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Structure-based inhibitors of tau aggregation


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.

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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.

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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.

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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.

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The authors declare no competing financial interests.

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Seidler, P., Boyer, D., Rodriguez, J. et al. Structure-based inhibitors of tau aggregation. Nature Chem 10, 170–176 (2018).

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