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How short peptides disassemble tau fibrils in Alzheimer’s disease

Author

Listed:
  • Ke Hou

    (University of California, Los Angeles
    University of California, Los Angeles
    UCLA-DOE Institute
    University of California, Los Angeles)

  • Peng Ge

    (University of California, Los Angeles
    University of California, Los Angeles
    UCLA-DOE Institute
    University of California, Los Angeles)

  • Michael R. Sawaya

    (University of California, Los Angeles
    University of California, Los Angeles
    UCLA-DOE Institute
    University of California, Los Angeles)

  • Liisa Lutter

    (University of California, Los Angeles
    University of California, Los Angeles
    UCLA-DOE Institute
    University of California, Los Angeles)

  • Joshua L. Dolinsky

    (University of California, Los Angeles
    University of California, Los Angeles
    UCLA-DOE Institute
    University of California, Los Angeles)

  • Yuan Yang

    (University of California, Los Angeles)

  • Yi Xiao Jiang

    (University of California, Los Angeles
    University of California, Los Angeles
    UCLA-DOE Institute
    University of California, Los Angeles)

  • David R. Boyer

    (University of California, Los Angeles
    University of California, Los Angeles
    UCLA-DOE Institute
    University of California, Los Angeles)

  • Xinyi Cheng

    (University of California, Los Angeles
    University of California, Los Angeles
    UCLA-DOE Institute
    University of California, Los Angeles)

  • Justin Pi

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Jeffrey Zhang

    (University of California, Los Angeles
    University of California, Los Angeles
    UCLA-DOE Institute
    University of California, Los Angeles)

  • Jiahui Lu

    (University of California, Los Angeles
    University of California, Los Angeles
    UCLA-DOE Institute
    University of California, Los Angeles)

  • Romany Abskharon

    (University of California, Los Angeles
    University of California, Los Angeles
    UCLA-DOE Institute
    University of California, Los Angeles)

  • Shixin Yang

    (Howard Hughes Medical Institute)

  • Zhiheng Yu

    (Howard Hughes Medical Institute)

  • Juli Feigon

    (University of California, Los Angeles
    University of California, Los Angeles)

  • David S. Eisenberg

    (University of California, Los Angeles
    University of California, Los Angeles
    UCLA-DOE Institute
    University of California, Los Angeles)

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.

Suggested Citation

  • Ke Hou & Peng Ge & Michael R. Sawaya & Liisa Lutter & Joshua L. Dolinsky & Yuan Yang & Yi Xiao Jiang & David R. Boyer & Xinyi Cheng & Justin Pi & Jeffrey Zhang & Jiahui Lu & Romany Abskharon & Shixin , 2025. "How short peptides disassemble tau fibrils in Alzheimer’s disease," Nature, Nature, vol. 644(8078), pages 1020-1027, August.
    • Handle: RePEc:nat:nature:v:644:y:2025:i:8078:d:10.1038_s41586-025-09244-z
    DOI: 10.1038/s41586-025-09244-z
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