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How short peptides disassemble tau fibrils in Alzheimer’s disease

Nature volume 644, pages 1020–1027 (2025)Cite this article

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Abstract

Reducing fibrous aggregates of the protein tau is a possible strategy for halting the progression of Alzheimer’s disease (AD)1. Previously, we found that in vitro, the d-enantiomeric peptide (D-peptide) D-TLKIVWC disassembles ultra-stable tau fibrils extracted from the autopsied brains of individuals with AD (hereafter, these tau fibrils are referred to as AD-tau) into benign segments, with no energy source other than ambient thermal agitation2. To consider D-peptide-mediated disassembly as a potential route to therapeutics for AD, it is essential to understand the mechanism and energy source of the disassembly action. Here, we show that the assembly of D-peptides into amyloid-like (‘mock-amyloid’) fibrils is essential for AD-tau disassembly. These mock-amyloid fibrils have a right-handed twist but are constrained to adopt a left-handed twist when templated in complex with AD-tau. The release of strain that accompanies the conversion of left-twisted to right-twisted, relaxed mock-amyloid produces a torque that is sufficient to break the local hydrogen bonding between tau molecules, and leads to the fragmentation of AD-tau. This strain-relief mechanism seems to operate in other examples of amyloid fibril disassembly, and could inform the development of first-in-class therapeutics for amyloid diseases.

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Fig. 1: D-TLKIVWX peptides disassemble AD-tau to non-seeding products with varying efficiency.
Fig. 2: D-TLKIVWI, D-TLKIVWS and D-TLKIVWR peptides form right-handed helical fibrils with conserved steric zipper motifs.
Fig. 3: D-TLKIVWX disassembly of AD-tau proceeds through the formation of D-TLKIVWX mock-amyloid fibrils.
Fig. 4: D-TLKIVWX mock-amyloid fibrils form along left-handed AD-tau and drive the fragmentation of AD-tau.
Fig. 5: Proposed strain-relief mechanism of disassembly of AD-tau PHFs by D-TLKIVWX peptides.

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Data availability

Cryo-EM maps and atomic models of the fibrils from peptides D-TLKIVWX (X = I, S or R) alone have been deposited in the Electron Microscopy Data Bank (EMDB) and the PDB under the accession codes EMD-44181 and 9B4I (D-TLKIVWI), EMD-44182 and 9B4J (D-TLKIVWS) and EMD-44183 and 9B4K (D-TLKIVWR). Cryo-EM maps and atomic models of tau PHFs from a patient with AD, in complex with the three peptides, have been deposited in the same databases under the accession codes EMD-44184 and 9B4L (Tau-D-TLKIVWI), EMD-44185 and 9B4M (Tau-D-TLKIVWS) and EMD-44186 and 9B4N (Tau-D-TLKIVWR). A cryo-EM map and atomic model of the PHFs from the same patient have been deposited under the accession codes EMD-44187 and 9B4O. All data presented in this Article are available in this Article and its Supplementary Information files. For gel source data, see Supplementary Fig. 2. Source data are provided with this paper.

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Acknowledgements

We thank the donors and their families for brain tissue; without them, this work would not have been possible. We acknowledge National Institutes of Health (NIH) 1R01AG070895 (D.S.E.), NIH RF1AG065407 (D.S.E.), DOE-FC02-02ERG and Alzheimer’s Association Research Fellowship AARF-21-848751 (K.H.) for support. We thank M. Diamond for sharing the HEK293T cells expressing YFP-labelled tau K18; V. Lee for the GT38 antibody; and the staff at the HHMI Janelia Cryo-EM Facility for help and support. Some of this work was performed at the National Center for CryoEM Access and Training (NCCAT) and the Simons Electron Microscopy Center at the New York Structural Biology Center, supported by the NIH Common Fund Transformative High-Resolution Cryo-Electron Microscopy program (U24 GM129539), and by grants from the Simons Foundation (SF349247) and the NY State Assembly. Some of this work was performed at the Stanford-SLAC Cryo-EM Center (S2C2), supported by the NIH Common Fund Transformative High-Resolution Cryo-Electron Microscopy program (U24 GM129541). This work used the Expanse GPU at San Diego Supercomputer Center through allocation BIO230174 from the Advanced Cyberinfrastructure Coordination Ecosystem: Services & Support (ACCESS) program, which is supported by National Science Foundation grants 2138259, 2138286, 2138307, 2137603 and 2138296. We acknowledge grants from the NIH (S10OD016336 and S10OD025073) and the Department of Energy (DE-FC02-02ER63421) for supporting the NMR equipment. Y.Y. was supported in part by grant R35GM131901 to J.F. We acknowledge the use of the Nano and Pico Characterization Lab in the California NanoSystems Institute at UCLA for collecting AFM data, and M. Ye and the staff of the Bruker Nano Surfaces and Metrology Division for collecting HS-AFM data and for technical discussion.

Author information

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA

    Ke Hou, Peng Ge, Michael R. Sawaya, Liisa Lutter, Joshua L. Dolinsky, Yuan Yang, Yi Xiao Jiang, David R. Boyer, Xinyi Cheng, Jeffrey Zhang, Jiahui Lu, Romany Abskharon, Juli Feigon & David S. Eisenberg

  2. Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA

    Ke Hou, Peng Ge, Michael R. Sawaya, Liisa Lutter, Joshua L. Dolinsky, Yi Xiao Jiang, David R. Boyer, Xinyi Cheng, Justin Pi, Jeffrey Zhang, Jiahui Lu, Romany Abskharon & David S. Eisenberg

  3. UCLA-DOE Institute, Los Angeles, CA, USA

    Ke Hou, Peng Ge, Michael R. Sawaya, Liisa Lutter, Joshua L. Dolinsky, Yi Xiao Jiang, David R. Boyer, Xinyi Cheng, Jeffrey Zhang, Jiahui Lu, Romany Abskharon & David S. Eisenberg

  4. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA

    Ke Hou, Peng Ge, Michael R. Sawaya, Liisa Lutter, Joshua L. Dolinsky, Yi Xiao Jiang, David R. Boyer, Xinyi Cheng, Justin Pi, Jeffrey Zhang, Jiahui Lu, Romany Abskharon, Juli Feigon & David S. Eisenberg

  5. Howard Hughes Medical Institute, Los Angeles, CA, USA

    Ke Hou, Peng Ge, Liisa Lutter, Joshua L. Dolinsky, Yi Xiao Jiang, David R. Boyer, Xinyi Cheng, Jeffrey Zhang, Jiahui Lu, Romany Abskharon & David S. Eisenberg

  6. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA

    Shixin Yang & Zhiheng Yu

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  1. Ke Hou
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  2. Peng Ge
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Contributions

The project was conceived and designed by K.H. and D.S.E. The cell seeding experiment was performed by J.L.D. and K.H. Dot blots, TEM and western blots were performed by K.H. and J.P. J.Z. and J.L.D. provided the recombinant tau K18+. J.P. extracted tau fibrils from brains with the help of X.C. X-ray diffraction was done by K.H. and Y.X.J. AFM was performed by L.L. Cryo-EM grids were prepared by K.H., Y.X.J. and P.G. Cryo-EM data were collected by P.G., with assistance from S.Y., Z.Y., Y.X.J. and D.R.B. K.H. and P.G. processed cryo-EM data, with assistance from Y.X.J., D.R.B., X.C. and J.L. M.R.S. built atomic models and did the energy calculation. Isotopically labelled tau K18+ was purified by K.H. and R.A. NMR experiments were performed and analysed by Y.Y. and J.F. The manuscript was prepared by K.H., M.R.S., P.G. and D.S.E., with contributions from all authors.

Corresponding authors

Correspondence to Ke Hou or David S. Eisenberg.

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Competing interests

D.S.E. is chair of the scientific advisory board of and an equity holder in ADRx. The remaining authors declare no competing interests. Part of the work was disclosed in our provisional patent application (serial no. 63/510,194).

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Extended data figures and tables

Extended Data Fig. 1 Variations of the sequence D-TLKIVWX (X = A, C, S, D, I, V, R, K, E, P or T) show varying efficacy in disassembling AD-tau.

a, ThT assay of 20 μM tau K18+ fibrils added with H2O, 50 μM D-TLKIVWC, a mix of 50 μM D-TLKIVWC and 100 μM glutathione (GSH), or a mix of 50 μM D-TLKIVWC and 100 μM Glutathione disulfide (GSSG), respectively. b, Dot blot staining of D-TLKIVW, D-TLKIVWX (X = C, A, S, D, I, V, R, K, E, P or T) alone using the GT38 antibody. AD-tau was stained as a positive control. c, Representative TEM images of AD-tau after incubation with 500 μM D-TLKIVW or D-TLKIVWX (X = C, A, D, V, K, E, P or T) at 37 °C for 48 h. The AD-tau and newly formed fibrils are labelled with red and blue arrows, respectively. Scale bars, 500 nm. d, Quantification of AD-tau in panels c (n = 12 TEM images per group). Error bars represent mean + s.d.

Source data

Extended Data Fig. 2 D-TLKIVWX shows specificity in disassembling tau fibrils.

a, Representative TEM images of tau fibrils extracted from progressive supranuclear palsy brain (PSP tau fibrils) alone and after incubation with 500 μM D-TLKIVWI for 48 h (representative image from n = 25). b, Representative TEM images of α-syn fibrils extracted from multiple system atrophy brain (MSA α-syn fibrils) alone and after incubation with 500 μM D-TLKIVWI for 48 h (representative image from n = 20). c, Representative TEM images of recombinant α-syn fibrils alone and after incubation with 50 μM D-TLKIVWI for 24 h (representative image from n = 10). d, Representative TEM images of wild-type (WT) hnRNPA2 LCD fibrils alone and after incubation with 100 μM D-TLKIVWI for 55 h (representative image from n = 10). e, ThT assay of 25 μM α-syn fibrils incubated with 50 μM fresh D-TLKIVW or D-TLKIVWX (X = C, A, S, D, I, V, R, E, P or T) at 95-h time point. f, ThT assay of 10 μM WT hnRNPA2 LCD fibrils incubated with 100 μM fresh D-TLKIVW or D-TLKIVWX (X = C, A, S, D, I, V, R, E, P or T) at the 15-h time point. Scale bars, 0.2 µm.

Source data

Extended Data Fig. 3 AD-tau disassembly products are non-seeding species in tau biosensor cells.

a, Representative fluorescent images of HEK293 cells expressing YFP-labelled tau K18 transfected with AD-tau seeds after overnight disassembly with various concentrations of D-TLKIVW, or D-TLKIVWX (X = P, D, E, K, R, S, T, A, V or I) (representative image from n = 15). Scale bars, 100 μm. b, Quantification of puncta formed in tau biosensor cells after overnight disassembly with various concentrations of special cases D-TLKIVWP and D-TLKIVW. c–f, Quantification of puncta formed in tau biosensor cells after overnight disassembly with various concentrations of (c) D-TLKIVWX (X = D or E), (d) D-TLKIVWX (X = K or R), (e) D-TLKIVWX (X = S or T), (f) D-TLKIVWX (X = A, V or I). N.A. represents not obtainable. Error bars in b–f represent mean ± s.d. All experiments were performed with n = 3 experimental replicates.

Source data

Extended Data Fig. 4 D-TLKIVWX (X = C, A, S, D, I, V, R, K, E or T) can self-aggregate and form right-handed amyloid-like fibrils, but D-TLKIVW and D-TLKIVWX (X = P) cannot.

a, Thioflavin T (ThT) assays of 500 μM D-TLKIVW, or 500 μM D-TLKIVWX (X = C, A, S, D, V, R, K, E, P or T) incubated in 20 mM Tris-HCl, pH 7.4, 100 mM NaCl and 40 μM ThT. b, TEM images of 500 μM D-TLKIVW, and 500 μM D-TLKIVWX (X = P, D, E, K, R, T, S, A, C, V or I) after incubation in 20 mM Tris-HCl, pH 7.4, 100 mM NaCl for 48 h (representative image from n = 10). Scale bars, 0.2 μm. c, Representative AFM images of D-TLKIVWI fibrils (n = 18). Scale bar, 100 nm. d, Quantification of the handedness of the observed fibrils (n = 18 independent samples) in c. Error bars represent mean ± s.d.

Source data

Extended Data Fig. 5 Cryo-EM studies of D-TLKIVWX (X = I, S or R) amyloid fibrils.

a–c, Cryo-EM imaging and data analysis of (a) D-TLKIVWI fibrils, (b) D-TLKIVWS fibrils and (c) D-TLKIVWR fibrils. Notice that all three peptide fibrils have a right-handed twist.

Source data

Extended Data Fig. 6 Structural explanation for why the absence of a seventh residue in D-TLKIVW prohibits its fibril formation.

a, Schematic model of the amyloid-like fibrils formed by D-TLKIVWI. b, Views perpendicular to the fibril axis (upper row) and down the fibril axis (lower row) of one steric zipper of D-TLKIVWX amyloid-like fibrils. c, D-TLKIVW fails to form stable amyloid fibrils like D-TLKIVWX due to its reduced number of backbone hydrogen bonds (10 versus 14) and the increased distance between the negatively charged C-terminal carboxyl group and the positively charged N-terminal amine group of the adjacent strand (5.0 Å versus 2.8 Å), as compared between the left- and right-side panels.

Extended Data Fig. 7 The aggregation ability of D-TLKIVWX is essential for the disassembly of AD-tau.

a,b, Negative-stain TEM image of 500 μM (a) D-TLK(N-Me-I)VWS, (b) D-TLK(N-Me-I)VWR in 20 mM Tris-HCl, pH 7.4 and 100 mM NaCl at 37 °C for 48 h (representative image from n  =  10). c,d, Representative TEM images of AD-tau after incubation with 500 μM (c) D-TLK(N-Me-I)VWS, (d) D-TLK(N-Me-I)VWR at 37 °C for 48 h (representative image from n = 10). Scale bars in panels a-d, 0.2 μm. e, Quantification of the dot blot staining in Fig. 3c. Results shown as mean + s.d. of triplicate dots. Statistical significance was analysed by one-way ANOVA (***p < 0.001; NS, not significant; the p vale is 0.000, 0.000, 0.000, 0.869, 0.999, 0.263 between AD-tau group and D-TLKIVWX (X = I, S or R) or D-TLK(N-Me-I)VWX (X = I, S or R) group, respectively). f, Negative-stain electron micrographs of AD-tau incubated with 500 μM D-TLKIVWI at 0, 1, 3, 6, 24 and 48 h time points (representative image from n = 15). AD-tau, newly formed D-TLKIVWI fibrils, and amorphous products are labelled with red, blue, and magenta arrows, respectively. Scale bars, 100 nm. g, Western blot of the supernatant and pellet of AD-tau before and after incubation with D-TLKIVWI for 48 h. The Dako antibody used here recognizes a linear tau epitope and so is unspecific for conformation. P, pellet; S, supernatant; HMW, high-molecular-weight aggregate.

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Extended Data Fig. 8 Cryo-EM data analysis workflow of AD-tau and the three complexes D-TLKIVWX (X = I, S or R) disassembling AD-tau.

a–d, Cryo-EM imaging and data analysis of (a) AD-tau PHF, (b) D-TLKIVWI (c) D-TLKIVWS and (d) D-TLKIVWR disassembling AD-tau.

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Extended Data Fig. 9 D-TLKIVWX can form left-handed amyloid-like fibrils templated by AD-tau, and right-handed fibrils by itself.

a, Cryo-EM data analysis workflow of thin fibrils in the dataset of the D-TLKIVWS-treated AD-tau sample. Both polymorphs display conserved D-TLKIVWX steric zippers (yellow arrows), and the unknown electron density (magenta arrows) which may correspond to cofactors from the brain. b, AFM of new fibrils observed in the D-TLKIVWS-treated AD-tau sample. c, Quantification of the length of the fragmented AD-tau caused by D-TLKIVWI in the HS-AFM. d, Change in the mean height of AD-tau fragments in the HS-AFM. e, Solvation energy calculations of D-TLKIVWI steric zipper structures with left-handed twist (left) and right-handed twist (right). Compared with its native structure with right-handed twist, the left-handed twisted D-TLKIVWI steric zipper that complexed with AD-tau stores about 2.9 kcal/mol of strain energy per peptide.

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Extended Data Fig. 10 L-TLKIVWX peptides show diminished efficacy in disassembling AD-tau compared with their enantiomers D-TLKIVWX.

a, Dot blot staining of AD-tau before and after incubation with 500 μM D-/L-TLKIVW, D-/L-TLKIVWX (X = C, S, I or R) at 37 °C for 48 h, probed by the GT38 antibody. Each sample was analysed in triplicate. b, Quantification of the level of AD-tau in panel a by ImageJ. All error bars represent mean + s.d. n = 3 experimental replicates were performed for each treatment condition. Statistical significance was analysed by one-way ANOVA (*p < 0.2; **p < 0.02; NS, not significant). The p values between the L- and D-enantiomers of peptides TLKIVW, TLKIVWR, TLKIVWS, TLKIVWC, and TLKIVWI are 0.896, 0.025, 0.001, 0.180, and 0.088, respectively. c, Negative-stain TEM image of 500 μM L-TLKIVWI after incubation in 20 mM Tris-HCl, pH 7.4, 100 mM NaCl for 48 h. Scale bar, 0.2 μm. d, 1H-15N-HSQC spectral overlay of free tau K18+ (pink) and with 10-fold molar excess of L-TLKIVWI peptide (black) after 2.5 months of incubation at 4 °C. All residues with backbone chemical shift assignments are labelled. e, 1H-15N-HSQC spectral overlay of free tau K18+ (pink) and with 10-fold molar excess of D-TLKIVWI (blue) after incubating for 2.5 month at 4 °C. Representative residues (Val306-Lys311 and Val313–Thr319) with significant chemical shift changes are labelled and resonance shifts indicated with arrows. f, Chemical shift perturbation (CSP) for each residue calculated from e. AVG represents average. STD means standard deviation. g, Comparison of fraction of tau K18+ that are bound by L- and D-TLKIVWI measured by peak intensities of representative residues (I308, V309, Y310, K311, S316 and V318). The slight difference may be due to the slow exchange regime on NMR chemical exchange timescale.

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Supplementary Video 1

D-TLKIVWI-mediated fragmentation of AD-tau followed by high-speed atomic force microscopy (HS-AFM), example 1.

Supplementary Video 2

D-TLKIVWI-mediated fragmentation of AD-tau followed by high-speed atomic force microscopy (HS-AFM), example 2.

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Hou, K., Ge, P., Sawaya, M.R. et al. How short peptides disassemble tau fibrils in Alzheimer’s disease. Nature 644, 1020–1027 (2025). https://doi.org/10.1038/s41586-025-09244-z

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