Cross-Interactions of Aβ Peptides Implicated in Alzheimer's Disease Shape Amyloid Oligomer Structures and Aggregation.

A defining hallmark of Alzheimer's disease (AD) is the synaptic aggregation of the amyloid β (Aβ) peptide. , Aβ production results in a diverse mixture of variants, of which Aβ40, Aβ42, and Aβ43 are profusely present in the AD brain, and their relative abundance is recognized to play a role in disease onset and progression. Nonetheless, the occurrence of Aβ40, Aβ42, and Aβ43 hetero-oligomerization and the subsequent effects on Aβ aggregation remain elusive and were investigated here.

A selection and optimization strategy for single-domain antibodies targeting the PHF6 linear peptide within the tau intrinsically disordered protein.

The use of variable domain of the heavy-chain of the heavy-chain-only antibodies (VHHs) as disease-modifying biomolecules in neurodegenerative disorders holds promises, including targeting of aggregation-sensitive proteins. Exploitation of their clinical values depends however on the capacity to deliver VHHs with optimal physico-chemical properties for their specific context of use. We described previously a VHH with high therapeutic potential in a family of neurodegenerative diseases called tauopathies.

Secondary Modification of S100B Influences Anti Amyloid-β Aggregation Activity and Alzheimer's Disease Pathology.

Proteinaceous aggregates accumulate in neurodegenerative diseases such as Alzheimer's Disease (AD), inducing cellular defense mechanisms and altering the redox status. S100 pro-inflammatory cytokines, particularly S100B, are activated during AD, but recent findings reveal an unconventional molecular chaperone role for S100B in hindering Aβ aggregation and toxicity. This suggests a potential protective role for S100B at the onset of Aβ proteotoxicity, occurring in a complex biochemical environment prone to oxidative damage.

M13 phage grafted with peptide motifs as a tool to detect amyloid-β oligomers in brain tissue.

Oligomeric clusters of amyloid-β (Aβ) are one of the major biomarkers for Alzheimer's disease (AD). However, proficient methods to detect Aβ-oligomers in brain tissue are lacking. Here we show that synthetic M13 bacteriophages displaying Aβ-derived peptides on their surface preferentially interact with Aβ-oligomers.

S100B chaperone multimers suppress the formation of oligomers during Aβ42 .

Extracellular aggregation of the amyloid-β 1-42 (Aβ42) peptide is a major hallmark of Alzheimer's disease (AD), with recent data suggesting that Aβ intermediate oligomers (AβO) are more cytotoxic than mature amyloid fibrils. Understanding how chaperones harness such amyloid oligomers is critical toward establishing the mechanisms underlying regulation of proteostasis in the diseased brain. This includes S100B, an extracellular signaling Ca-binding protein which is increased in AD as a response to neuronal damage and whose holdase-type chaperone activity was recently unveiled.

Tau liquid-liquid phase separation is modulated by the Ca -switched chaperone activity of the S100B protein.

Aggregation of the microtubule-associated protein tau is implicated in several neurodegenerative tauopathies including Alzheimer's disease (AD). Recent studies evidenced tau liquid-liquid phase separation (LLPS) into droplets as an early event in tau pathogenesis with the potential to enhance aggregation. Tauopathies like AD are accompanied by sustained neuroinflammation and the release of alarmins at early stages of inflammatory responses encompass protective functions.

Matrix Metalloproteinases 2 and 9 and Their Tissue Inhibitors in the Diagnostics of Medullary Thyroid Carcinoma.

Medullary Thyroid Carcinoma (MTC) is a tumor of the neuroendocrine system. In recent years, the need to assess the MTC diagnostic-related parameters has emerged with the aim to elucidate the mechanisms involved in this pathology. The objective of this study was to evaluate the role of Matrix Metalloproteinases (MMPs) 2 and 9, their tissue inhibitors of matrix metalloproteinases (TIMPs), S100 protein, and amyloid in the diagnostic of MTC.

Relationship between Trace Elements and Matrix Metalloproteinases 2 and 9 and their Tissue Inhibitors in Medullary Thyroid Carcinoma.

Medullary Thyroid Carcinoma (MTC) constitutes around 5% of all thyroid cancers. Trace elements assessment has emerged as a useful strategy in the diagnostics of MTC combined with Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Matrix Metalloproteinases (TIMPs) analysis. The aim of this study was to compare the presence and content of trace elements (i.

Tetramerization of the S100B Chaperone Spawns a Ca Independent Regulatory Surface that Enhances Anti-aggregation Activity and Client Specificity.

Alzheimer's disease (AD) hallmarks include the aggregation of amyloid-β (Aβ), tau and neuroinflammation promoted by several alarmins. Among these is S100B, a small astrocytic homodimeric protein, upregulated in AD, whose multiple biological activities depend on localization, concentration, and assembly state. S100B was reported to inhibit the aggregation and toxicity of Aβ42 and tau similarly to a holdase-type chaperone.

Zinc-binding metallophores protect Pseudomonas aeruginosa from calprotectin-mediated metal starvation.

Pseudomonas aeruginosa is known to exhibit considerable resistance to the antimicrobial activity of the metal-sequestering protein calprotectin (CP). In this study, we demonstrate that although CP induces zinc deficiency in P. aeruginosa, a strain unable to import zinc through the two most important metal acquisition systems, namely ZnuABC and ZrmABCD, maintains significant growth capacity in the presence of high concentrations of CP.

Deglutarylation of glutaryl-CoA dehydrogenase by deacylating enzyme SIRT5 promotes lysine oxidation in mice.

A wide range of protein acyl modifications has been identified on enzymes across various metabolic processes; however, the impact of these modifications remains poorly understood. Protein glutarylation is a recently identified modification that can be nonenzymatically driven by glutaryl-CoA. In mammalian systems, this unique metabolite is only produced in the lysine and tryptophan oxidative pathways.

S100B dysregulation during brain development affects synaptic SHANK protein networks via alteration of zinc homeostasis.

Autism Spectrum Disorders (ASD) are caused by a combination of genetic predisposition and nongenetic factors. Among the nongenetic factors, maternal immune system activation and zinc deficiency have been proposed. Intriguingly, as a genetic factor, copy-number variations in S100B, a pro-inflammatory damage-associated molecular pattern (DAMP), have been associated with ASD, and increased serum S100B has been found in ASD.

Hofmeister effects on protein stability are dependent on the nature of the unfolded state.

The interpretation of a salt's effect on protein stability traditionally discriminates low concentration regimes (<0.3 M), dominated by electrostatic forces, and high concentration regimes, generally described by ion-specific Hofmeister effects. However, increased theoretical and experimental studies have highlighted observations of the Hofmeister phenomena at concentration ranges as low as 0.

Dynamic interactions and Ca-binding modulate the holdase-type chaperone activity of S100B preventing tau aggregation and seeding.

The microtubule-associated protein tau is implicated in the formation of oligomers and fibrillar aggregates that evade proteostasis control and spread from cell-to-cell. Tau pathology is accompanied by sustained neuroinflammation and, while the release of alarmin mediators aggravates disease at late stages, early inflammatory responses encompass protective functions. This is the case of the Ca-binding S100B protein, an astrocytic alarmin which is augmented in AD and which has been recently implicated as a proteostasis regulator, acting over amyloid β aggregation.

Hypercholesterolemia and 27-Hydroxycholesterol Increase S100A8 and RAGE Expression in the Brain: a Link Between Cholesterol, Alarmins, and Neurodegeneration.

Alterations in cholesterol metabolism in the brain have a major role in the physiology of Alzheimer's disease (AD). Oxysterols are cholesterol metabolites with multiple implications in memory functions and in neurodegeneration. Previous studies have shown detrimental effects of cholesterol metabolites in neurons, but its effect in glial cells is unknown.

Computational Analysis of the Interactions between the S100B Extracellular Chaperone and Its Amyloid β Peptide Client.

S100B is an astrocytic extracellular Ca-binding protein implicated in Alzheimer's disease, whose role as a holdase-type chaperone delaying Aβ aggregation and toxicity was recently uncovered. Here, we employ computational biology approaches to dissect the structural details and dynamics of the interaction between S100B and Aβ. Driven by previous structural data, we used the Aβ segment, which recapitulates key aspects of S100B activity, as a starting guide for the analysis.

Targeting S100B with Peptides Encoding Intrinsic Aggregation-Prone Sequence Segments.

S100 proteins assume a diversity of oligomeric states including large order self-assemblies, with an impact on protein structure and function. Previous work has uncovered that S100 proteins, including S100B, are prone to undergo β-aggregation under destabilizing conditions. This propensity is encoded in aggregation-prone regions (APR) mainly located in segments at the homodimer interface, and which are therefore mostly shielded from the solvent and from deleterious interactions, under native conditions.

Electron transfer flavoprotein and its role in mitochondrial energy metabolism in health and disease.

Electron transfer flavoprotein (ETF) is an enzyme with orthologs from bacteria to humans. Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors.

MIRRAGGE - Minimum Information Required for Reproducible AGGregation Experiments.

Reports on phase separation and amyloid formation for multiple proteins and aggregation-prone peptides are recurrently used to explore the molecular mechanisms associated with several human diseases. The information conveyed by these reports can be used directly in translational investigation, e.g.

Cu-binding to S100B triggers polymerization of disulfide cross-linked tetramers with enhanced chaperone activity against amyloid-β aggregation.

S100B is an extracellular protein implicated in Alzheimer's Disease and a suppressor of amyloid-β aggregation. Herein we report a mechanism tying Cu2+ binding to a change in assembly state yielding disulfide cross-linked oligomers with higher anti-aggregation activity. This chemical control of chaperone function illustrates a regulatory process relevant under metal and proteostasis dysfunction as in neurodegeneration.

Functional Recovery of a GCDH Variant Associated to Severe Deflavinylation-Molecular Insights into Potential Beneficial Effects of Riboflavin Supplementation in Glutaric Aciduria-Type I Patients.

Riboflavin is the biological precursor of two important flavin cofactors-flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN)-that are critical prosthetic groups in several redox enzymes. While dietary supplementation with riboflavin is a recognized support therapy in several inborn errors of metabolism, it has yet unproven benefits in several other pathologies affecting flavoproteins. This is the case for glutaric aciduria type I (GA-I), a rare neurometabolic disorder associated with mutations in the gene, which encodes for glutaryl-coenzyme A (CoA) dehydrogenase (GCDH).