Abstract
Reducing fibrous aggregates of protein tau is a possible strategy for halting progression of Alzheimer’s disease (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 disassembly 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 assembly 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 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 Interest Statement
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).
Abbreviations
- Aβ
- amyloid beta protein
- AD
- Alzheimer’s disease, AD-tau, tau fibrils extracted from AD brains
- All D-peptides TLKIVWX (D-TLKIVWX)
- in which X can be any enantiomorph of the 20 coded amino acid residues
- PHFs
- paired helical filaments, the most abundant polymorph of AD-tau fibril