The prevailing view frames microglia and macrophages as guardians against amyloid beta (Aβ) accumulation in Alzheimer's disease (AD). Here, we overturn this paradigm by demonstrating that human phagocytic cells, including differentiated THP-1 macrophages and hESC-derived microglia, are not merely passive responders but active producers of extracellular, seeding-competent Aβ42 fibrils, the amyloid species most strongly linked to parenchymal plaque formation and neurodegeneration. These cell-generated aggregates differ structurally and functionally from synthetic fibrils, displaying enhanced seeding and tau cross-seeding activity in biosensor models. Notably, Aβ42 fibril formation in this system requires active cellular processes and is exacerbated by loss of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a major AD risk gene. Transcriptomic profiling reveals an early inflammatory response resembling microglial states observed in human AD models. Together, these findings support emerging evidence from in vivo studies that macrophages and microglia can influence amyloid seeding and introduce a human-relevant in vitro platform to explore how Aβ aggregation intersects with innate immune function and genetic risk. Our results reinforce the concept that microglia may play a dual role in AD, acting both as responders and inadvertent facilitators of amyloid assembly, with implications for early therapeutic intervention.

Formation of pea protein fibrils via novel trypsin-assisted self-assembling process

Effects of ultrasound treatment on the formation of food-derived amyloid fibrils: A review.

β-Hydroxybutyrate attenuates glycation-induced structural destabilization and amyloidogenic aggregation in human serum albumin.

Effects of cationic urethane gemini surfactants on the fibrillation of insulin: spectroscopic studies.

Aggregated amyloid beta peptide (Aβ) contributes to Alzheimer's disease through neurotoxic effects and a prion-like mode of transmission. We report that protein disulfide isomerase (PDI) exhibits disaggregase activity against oligomeric but not fibrillar forms of Aβ. PDI did not bind monomeric Aβ, indicating its highly effective inhibition of fibril formation occurs through reversal of early-stage oligomers rather than prevention of the initial aggregate. Cells exposed to both PDI and oligomeric Aβ were protected from Aβ-induced toxicity. An S-nitrosylated form of PDI that is associated with neurodegeneration could not bind to oligomeric Aβ, thereby eliminating its neuroprotective disaggregase activity. Our observations suggest PDI could be used both physiologically and therapeutically to dissolve the oligomeric forms of Aβ.

Formation of new amyloid fibrils and oligomers from monomeric protein on the surfaces of existing fibrils is an important driver of many disorders such as Alzheimer's and Parkinson's diseases. The structural basis of this secondary nucleation process, however, is poorly understood. Here, we ask whether secondary nucleation sites are found predominantly at rare growth defects: irregularities in the fibril core structure incorporated during their original assembly. We first demonstrate using the specific inhibitor of secondary nucleation, Brichos, that secondary nucleation sites on Alzheimer's disease-associated fibrils composed of Aβ40 and Aβ42 peptides are rare compared to the number of protein molecules they contain. We then grow Aβ40 fibrils under conditions designed to eliminate most growth defects while leaving the regular fibril morphology unchanged, and confirm the latter using cryo-electron microscopy. We measure both the ability of these annealed fibrils to promote secondary nucleation and the stoichiometry of their secondary nucleation sites, finding that both are greatly reduced as predicted. Re-analysis of published data for other proteins suggests that fibril growth defects may also drive secondary nucleation generally across most amyloids. These findings could unlock structure-based drug design of therapeutics that aim to halt amyloid disorders by inhibiting secondary nucleation sites.

Abstract Protein misfolding and aggregation are critical in amyloidogenic diseases such as Alzheimer's disease, diabetes, and prion disorders. While aggregation has been widely studied in terms of extrinsic factors, the influence of intrinsic molecular features, particularly histidine tautomerism, remains poorly understood. In this mini‐review, we summarize recent computational studies elucidating how histidine tautomeric states regulate the structural changes, aggregation propensity, and intermolecular interactions of major amyloidogenic proteins, including amyloid‐β (Aβ40/42), Tau, amylin, prion protein, and profilin‐1, as well as their disease‐associated variants. We discuss tautomer‐dependent effects on monomer conformations, early oligomerization, fibril formation, and cross‐seeding behavior, and highlight the integration of molecular dynamics simulations and computational two‐dimensional infrared spectroscopy for resolving tautomer‐specific signatures. These findings emphasize histidine tautomerism as a critical but underestimated factor in amyloid aggregation mechanisms.

Parkinson's disease is an age-related neurodegenerative disease that is characterized by the deposition of α-synuclein aggregates in the brain. Nevertheless, the molecular mechanisms that regulate α-synuclein aggregation have not yet been fully identified. TMEM106B is a lysosomal transmembrane protein that has been reported to be associated with brain aging and neurodegenerative diseases including Parkinson's disease. Here we show that TMEM106B is reduced in the brains of patients with Parkinson's disease. Knockdown of TMEM106B increases the formation of α-synuclein aggregates in primary neurons and mouse brains. TMEM106B deficiency results in impaired lysosomal acidification, lipid metabolism disorders, and lipid droplet deposition in neurons. Interestingly, lipid droplets promote α-synuclein aggregation, resulting in the formation of α-synuclein fibrils with enhanced seeding activity and neurotoxicity compared with α-synuclein fibrils formed in the absence of lipid droplets. TMEM106B deficiency also leads to retardation of α-synuclein degradation by reducing the enzymatic activity of the lysosomal protease cathepsin D. Taken together, these results indicate that TMEM106B deficiency contributes to Parkinson's disease pathogenesis by accelerating α-synuclein aggregation and halting α-synuclein degradation.

Amyloid aggregation is a key process involved in many neurodegenerative diseases including Alzheimer's disease. It affects the brain and peripheral tissues, where different types of protein aggregates are accumulated. Pluronic PEO-PPO-PEO block copolymer self-assemblies are widely used as nanocarriers for the brain-targeted delivery of therapeutic agents. Elucidating protein aggregation at these polymer interfaces can provide critical insights into how macromolecular crowding and protein-polymer interactions influence the kinetics of protein aggregation. Here, we investigate the roles of two pluronic copolymers, namely, P123 and F127, which have a similar size of hydrophobic PPO block but different PEO block length on protein aggregation using hen egg white lysozyme (HEWL) as a model protein. Our study reveals that the more hydrated F127 self-assemblies with thicker PEO hydration shells accelerate the onset of protein-aggregation yet moderately retard the extent of overall fibril formation. On the other hand, the less hydrated P123 self-assemblies with compact hydration shells significantly delay the onset of protein aggregation and efficiently inhibit fibril formation. The binding of protein within the hydrated and longer PEO corona of F127 micelles favors accelerated kinetics of β-rich oligomers and fibril formation without a delay phase through soft-chemical interactions. For the less hydrated P123 micellar assemblies, the hydrophobic interactions and strong excluded volume effects probably contribute to stabilization of the protein. The addition of the widely used osmolyte trehalose further delays the protein aggregation and significantly retards the fibril formation through the synergistic inhibitory effects of trehalose and polymer assemblies. The trehalose-bearing pluronic micelles can, therefore, emerge as a potentially efficient inhibitor with great promise in therapeutic applications. The pluronic self-assemblies are also found to be highly effective in protecting the protein from toxicity associated with Cu2+ induced enhanced amyloid fibrillation. The binding of Cu2+ within the hydrated PEO corona makes them inaccessible to protein interactions and fibril formation.

The age-dependent transition of metastable, liquid-like protein condensates to amyloid fibrils is an emergent phenomenon in numerous neurodegeneration-linked protein systems. A key question is whether the thermodynamic driving forces underlying phase separation and maturation to amyloid fibrils are distinct and separable. Here, we address this question using an engineered version of microtubule-associated protein Tau, which forms biochemically-active condensates. These metastable protein condensates rapidly convert to amyloid fibrils under quiescent, cofactor-free conditions. In particular, the interfaces of condensates promote fibril nucleation, impairing condensate activity in recruiting tubulin and catalyzing microtubule assembly. Remarkably, a small molecule metabolite, L-arginine, selectively impedes age-dependent amyloid formation in a valence and chemistry-specific manner without perturbing phase separation. By enhancing condensate viscoelasticity, L-arginine counteracts the age-dependent decline in condensate activity. These results provide a proof-of-principle demonstration that small molecule metabolites can enhance the metastability of protein condensates and delay the formation of amyloid fibrils, thereby preserving biochemical function.

Conformational variations in α-syn fibrils are thought to underlie the distinct clinical features of synucleinopathies, including Lewy body dementia (LBD), Parkinsons's disease (PD), and multiple system atrophy (MSA), suggesting that distinct fibril structures act as molecular fingerprints linked to disease phenotype. While the origins of these conformational variations remain unclear, increasing evidence points to membranes as key modulators of fibrils conformations. In this study, we investigated how age-related alterations in membrane composition and fluidity influence α-syn fibril formation and cellular outcomes. Using complex mixture membranes that mimic normal neuronal membranes and their age-related modifications in fatty acid chains, we found that α-syn fibrils grown with these membranes displayed distinct 2D ssNMR spectral patterns compared to lipid-free α-syn fibrils, reflecting differences in rigid fibril cores. Moreover, fibrils grown with age-related membranes exhibited weaker membrane association than those grown with normal neuronal membranes. These membrane-associated fibrils induce stronger neuronal pathologies than lipid-free fibrils, though the severity differed in intraneuronal aggregation and inflammation responses. Overall, our findings provide new insights into how age-related changes in membrane composition shape α-syn fibril structure and pathogenicity, strengthening the link between membrane dynamics and amyloid-driven neurodegeneration.

Tuning charge and hydrophobicity in ovalbumin-derived peptide nanostructures enhances inhibition of Aβ42 fibril formation

Erratum: "Rotary activity as the main electrophysiology mechanism of the persistent form of atrial fibrillation of patients with type 2 diabetes mellitus" by Irina A. Bulavina, Igor A. Khamnagadaev, Nikolay I. Tyurin, Ekaterina K. Melkozerova, Leonid A. Belousov, Irina Z. Bondarenko, Olga A. Shatskaya, Ilya L. Ilyich, Viktor Y. Kalashnikov published in Diabetes Mellitus. 2025;28(6):314-320. doi: 10.14341/DM13412.An error occurred in the author list of the original article: Natalia G. Mokrysheva was inadvertently omitted from the author list. The correct list of authors is as follows: Irina A. Bulavina, Igor A. Khamnagadaev, Nikolay I. Tyurin, Ekaterina K. Melkozerova, Leonid A. Belousov, Irina Z. Bondarenko, Olga A. Shatskaya, Ilya L. Ilyich, Viktor Y. Kalashnikov, Natalia G. Mokrysheva. The Editorial Office regrets this error. The original version of the article has been replaced.

De novo identification of potent ingredients for proteasome activation in MT101-5 using an AI-driven approach.

The increasing resistance of bacteria and fungi to antimicrobial agents demands therapeutic strategies with higher target selectivity and a lower risk of rapid resistance development. The Biologically Active Metallopeptides (BAM) group develops an approach based on the controlled interaction of metal ions with peptides and pathogen-derived proteins. In our work, metal ions (including Cu(II)/Cu(I), Zn(II), and Ni(II)) are treated as functional modules: they stabilize peptide structure, induce defined conformations and aggregation states, conditionally activate antimicrobial activity, and modulate the pathogen’s access to essential micronutrients. We elucidate the mechanisms of metal uptake and homeostasis in pathogens (including Cu and Zn acquisition systems, zincophores, and metal chaperones), identifying protein fragments that can act either as therapeutic targets or as targeting domains for the selective delivery of antimicrobial agents (a “Trojan horse” strategy). In parallel, we investigate antimicrobial peptides and endogenous peptides in the presence of metal ions, demonstrating that coordination of Cu(II) and Zn(II) can markedly enhance their bactericidal or antifungal activity by enforcing active conformations, inducing aggregation (e.g. fibril formation), and promoting the generation of reactive oxygen species locally at the infection site. Building on these principles, we design selective targeted antimicrobial peptides (STAMPs, ang. specifically targeted antimicrobial peptides) and chemically stabilized peptide and glycopeptide constructs with improved biological stability and tissue selectivity. We show that metal ion coordination chemistry can serve as a platform for engineering a new class of selective antimicrobial therapeutics.

Insulin amyloid aggregation is a key pathological and pharmaceutical concern, particularly in the context of Type-2 Diabetes (T2D), where amyloid deposition of protein can impair therapeutic efficacy and contribute to cell death leading to local tissue damage. Although gangliosides—glycosphingolipids containing sialic acid residues—are known to modulate amyloid formation in neurodegenerative disorders, their influence on insulin aggregation remains largely unexplored. In this study, we investigate the effects of gangliosides GM3 and GD3 on insulin aggregation. Using Thioflavin-T (ThT) based fluorescence kinetics, Fourier Transform Infrared (FTIR) spectroscopy, Circular Dichroism (CD) spectroscopy, Small Angle X-ray Scattering (SAXS), Nuclear Magnetic Resonance (NMR) spectroscopy, and Transmission Electron Microscopy (TEM), the aggregation pathway, changes in the secondary structure and morphology of insulin aggregates have been characterized. Our results show that both GM3 and GD3 lipids accelerated insulin aggregation in a concentration-dependent manner while steering the pathway away from classical fibril formation, producing short, beaded structures distinct from the extended fibrils observed under lipid-free conditions. CD and FTIR data analyses revealed that insulin in the presence of gangliosides formed non-fibrillar intermediates with distinct secondary structures: β-sheet-rich globular clusters in presence of GD3 and α-helical intermediates in GM3-treated samples. Cytotoxicity assays further demonstrated that ganglioside-induced aggregates are significantly less toxic to cells when compared to insulin-only aggregates. Furthermore, ganglioside-bound insulin oligomers retain seeding capacity, suggesting that they can nucleate further aggregation despite their non-fibrillar morphology. These findings underscore the role of gangliosides in modulating insulin amyloid polymorphism and toxicity, offering new insights into their potential impact on the pathology of T2D and treatment strategies. FigureHighlightsGangliosides GD3 and GM3 accelerate insulin aggregation, forming non-fibrillar assemblies.Ganglioside-bound insulin aggregates are less cytotoxic than fibrillar aggregates.Despite altered morphology, ganglioside-bound aggregates retain seeding ability.

Formation mechanism of alkali-heat induced self-assembly fibrillation of zein.

TPGS-coated zein nanoparticles encapsulating Haematococcus pluvialis extract for Alzheimer's disease: An in vitro evaluation towards brain-targeted delivery.

Acid-heat induced structural remodeling and gelation of egg yolk high-density lipoproteins: Insights into fibrillation pathways and rheological behavior.