How short peptides disassemble tau fibrils in Alzheimer's disease.

The study reveals that the D-peptide D-TLKIVWC can disassemble tau fibrils in vitro, but its clinical applicability is not established.

Summary and findings

This study investigates the disassembly of tau fibrils in Alzheimer's disease using the D-peptide D-TLKIVWC. The research demonstrates that D-peptides can disassemble tau fibrils into benign segments without an external energy source. The findings suggest a potential mechanism for therapeutic development, although no clinical data are provided.

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.

Limitations

Not reported in abstract.

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