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

Reducing fibrous aggregates of the protein tau is a possible strategy for halting the progression of Alzheimer's disease (AD). 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 agitation. 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.

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

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.

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

Reducing fibrous aggregates of protein tau is a possible strategy for halting progression of Alzheimer's disease (AD). Previously we found that 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.

An Additive-Free Model for Tau Self-Assembly.

Tau is a natively unfolded protein that contributes to the stability of microtubules. Under pathological conditions such as Alzheimer's disease (AD), tau protein misfolds and self-assembles to form paired helical filaments (PHFs) and straight filaments (SFs). Full-length tau protein assembles poorly and its self-assembly is enhanced with polyanions such as heparin and RNA in vitro, but a role for heparin or other polyanions in vivo remains unclear.

Structural Identification of Individual Helical Amyloid Filaments by Integration of Cryo-Electron Microscopy-Derived Maps in Comparative Morphometric Atomic Force Microscopy Image Analysis.

The presence of amyloid fibrils is a hallmark of more than 50 human disorders, including neurodegenerative diseases and systemic amyloidoses. A key unresolved challenge in understanding the involvement of amyloid in disease is to explain the relationship between individual structural polymorphs of amyloid fibrils, in potentially mixed populations, and the specific pathologies with which they are associated. Although cryo-electron microscopy (cryo-EM) and solid-state nuclear magnetic resonance (ssNMR) spectroscopy methods have been successfully employed in recent years to determine the structures of amyloid fibrils with high resolution detail, they rely on ensemble averaging of fibril structures in the entire sample or significant subpopulations.

On the Structural Diversity and Individuality of Polymorphic Amyloid Protein Assemblies.

The prediction of highly ordered three-dimensional structures of amyloid protein fibrils from the amino acid sequences of their monomeric self-assembly precursors constitutes a challenging and unresolved aspect of the classical protein folding problem. Because of the polymorphic nature of amyloid assembly whereby polypeptide chains of identical amino acid sequences under identical conditions are capable of self-assembly into a spectrum of different fibril structures, the prediction of amyloid structures from an amino acid sequence requires a detailed and holistic understanding of its assembly free energy landscape. The full extent of the structure space accessible to the cross-β molecular architecture of amyloid must also be resolved.

Quantification of amyloid fibril polymorphism by nano-morphometry reveals the individuality of filament assembly.

Amyloid fibrils are highly polymorphic structures formed by many different proteins. They provide biological function but also abnormally accumulate in numerous human diseases. The physicochemical principles of amyloid polymorphism are not understood due to lack of structural insights at the single-fibril level.

Three-dimensional reconstruction of individual helical nano-filament structures from atomic force microscopy topographs.

Atomic force microscopy, AFM, is a powerful tool that can produce detailed topographical images of individual nano-structures with a high signal-to-noise ratio without the need for ensemble averaging. However, the application of AFM in structural biology has been hampered by the tip-sample convolution effect, which distorts images of nano-structures, particularly those that are of similar dimensions to the cantilever probe tips used in AFM. Here we show that the tip-sample convolution results in a feature-dependent and non-uniform distribution of image resolution on AFM topographs.

Tau (297-391) forms filaments that structurally mimic the core of paired helical filaments in Alzheimer's disease brain.

The constituent paired helical filaments (PHFs) in neurofibrillary tangles are insoluble intracellular deposits central to the development of Alzheimer's disease (AD) and other tauopathies. Full-length tau requires the addition of anionic cofactors such as heparin to enhance assembly. We have shown that a fragment from the proteolytically stable core of the PHF, tau 297-391 known as 'dGAE', spontaneously forms cross-β-containing PHFs and straight filaments under physiological conditions.

The molecular lifecycle of amyloid - Mechanism of assembly, mesoscopic organisation, polymorphism, suprastructures, and biological consequences.

The formation of a diverse range of amyloid structures from normally soluble proteins and peptides is a hallmark of devastating human disorders as well as biological functions. The current molecular understanding of the amyloid lifecycle reveals four processes central to their growth and propagation: primary nucleation, elongation, secondary nucleation and division. However, these processes result in a wide range of cross-β packing and filament arrangements, including diverse assemblies formed from identical monomeric precursors with the same amino acid sequences.