by Keyword: Amyloid fibrils

Noble Jesus C, Evans R, Forth J, Estarellas C, Gervasio FL, Battaglia G, (2021). Amphiphilic Histidine-Based Oligopeptides Exhibit pH-Reversible Fibril Formation Acs Macro Letters 10, 984-989

We report the design, simulation, synthesis, and reversible self-assembly of nanofibrils using polyhistidine-based oligopeptides. The inclusion of aromatic amino acids in the histidine block produces distinct antiparallel β-strands that lead to the formation of amyloid-like fibrils. The structures undergo self-assembly in response to a change in pH. This creates the potential to produce well-defined fibrils for biotechnological and biomedical applications that are pH-responsive in a physiologically relevant range.

JTD Keywords: peptide, recognition, Amyloid fibrils

Arimon, M., Sanz, F., Giralt, E., Carulla, N., (2012). Template-assisted lateral growth of amyloid-β42 fibrils studied by differential labeling with gold nanoparticles Bioconjugate Chemistry , 23, (1), 27-32

Amyloid-β protein (Aβ) aggregation into amyloid fibrils is central to the origin and development of Alzheimer’s disease (AD), yet this highly complex process is poorly understood at the molecular level. Extensive studies have shown that Aβ fibril growth occurs through fibril elongation, whereby soluble molecules add to the fibril ends. Nevertheless, fibril morphology strongly depends on aggregation conditions. For example, at high ionic strength, Aβ fibrils laterally associate into bundles. To further study the mechanisms leading to fibril growth, we developed a single-fibril growth assay based on differential labeling of two Aβ42 variants with gold nanoparticles. We used this assay to study Aβ42 fibril growth under different conditions and observed that bundle formation is preceded by lateral interaction of soluble Aβ42 molecules with pre-existing fibrils. Based on this data, we propose template-assisted lateral fibril growth as an additional mechanism to elongation for Aβ42 fibril growth.

JTD Keywords: AFM, Beta-Amyloid Fibrils, Polymorphism, Association, Elongation, Dynamics, State

Villar-Pique, A., De Groot, N. S., Sabaté, R., Acebrón, S. P., Celaya, G., Fernàndez-Busquets, X., Muga, A., Ventura, S., (2012). The effect of amyloidogenic peptides on bacterial aging correlates with their intrinsic aggregation propensity Journal of Molecular Biology , 421, (2-3), 270-281

The formation of aggregates by misfolded proteins is thought to be inherently toxic, affecting cell fitness. This observation has led to the suggestion that selection against protein aggregation might be a major constraint on protein evolution. The precise fitness cost associated with protein aggregation has been traditionally difficult to evaluate. Moreover, it is not known if the detrimental effect of aggregates on cell physiology is generic or depends on the specific structural features of the protein deposit. In bacteria, the accumulation of intracellular protein aggregates reduces cell reproductive ability, promoting cellular aging. Here, we exploit the cell division defects promoted by the intracellular aggregation of Alzheimer's-disease-related amyloid β peptide in bacteria to demonstrate that the fitness cost associated with protein misfolding and aggregation is connected to the protein sequence, which controls both the in vivo aggregation rates and the conformational properties of the aggregates. We also show that the deleterious impact of protein aggregation on bacterial division can be buffered by molecular chaperones, likely broadening the sequential space on which natural selection can act. Overall, the results in the present work have potential implications for the evolution of proteins and provide a robust system to experimentally model and quantify the impact of protein aggregation on cell fitness.

JTD Keywords: Amyloid fibrils, Chaperones, Escherichia coli, Inclusion bodies, Protein aggregation

Fernàndez-Busquets, X., Ponce, J., Bravo, R., Arimon, M., Martianez, T., Gella, A., Cladera, J., Durany, N., (2010). Modulation of amyloid beta peptide(1-42) cytotoxicity and aggregation in vitro by glucose and chondroitin sulfate Current Alzheimer Research , 7, (5), 428-438

One mechanism leading to neurodegeneration during Alzheimer's Disease (AD) is amyloid beta peptide (A beta)-induced neurotoxicity. Among the factors proposed to potentiate A beta toxicity is its covalent modification through carbohydrate-derived advanced glycation endproducts (AGEs). Other experimental evidence, though, indicates that certain polymeric carbohydrates like the glycosaminoglycan (GAG) chains found in proteoglycan molecules attenuate the neurotoxic effect of A beta in primary neuronal cultures. Pretreatment of the 42-residue A beta fragment (A beta(1-42)) with the ubiquitous brain carbohydrates, glucose, fructose, and the GAG chondroitin sulfate B (CSB) inhibits A beta beta(1-42)-induced apoptosis and reduces the peptide neurotoxicity on neuroblastoma cells, a cytoprotective effect that is partially reverted by AGE inhibitors such as pyridoxamine and L-carnosine. Thioflavin T fluorescence measurements indicate that at concentrations close to physiological, only CSB promotes the formation of A beta amyloid fibril structure. Atomic force microscopy imaging and Western blot analysis suggest that glucose favours the formation of globular oligomeric structures derived from aggregated species. Our data suggest that at short times carbohydrates reduce A beta(1-42) toxicity through different mechanisms both dependent and independent of AGE formation.

JTD Keywords: Alzheimer's disease, Advanced glycation endproducts, Amyloid fibrils, Amyloid beta peptide, Apoptosis, Carbohydrates, Glycosaminoglycans

Morell, M., Bravo, R., Espargaro, A., Sisquella, X., Aviles, F. X., Fernàndez-Busquets, X., Ventura, S., (2008). Inclusion bodies: Specificity in their aggregation process and amyloid-like structure Biochimica et Biophysica Acta - Molecular Cell Research , 1783, (10), 1815-1825

The accumulation of aggregated protein in the cell is associated with the pathology of many diseases and constitutes a major concern in protein production. Intracellular aggregates have been traditionally regarded as nonspecific associations of misfolded polypeptides. This view is challenged by studies demonstrating that, in vitro, aggregation often involves specific interactions. However, little is known about the specificity of in vivo protein deposition. Here, we investigate the degree of in vivo co-aggregation between two self-aggregating proteins, A beta A2 amyloid peptide and foot-and-mouth disease virus VP1 capsid protein, in prokaryotic cells. In addition, the ultrastructure of intracellular aggregates is explored to decipher whether amyloid fibrils and intracellular protein inclusions share structural properties. The data indicate that in vivo protein aggregation exhibits a remarkable specificity that depends on the establishment of selective interactions and results in the formation of oligomeric and fibrillar structures displaying amyloid-like properties. These features allow prokaryotic A beta A2 intracellular aggregates to act as effective seeds in the formation of A beta A2 amyloid fibrils. overall, our results suggest that conserved mechanisms underlie protein aggregation in different organisms. They also have important implications for biotechnological and biomedical applications of recombinant polypeptides.

JTD Keywords: Protein aggregation, Inclusion bodies, Conformational diseases, Amyloid fibrils, Protein folding