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. houkhouk09@gmail.com.
2 Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA. houkhouk09@gmail.com.
3 UCLA-DOE Institute, Los Angeles, CA, USA. houkhouk09@gmail.com.
4 Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. houkhouk09@gmail.com.
5 Howard Hughes Medical Institute, Los Angeles, CA, USA. houkhouk09@gmail.com.
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. david@mbi.ucla.edu.
13 Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA. david@mbi.ucla.edu.
14 UCLA-DOE Institute, Los Angeles, CA, USA. david@mbi.ucla.edu.
15 Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. david@mbi.ucla.edu.
16 Howard Hughes Medical Institute, Los Angeles, CA, USA. david@mbi.ucla.edu.

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-P11593

D-TLKIVWC

Tau分解剂

Tau Protein

Neurological Disease

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