracts
Biosensors
Electron diffraction
Nucleic Acids
Neurons
Progressive Supranuclear Palsy
Biosensing Techniques
Peptides
Electrons

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Seidler, P. M., Boyer, D. R., Murray, K. A., Yang, T. P., Bentzel, M., Sawaya, M. R., ... Eisenberg, D. S. (2019). Structure-based inhibitors halt prion-like seeding by Alzheimer's disease-and tauopathy-derived brain tissue samples. Journal of Biological Chemistry, 294(44), 16451-16464. https://doi.org/10.1074/jbc.RA119.009688

Structure-based inhibitors halt prion-like seeding by Alzheimer's disease-and tauopathy-derived brain tissue samples. / Seidler, Paul Matthew; Boyer, David R.; Murray, Kevin A.; Yang, Tianxiao P.; Bentzel, Megan; Sawaya, Michael R.; Rosenberg, Gregory; Cascio, Duilio; Williams, Christopher Kazu; Newell, Kathy L.; Ghetti, Bernardino; DeTure, Michael A.; Dickson, Dennis W.; Vinters, Harry V.; Eisenberg, David S.

In: Journal of Biological Chemistry, Vol. 294, No. 44, 01.01.2019, p. 16451-16464.

Research output: Contribution to journalArticle

Seidler, PM, Boyer, DR, Murray, KA, Yang, TP, Bentzel, M, Sawaya, MR, Rosenberg, G, Cascio, D, Williams, CK, Newell, KL, Ghetti, B, DeTure, MA, Dickson, DW, Vinters, HV & Eisenberg, DS 2019, 'Structure-based inhibitors halt prion-like seeding by Alzheimer's disease-and tauopathy-derived brain tissue samples', Journal of Biological Chemistry, vol. 294, no. 44, pp. 16451-16464. https://doi.org/10.1074/jbc.RA119.009688
Seidler, Paul Matthew ; Boyer, David R. ; Murray, Kevin A. ; Yang, Tianxiao P. ; Bentzel, Megan ; Sawaya, Michael R. ; Rosenberg, Gregory ; Cascio, Duilio ; Williams, Christopher Kazu ; Newell, Kathy L. ; Ghetti, Bernardino ; DeTure, Michael A. ; Dickson, Dennis W. ; Vinters, Harry V. ; Eisenberg, David S. / Structure-based inhibitors halt prion-like seeding by Alzheimer's disease-and tauopathy-derived brain tissue samples. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 44. pp. 16451-16464.
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