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Interactions with tau’s microtubule-binding repeats modulate amyloid-β aggregation and toxicity

Nature Chemical Biology (2025)Cite this article

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Abstract

The complicated pathogenesis of Alzheimer’s disease (AD) is characterized by the accumulation of neurofibrillary tangles and senile plaques, primarily composed of tau and amyloid-β (Aβ) aggregates, respectively. While substantial efforts have focused on unraveling the individual roles of tau and Aβ in AD development, the intricate interplay between these components remains elusive. Here we report how the microtubule-binding repeats of tau engage with Aβ in a distinct manner. Crucially, this interaction notably modifies Aβ aggregation behavior, thereby altering Aβ-associated toxicity within both extracellular and intracellular milieus. Our mechanistic investigations at the molecular level manifest specific fragments within tau’s microtubule-binding domain that possess a balance of hydrophobic and hydrophilic properties, promoting the formation of hetero-adducts with Aβ peptides. These findings offer avenues for understanding and treating AD by emphasizing the tau–Aβ interplay in the pathogenesis.

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Fig. 1: Tau fragments and Aβ studied in this work.
Fig. 2: Effects of tau fragments on the aggregation kinetics of Aβ.
Fig. 3: Analysis of peptide or protein aggregates produced by incubation of Aβ with tau fragments and their influence on the cytotoxicity induced by Aβ.
Fig. 4: Analysis of Aβ with tau fragments.
Fig. 5: Interactions of Aβ with tau fragments.
Fig. 6: Interaction between K18 and Aβ.

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Data availability

All experimental details and data supporting the main findings of this study are available within the article, Extended Data Figs. 1–4, Supplementary Data 1–4 and Supplementary Information. Alternatively, data are also available from the corresponding authors upon reasonable request. Source data are provided with this paper.

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Acknowledgements

This work was supported by the National Research Foundation of Korea grants funded by the Korean government (NRF grant nos. RS-2022-NR070709 to M.H.L., RS-2022-NR069719 and RS-2021-NR057690 to Y.-H.L. and 2022R1C1C1007146 to S.L.); the KBSI funds (grant nos. A439200, A423310, A412580, C512120, C523200 and C539200 to Y.-H.L.); the Korea Institute of Science and Technology Institutional Program (grant no. 2E33681 to Y.K.K.). M.K. thanks the Sejong Science Fellowship grant (no. RS-2023-00214034). We thank G. Nam for helping the initial research design, and K.-S. Ryu and D. Seo (KBSI) for providing 15N-labeled K18.

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Authors and Affiliations

  1. Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea

    Mingeun Kim, Eunju Nam & Mi Hee Lim

  2. Biopharmaceutical Research Center, Korea Basic Science Institute (KBSI), Cheongju, Republic of Korea

    Yuxi Lin & Young-Ho Lee

  3. Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea

    Dong Min Kang, Sungsu Lim & Yun Kyung Kim

  4. Department of Life Science, Korea University, Seoul, Republic of Korea

    Dong Min Kang

  5. Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul, Republic of Korea

    Sungsu Lim & Yun Kyung Kim

  6. Bio-Analytical Science, University of Science and Technology (UST), Daejeon, Republic of Korea

    Young-Ho Lee

  7. Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon, Republic of Korea

    Young-Ho Lee

  8. Department of Systems Biotechnology, Chung-Ang University (CAU), Anseong, Republic of Korea

    Young-Ho Lee

  9. Frontier Research Institute for Interdisciplinary Sciences (FRIS), Tohoku University, Sendai, Japan

    Young-Ho Lee

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Contributions

M.K., Y.-H.L. and M.H.L. designed the research. M.K. performed the hydropathicity, WALTZ, TANGO, AGGRESCAN, ThT, biochemical assays, TEM and ESI–MS with data analyses. M.K. and E.N. carried out cell studies. Y.L. and Y.-H.L. conducted ITC and 2D NMR experiments with data analyses. S.L., Y.K.K. and D.M.K. prepared K18 and K18 mutants. M.K. and M.H.L. wrote the paper with input from all authors.

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Correspondence to Young-Ho Lee or Mi Hee Lim.

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Extended data

Extended Data Fig. 1 Impact of tau fragments on the aggregation kinetics of Aβ.

a, Analysis of the aggregation kinetics of Aβ40 incubated with different concentrations of R1, R4, PHF6*, and PHF6. The ThT intensity of tau fragments is presented with triangles. b, Values of tlag and t1/2. These values were calculated by fitting the ThT emission with a sigmoidal equation45. Conditions: [tau fragment] = 10, 50, and 100 μM; [Aβ40] = 10 μM; [ThT] = 5 μM; 20 mM HEPES, pH 7.4, 150 mM NaCl; 37 °C; 250 rpm; λex = 440 nm; λem = 490 nm. All values in the ThT-sigmoidal graphs are indicated as mean ± s.e.m. for n = 7 examined over three independent experiments. The error values of tlag and t1/2 represent the fitting error.

Source data

Extended Data Fig. 2 Effects of tau fragments on the aggregation kinetics of Aβ.

a, Analysis of the aggregation kinetics of Aβ40 incubated with different concentrations of K18ΔPHF6*, K18ΔPHF6, and K18ΔPHF6*ΔPHF6. The ThT intensity of tau fragments is presented with triangles. b, Values of tlag and t1/2. These values were calculated by fitting the ThT emission with a sigmoidal equation45. Conditions: [tau fragment] = 10, 50, and 100 μM; [Aβ40] = 10 μM; [DTT] = 0.35, 1.75, and 3.5 mM (35 equiv of each concentration of tau fragments); [ThT] = 5 μM; 20 mM HEPES, pH 7.4, 150 mM NaCl; 37 °C; 250 rpm; λex = 440 nm; λem = 490 nm. All values in the ThT-sigmoidal graphs are indicated as mean ± s.e.m. for n = 7 examined over three independent experiments. The error values of tlag and t1/2 represent the fitting error.

Source data

Extended Data Fig. 3 Cytotoxicity of Aβ incubated with tau fragments.

Cell survival (%) was calculated in comparison to that with an equivalent amount of the buffered solution. Conditions: [Aβ40] = 10 μM; [tau fragment] = 10, 50, and 100 μM; 20 mM HEPES, pH 7.4, 150 mM NaCl; 37 °C. All values are indicated as mean ± s.e.m. for n = 6 examined over three independent experiments. The P values for Aβ40 with PHF6* or PHF6 are summarized: for PHF6* (10 equiv, P = 0.0038); for PHF6 (10 equiv, P = 0.0363). The P values for tau fragments with Aβ40 are obtained: for R1 (1 equiv, P = 2.9 × 10−11; 5 equiv, P = 4.7 × 10−14; 10 equiv, P = 1.2 × 10−11); for R4 (1 equiv, P = 4.1 × 10−12; 5 equiv, P = 3.8 × 10−9; 10 equiv, P = 9.3 × 10−10); for PHF6* (1 equiv, P = 2.2 × 10−13; 5 equiv, P = 2.4 × 10−11; 10 equiv, P = 7.4 × 10−10); for PHF6 (1 equiv, P = 5.1 × 10−10; 5 equiv, P = 1.0 × 10−10; 10 equiv, P = 1.7 × 10−11). *P < 0.05, **P < 0.01, or ****P < 0.0001 by a two-sided unpaired Student’s t-test.

Source data

Extended Data Fig. 4 Detection of the aggregates composed of Aβ and tau fragments by ESI–MS.

a, Deconvoluted MS spectra of Aβ40 with R4 or PHF6*. The peaks obtained by the mass-to-charge ratio of Aβ40 with R4 or PHF6* are presented in Supplementary Fig. 18. Hetero-assemblies of Aβ40 with R4 or PHF6* with the different Aβ40-to-tau fragment stoichiometry are displayed with diamonds. b, Relative abundance of Aβ40 species unbound and bound with R4 or PHF6* calculated by integrating the characterized peaks from the deconvoluted mass by UniDec57. Conditions: [Aβ40] = 10 μM; [tau fragment] = 10, 50, and 100 μM; 20 mM ammonium acetate, pH 7.4; 1 h; 37 °C; 250 rpm. All values are indicated as mean ± s.e.m. for n = 3 examined over three independent experiments. *Values of the relative abundance of heterogeneous oligomers of Aβ40 species with PHF6* could not be determined because they were not observed under our experimental conditions.

Source data

Supplementary information

Supplementary Information

Supplementary Scheme 1, Tables 1–4, Figs. 1–19 and uncropped gel–western blot data.

Reporting Summary

Supplementary Data 1

Source data for the ThT assay of Aβ40 aggregation at different concentrations in Supplementary Fig. 5a,b.

Supplementary Data 2

Source data for the ThT assay of Aβ40 aggregation with different concentrations of DTT in Supplementary Fig. 9a.

Supplementary Data 3

Source data for the turbidity and light scattering assays of tau fragments in Supplementary Fig. 15b,c.

Supplementary Data 4

Source data for the relative abundance of Aβ40 species detected by ESI–MS in Supplementary Fig. 16c.

Source data

Source Data Fig. 2

Statistical source data for Fig. 2b.

Source Data Fig. 3

Uncropped blots for Fig. 3b.

Source Data Fig. 3

Statistical source data for Fig. 3e,f.

Source Data Fig. 4

Statistical source data for Fig. 4b.

Source Data Fig. 5

Statistical source data for Fig. 5b.

Source Data Fig. 6

Statistical source data for Fig. 6b.

Source Data Extended Data Fig. 1

Statistical source data for Extended Data Fig. 1a.

Source Data Extended Data Fig. 2

Statistical source data for Extended Data Fig. 2a.

Source Data Extended Data Fig. 3

Statistical source data for Extended Data Fig. 3.

Source Data Extended Data Fig. 4

Statistical source data for Extended Data Fig. 4b.

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Kim, M., Lin, Y., Nam, E. et al. Interactions with tau’s microtubule-binding repeats modulate amyloid-β aggregation and toxicity. Nat Chem Biol (2025). https://doi.org/10.1038/s41589-025-01987-0

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