Search Results (634)

The formation of mixed adsorption layers of amyloid fibrils of a plant protein, oat globulin (OG), and a strong polyelectrolyte, sodium polystyrene sulfonate (PSS), at the liquid–gas interface was studied by measurements of the kinetic dependencies of surface tension, dynamic surface elasticity, and ellipsometric angle. The micromorphology of the layers was determined by atomic force microscopy. A strong increase in the surface elasticity was discovered when both components had similar concentrations and formed a network of threadlike aggregates at the interface, thereby explaining the high foam stability in this concentration range. The sequential adsorption of PSS and OG resulted in the formation of thick mixed multilayers and the surface elasticity increased with the number of duplex layers. Full article

Alzheimer’s disease (AD) is a worldwide problem due to the lack of effective therapy and accurate methods for timely diagnosis. The complexity of AD’s pathophysiology complicates the development of effective therapeutic agents, as most drugs act on only one therapeutic target, bypassing others. The design and development of multifunctional agents capable of altering metal ion-induced abnormalities, oxidative stress, and toxic beta amyloid (Aβ) aggregates is of interest. Herein, we report the first boron dipyrromethene (BODIPY) based bifunctional copper chelator with clioquinol, BDP-CLQ, capable of both optical detection of Aβ fibrils and copper chelation, with multiple anti-AD properties. Foremost, BDP-CLQ demonstrated a 3-fold and 5-fold fluorescence increase at 650 nm and 565 nm in the presence of Aβ and effective copper chelation (pK_d = 16.6 ± 0.3). In addition, BDP-CLQ demonstrated a potent inhibition of Aβ aggregation, reduction in Aβ-induced stiffness of neuronal cells, and antioxidant activity. BDP-CLQ is the first BODIPY-based fluorescent probe with multiple anti-AD activities, as well as the first clioquinol-based probe capable of Aβ optical visualization. This study demonstrates the prospects of the development of clioquinol-based theranostic probes since this allows combining several promising anti-AD actions in a single molecule and developing multi-targeted drugs. Full article

One of the most important events in the pathogenesis of Parkinson’s disease and related disorders is the formation of abnormal fibrils via the aggregation of α-synuclein (α-syn) with β-sheet-rich organization. The use of Cryo-EM has uncovered different polymorphs of the fibrils, each having unique structural interfaces, which has made the design of inhibitors even more challenging. Here, a structure-guided framework incorporating AI-assisted peptide generation was set up with the objective of targeting the conserved β-sheet motifs that are present in various forms of α-syn fibrils. The ProteinMPNN, then, AlphaFold-Multimer, and PepMLM were employed to create short peptides that would interfere with the growth of the fibrils. The two selected candidates, T1 and S1, showed a significant inhibition of α-syn fibrillation, as measured by a decrease in the ThT fluorescence and the generation of either amorphous or fragmented aggregates. The inhibitory potency of the peptides was in line with the predicted interface energies. This research work illustrates that the integration of cryo-EM structural knowledge with the computational design method leads to the quick discovery of the wide-spectrum peptide inhibitors, which is a good strategy for the precision treatment of neurodegenerative diseases. Full article

In this study, the structural changes and reconstruction mechanism of sesame protein-derived amyloid fibrils under varied digestive parameters (pepsin concentration, digestive pH and ionic strength) during gastric digestion were investigated, and the effect of fibril reconstruction on the gastric digestion stability of β-carotene nanoparticles was also explored. The results demonstrated that amyloid fibrils underwent a three-stage dynamic process of enzymatic hydrolysis, regeneration and degradation during gastric digestion. The pepsin concentration of 2 mg/mL was found to promote the balance between fibril hydrolysis and regeneration. The fibrils displayed a pronounced regenerative capacity at pH values of 1.5 and 2.5, whereas at pH 3.5, which was proximal to the isoelectric point of protein, aggregation and precipitation were observed. Furthermore, it was found that 10 mM NaCl exerted minimal influence on fibril stability, whereas the higher concentrations of salt ions were shown to obstruct regeneration and promote aggregation. Analyses through SDS-PAGE, GPC, and MALDI-TOF-MS revealed a gradual reduction in the molecular weight of the fibrils during gastric digestion, with certain fragments reaggregating to form new fibril structures. The fibril-based delivery system formed a stable protective structure for β-carotene nanoparticles, which not only prevented their aggregation but also facilitated their release in the small intestine. Full article

The formation of hemoglobin (Hb) and myoglobin (Mb) supramolecular complexes is examined. These key proteins for oxygen transport and storage undergo conformational transitions, some of which are induced by stress factors, particularly redox-active and toxic substances, e.g., reactive oxygen species (ROS) and reactive carbonyl compounds (RCC). These modifications can lead to partial denaturation, exposure of hydrophobic regions, and loss of stability, promoting self-assembly into high-molecular structures. Reversible associations serve regulatory roles: protein stabilization, transient functional inactivation, and generation of biological signals. Irreversible associations result in the formation of stable aggregates constituting pathological hallmarks of amyloidosis and other proteopathies. Although Hb and Mb fibrillization is not part of their physiological function, under oxidative stress, altered pH, high temperatures, or the presence of post-translational modifications, they can adopt amyloid-like structures characterized by cross-β conformation. Such aggregates exhibit high resistance to proteolysis and accumulate in tissues. Understanding molecular mechanisms behind Hb and Mb aggregation is critical for the diagnosis and timely therapy of amyloid-related diseases. The stability, regular structure, and biocompatibility of Hb and Mb fibrils make them promising for biomedical applications. Functional nanomaterials based on these fibrils are being developed for high-sensitivity biosensors, bioelectronic devices, and nanocarriers for targeted drug delivery. Full article

Type V collagen (Col V) has been implicated in the development of fibrosis in systemic sclerosis (SSc). In this study, we aimed to investigate the role of Col V in fibrillar matrix remodeling and fibroblast differentiation using an experimental SSc model. Skin fibroblasts from healthy C57BL/6 mice were stimulated in vitro with 25 and 50 μg of Col V to assess fibrillar collagen expression. An SSc model was induced in C57BL/6 mice by immunization with Col V emulsified in Freund’s adjuvant (IMU-COLV), with animals assigned to 15-, 30-, and 45-day IMU-COLV or control groups. In vitro, Col V stimulation caused a dose-dependent increase in myofibroblast markers (α-SMA, Col I, and Col V) and altered fibrillar collagen structure. Immunofluorescence revealed thickened Col V and Col III fibrils around myofibroblasts and the formation of a spiderweb-like matrix. In vivo, fibrosis progressed over time, characterized by increased myofibroblast accumulation and elevated Col I and Col V levels. Histological analysis revealed fibrillar disorganization and aggregated collagen fibers resembling early-stage human SSc. These findings suggest that enhanced Col V synthesis disrupts the fibrillar matrix, promoting myofibroblast differentiation and collagen deposition, which are hallmarks of SSc-related fibrosis. Full article

Protein fibrils are highly ordered structures. Mung bean protein (MBP) fibrils were fabricated after heating under acidic condition. The formation mechanism, structural variety and antioxidant capacities of mung bean protein fibrils were investigated under different pH conditions. The fibrillation process was characterized by extensive hydrolysis of MBP into low-molecular-weight peptides, which subsequently self-assembled into fibrils with increasing contour length over time. The formed fibrils exhibited a dominant β-sheet structure but demonstrated high sensitivity to pH changes. Upon adjustment to pH 7.0, the fibrils changed into amorphous aggregates, accompanied by a structural transition to random coils. Pretreatment of MBP with neutral protease and chymotrypsin yielded hydrolysates with distinct peptide profiles, leading to the formation of fibrils with varied morphologies upon acidic heating. Furthermore, the antioxidant activity of MBP and its fibrillar aggregates was highly dependent on pH and structural state. While fibril formation at pH 2.0 led to a reduction in radical scavenging activity of MBP, the subsequent pH-shifted aggregates at pH 7.0 resulted in a significant enhancement of antioxidant capacity. These findings provide fundamental insights into the formation, stability, and bioactive properties of MBP fibrils, emphasizing their pH-dependent behavior. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and the presence of intracellular α-synuclein (αSyn) aggregates known as Lewy bodies (LB). αSyn, a presynaptic protein, is believed to play a crucial role in synaptic function, neurotransmitter release, and neuronal plasticity. However, its misfolding and aggregation are thought to be central to PD pathogenesis. This review provides a comprehensive analysis of αSyn’s role in PD, exploring its normal physiological functions, pathological mechanisms, and therapeutic potential. The pathological transformation of αSyn involves structural alterations that promote oligomerization and fibrillization, leading to toxic gain-of-function effects. These aggregates disrupt cellular homeostasis through mechanisms including mitochondrial dysfunction, oxidative stress, lysosomal impairment, and endoplasmic reticulum stress. Furthermore, pathogenic αSyn is thought to exacerbate neurodegeneration via prion-like spread along interconnected neuronal circuits. Emerging evidence highlights the frequent co-occurrence of other proteinopathies, such as tau and amyloid-β, which may synergistically accelerate disease progression. Targeting αSyn has emerged as a potential therapeutic strategy. Approaches such as immunotherapy, small-molecule inhibitors, gene silencing, and modulation of protein degradation pathways (e.g., autophagy and proteasomal systems) are actively being explored. Additionally, lifestyle-based interventions, particularly exercise, have shown neuroprotective effects, potentially mediated by irisin—a myokine implicated in protein clearance and synaptic resilience—underscoring the importance of multimodal strategies in PD management. Full article

Alzheimer’s disease (AD) signifies a devastating impact on the quality of life of patients and their families. At a biomolecular level, AD is characterized by the deposition of extracellular plaques of β-amyloid (Aβ), affecting language, spatial navigation, recognition abilities and memory. Among the selected 30 articles about polyoxometalates (POMs) and AD published from 2011 to 2025, pure POMs, hybrid POMs and POM nanoparticles can be found. The majority of POMs are polyoxotungstates (62%), the Keggin-type SiW₁₁O₃₉ being the most studied in AD. The main effect described is the inhibition of Aβ aggregates. Other effects include reversing the neurotoxicity induced by Aβ aggregates, decreasing ROS production and neuroinflammation, restoring memory and sequestering Zn²⁺ and Cu²⁺, among others, features that are well known to be associated with the pathology of AD. POMs have also shown the ability to induce the disaggregation of Aβ fibrils, particularly after irradiation, and to inhibit acetylcholinesterase activity at an nM range. Putting it all together, this review highlights a predominant trend in the exploration of POMs to act directly at the level of the formation and/or disaggregation of Aβ aggregates in the treatment of AD. Full article

Amyloid fibrillization represents an effective strategy for extending and enhancing protein function, particularly for the delivery of hydrophobic active substances. In this study, oat globulin (OG) and its fibrils were complexed with quercetin (Que) to construct the delivery system, and ultrasonic pretreatment was applied during fibril preparation to explore the promoter of complex formation. The results demonstrated that complexation with Que induced a dose-dependent static quenching of the intrinsic fluorescence of the protein/fibrils, with hydrophobic interactions and tryptophan residues being the primary interaction forces and the main fluorescence quenching groups, respectively. In comparison, OG fibrils prepared with ultrasound pretreatment (UOGF) exhibited the strongest encapsulation and loading capacity for Que, ranging from 97.16% at a mass ratio of 200:1 to 42.48% at a ratio of 25:1. Subsequently, complexes were prepared with a ratio of 50:1. Structural analysis revealed that Que primarily interacts with the protein/fibril carriers through hydrogen bonds and hydrophobic interactions, inducing structural changes and ultimately being encapsulated in an amorphous form within the composite material. Additionally, Que promoted the mutual aggregation and cross-linking of protein/fibril units, leading to increased hydrodynamic diameter and zeta-potential. Moreover, UOGF-Que showed the greatest improvement in the thermal stability and the photostability of Que, and enhancing the bioaccessibility. These findings provide valuable insights into using ultrasound as an auxiliary measure for fibril self-assembly to enhance the application potential of fibrils, especially the delivery of hydrophobic functional substances. Full article

The hitherto unknown thiol-disulfide redox potential (E₀′) of the β93Cys residue in the HbS (β^6Glu→Val) variant of human hemoglobin was calculated by MALDI-ToF mass spectrometry, which analyzes blood from a heterozygous carrier. To calculate the (E₀′) value, a redox equilibrium model was adopted, and the previously calculated value for wild-type β-Hb chain (E₀′ −121 mV) was used. An E₀′ value of −130.5 ± 1.7 mV for the β93Cys residue of HbS was obtained, thus a more reducing value than E₀′ in the wild-type isoform. Glutathionylation from this residue in the HbS tetramer lowers the extent of protein aggregation in fibrils and the clinical consequences, such as painful capillary occlusion and hemolysis. This finding confirmed the peculiar property of HbS as a more reactive scavenger of glutathione sulphinic acid (E₀′ = −264 mV), which forms in the cytoplasm of red blood cells and reacts with structural and regulatory proteins, including hemoglobin. The ability to assess the erythrocyte oxidative status in sickle cell carriers can be developed into an additional functional test to rationally assess the effect of drug treatment and antioxidant dietary interventions on improving disease control. Full article

To investigate the effects of different treatment methods on soybean protein amyloid fibrils (SPAF), this study examined the effects of ultrasonication, cold plasma, heat, and NaCl treatment on the formation, structure, and functional properties of SPAF. SPAF structural analyses indicated that all treatments promoted SPAF assembly, with the order of effectiveness being: heat treatment > ultrasonication > cold plasma treatment > NaCl treatment. Regarding functional properties, the heat treatment group also demonstrated superior overall performance, including the highest solubility (88.15%), optimal emulsifying activity (79.63 m²/g) and foaming capacity (169.44%), and the highest thermal denaturation temperature (107.49 °C). Conversely, ultrasonication and cold plasma treatments, which generated shorter fibrils, offered moderate functional improvements. In contrast, NaCl treatment provided limited functional enhancement due to the formation of coarse aggregates. Consequently, heat treatment was identified as the most effective approach to promote SPAF formation and enhance functional properties. These findings provide a theoretical basis for the process optimization of SPAF in the food industry. Full article

Alzheimer’s disease is driven by multiple molecular drivers, including the pathological behavior of two intrinsically disordered proteins, amyloid-β (Aβ) and tau, whose aggregation is regulated by sequence-encoded ensembles and liquid–liquid phase separation (LLPS). This review integrates recent advances in biophysics, structural biology, and computational modeling to provide a multiscale perspective on how sequence determinants, post-translational modifications, and protein dynamics regulate the conformational landscapes of Aβ and tau. We discuss sequence-to-ensemble principles, from charge patterning and aromatic binders to familial mutations that reprogram structural ensembles and modulate LLPS. Structural studies, including NMR, SAXS, cryo-EM, and cryo-electron tomography, trace transitions from disordered monomers to fibrils and tissue-level structures. We highlight experimental challenges in LLPS assays, emerging standards for reproducibility, e.g., LLPSDB, PhaSePro, and FUS benchmarks, and computational strategies to refine and condensate modeling. Finally, we explore the therapeutic implications, including condensate-aware medicinal chemistry, ensemble-driven docking, and novel insights from clinical trials of anti-Aβ antibodies. Together, these perspectives underscore a paradigm shift toward environment- and ensemble-aware therapeutic design for Alzheimer’s and related protein condensation disorders. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and cognitive decline, primarily due to amyloid β (Aβ) aggregation in the brain. Astaxanthin (AxN), a xanthophyll carotenoid derived from Haematococcus pluvialis, possesses antioxidant and neuroprotective properties. This study investigated the neuroprotective effects of AxN against Aβ aggregation in human neuroblastoma SH-SY5Y cells. Initially, AxN inhibited Aβ aggregation in DMEM/F12 culture medium but not in PBS, suggesting a medium-dependent effect. Using quantum dot nanoprobes, Aβ aggregation was visualized in the presence of SH-SY5Y cells. AxN treatment (0.032–20 µM) significantly reduced Aβ aggregation and accumulation on SH-SY5Y cells. AxN also prevented Aβ-induced early apoptotic cell death but was less effective against late necrosis. Furthermore, a wound-healing assay showed that AxN restored the impaired cell motility caused by Aβ aggregation. Thioflavin T staining confirmed the reduction in Aβ fibril formation around the cells following AxN treatment. In conclusion, our study suggests that AxN prevents Aβ aggregation and accumulation on the cell surface, thereby restoring cell motility and preventing early apoptosis in neuronal cells. Full article

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles, which synergistically accelerate disease progression. Since Aβ plaques and tau tangles are key factors in the development of AD, dual-targeting of Aβ and tau aggregation represents a promising therapeutic strategy. Amodiaquine (AQ), a quinoline-based antimalarial, has recently attracted attention for its ability to suppress protein aggregation. However, direct effects of AQ on both Aβ and tau aggregation remain unclear. Methods: The effects of AQ on the aggregation and dissociation of Aβ and tau were examined using a thioflavin T (ThT) assays. Molecular docking and molecular dynamics (MD) simulations were performed to examine binding characteristics and structural interactions. The effects of AQ on the expression of pro-inflammatory cytokines induced by Aβ and tau aggregation in BV2 microglial cells were analyzed by qRT-PCR. Results: ThT assay demonstrated a dose-dependent dual effect of AQ on Aβ, where 25 μM inhibited aggregation after 36 h, while 250 μM markedly accelerated it, reaching a plateau within 12 h. All concentrations of AQ promoted the disassembly of mature Aβ fibrils within 12 h. Molecular docking revealed stronger binding of AQ to aggregated Aβ (−45.17 and −23.32 kcal/mol for pentameric 2BEG and hexameric 2NAO) than to monomeric Aβ (−4.81 and −7.29 kcal/mol for 1Z0Q and 2BEG). MD simulation suggested that AQ disrupted the cross-β-sheet interactions of Aβ aggregates. In the case of tau, ThT assay showed that all concentrations of AQ inhibited tau aggregation from 6 h, and 350 μM AQ promoted the disassembly of mature fibrils from 6 h. Molecular docking indicated stronger binding of AQ to aggregated tau (−27.95 and −12.13 kcal/mol for the pentameric and decameric 5O3L) than to monomeric tau (−3.05 kcal/mol for 8Q96). MD simulations revealed no major structural changes in the aggregates. In BV2 cells, 1 and 10 μM AQ significantly reduced Aβ and tau-induced TNF-α and IL-6 mRNA expressions. In APP-H4 cells, 10 μM AQ decreased the level of Aβ compared to the control. Conclusions: AQ modulates both Aβ and tau aggregation and attenuates neuroinflammation and reduces Aβ pathology, supporting its potential as a dual-target therapeutic candidate for AD. Full article