How short peptides disassemble tau fibrils in Alzheimer's disease

  • Nature. 2025 Aug;644(8078):1020-1027. doi: 10.1038/s41586-025-09244-z.
Ke Hou  1  2  3  4  5 ,  Peng Ge  6  7  8  9  10 ,  Michael R Sawaya  6  7  8  9 ,  Liisa Lutter  6  7  8  9  10 ,  Joshua L Dolinsky  6  7  8  9  10 ,  Yuan Yang  6 ,  Yi Xiao Jiang  6  7  8  9  10 ,  David R Boyer  6  7  8  9  10 ,  Xinyi Cheng  6  7  8  9  10 ,  Justin Pi  7  9 ,  Jeffrey Zhang  6  7  8  9  10 ,  Jiahui Lu  6  7  8  9  10 ,  Romany Abskharon  6  7  8  9  10 ,  Shixin Yang  11 ,  Zhiheng Yu  11 ,  Juli Feigon  6  9 ,  David S Eisenberg  12  13  14  15  16
Affiliations
  • 1. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA. [email protected].
  • 2. Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA. [email protected].
  • 3. UCLA-DOE Institute, Los Angeles, CA, USA. [email protected].
  • 4. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. [email protected].
  • 5. Howard Hughes Medical Institute, Los Angeles, CA, USA. [email protected].
  • 6. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.
  • 7. Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
  • 8. UCLA-DOE Institute, Los Angeles, CA, USA.
  • 9. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • 10. Howard Hughes Medical Institute, Los Angeles, CA, USA.
  • 11. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA.
  • 12. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA. [email protected].
  • 13. Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA. [email protected].
  • 14. UCLA-DOE Institute, Los Angeles, CA, USA. [email protected].
  • 15. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. [email protected].
  • 16. Howard Hughes Medical Institute, Los Angeles, CA, USA. [email protected].
PMID: 40634605 DOI: 10.1038/s41586-025-09244-z
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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