How short peptides can disassemble ultra-stable tau fibrils extracted from Alzheimer's disease brain by a strain-relief mechanism.

Autor:	Eisenberg D; UCLA., Hou K; University of California, Los Angeles., Ge P; University of California, Los Angeles., Sawaya M; University of California Los Angeles., Dolinsky J; University of California, Los Angeles., Yang Y; University of California Los Angeles., Jiang YX; University of California, Los Angeles., Lutter L; University of California, Los Angeles., Boyer D; University of California Los Angeles., Cheng X; UCLA., Pi J; University of California, Los Angeles., Zhang J; University of California, Los Angeles., Lu J; University of California, Los Angeles., Yang S; Janelia Research Campus, Howard Hughes Medical Institute., Yu Z; Howard Hughes Medical Institute., Feigon J; University of California, Los Angeles.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2024 May 08. Date of Electronic Publication: 2024 May 08.
DOI:	10.21203/rs.3.rs-4152095/v1
Abstrakt:	Reducing fibrous aggregates of protein tau is a possible strategy for halting progression of Alzheimer's dis-ease (AD). Previously we found that in vitro the D-peptide D-TLKIVWC disassembles tau fibrils from AD brains (AD-tau) into benign segments with no energy source present beyond ambient thermal agitation. This disassembly by a short peptide was unexpected, given that AD-tau is sufficiently stable to withstand disas-sembly in boiling SDS detergent. To consider D peptide-mediated disassembly as a potential therapeutic for AD, it is essential to understand the mechanism and energy source of the disassembly action. We find as-sembly of D-peptides into amyloid-like fibrils is essential for tau fibril disassembly. Cryo-EM and atomic force microscopy reveal that these D-peptide fibrils have a right-handed twist and embrace tau fibrils which have a left-handed twist. In binding to the AD-tau fibril, the oppositely twisted D-peptide fibril produces a strain, which is relieved by the disassembly of both fibrils. This strain-relief mechanism appears to operate in other examples of amyloid fibril disassembly and provides a new direction for the development of first-in-class therapeutics for amyloid diseases. Competing Interests: Declarations Competing interests D.S.E. is SAB chair and equity holder of ADRx, Inc. All other authors declare no conflicts. Part of the work was disclosed in our provisional patent application (Serial No. 63/510,194).
Databáze:	MEDLINE
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