bims-amyloi 2026-10-18 papers

Int J Biol Macromol. 2026 Oct 13. pii: S0141-8130(26)04795-1. [Epub ahead of print]384(Pt 2): 154845

Effect of freeze-thaw cycle induced oligomers on alpha-synuclein liquid-liquid phase separation and aggregation.

Kamile Mikalauskaite, Dominykas Veiveris, Vytautas Smirnovas, Mantas Ziaunys.

Protein aggregation in the form of amyloid fibrils is linked with the onset and progression of several widespread and incurable disorders, including neurodegenerative Alzheimer's and Parkinson's diseases. Despite decades of research and countless attempts to discover potential aggregation-altering treatment modalities, there are still no effective cures for the majority of amyloid-related disorders. This is, in part, due to our incomplete understanding of the underlying factors that influence the phase separation and aggregation of these various disease-related proteins. Over the last few years, it has been shown that even factors such as storage conditions or sample preincubation times can affect the formation kinetics of amyloid fibrils. In the case of alpha-synuclein, even the protein purification procedure yielded different concentrations of oligomeric species, which altered the aggregation mechanism. In this work, we further explore the role of alpha-synuclein oligomers by inducing their formation via freeze-thaw cycles and analyzing their effect on liquid-liquid and liquid-solid phase transitions. Using real-time kinetic monitoring, brightfield microscopy, Fourier-transform infrared spectroscopy and atomic force microscopy, we show that the presence of freeze-thaw cycle induced alpha-synuclein oligomers has significant effects on its condensate assembly and subsequent aggregation, as well as the final structure of the formed aggregates.

Keywords: Alpha-synuclein aggregation; Alpha-synuclein oligomers; Fibril structures; Liquid-liquid phase separation

DOI: https://doi.org/10.1016/j.ijbiomac.2026.154845

Int J Biol Macromol. 2026 Oct 11. pii: S0141-8130(26)04761-6. [Epub ahead of print]384(Pt 2): 154811

Field-assisted interfacial passivation: Microwave-enhanced EGCG remodeling of amyloid-β42 aggregates.

Ming Wang, Han Zhao, Xinran Lin, Zaihang Ye, Bin Tu, Yanlian Yang, Chen Wang, Xiaocui Fang, Qiaojun Fang.

Amyloid misfolding and self-assembly are central pathological events of Alzheimer's disease and related proteinopathies. Although soluble oligomers are widely considered as the primary toxic species, how therapeutic modulators alter toxicity-relevant aggregate surfaces remains poorly understood. Here, we combine cell viability assays, thioflavin T (ThT) aggregation kinetics, circular dichroism (CD), transmission electron microscopy (TEM), and atomistic molecular dynamics (MD) simulations to investigate how microwave-assisted Epigallocatechin gallate (EGCG) remodels Aβ42 aggregates. We show that microwave exposure markedly enhanced EGCG-mediated cytoprotection in BV2 microglial cells while concurrently suppressing the formation of canonical ThT-responsive amyloid species. MD simulations revealed that oscillating electric fields promote a constrained, interface-selective remodeling of protofibrillar-like aggregates rather than catastrophic depolymerization. In the initial trajectory pair, field assistance redistributed EGCG contacts across more surface residues, accompanied by reduced overall and hydrophobic protein-only solvent-accessible surface area. At a key hydrophobic interface identified by contact-occupancy analysis, the combined treatment decreased local water density and solvent accessibility, indicating reduced local hydration. We define this collective surface state- characterized by expanded EGCG coverage, reduced hydrophobic exposure, and diminished solvent accessibility - as interfacial passivation. Moreover, simulation analysis revealed that the field-assisted EGCG adsorption state remains stable for at least 500 ns after field removal, suggesting that the electric field facilitates formation of a kinetically stable surface-bound configuration. Together, these findings support field-assisted interfacial passivation as a possible mechanism for amyloid modulation and suggest that passivating toxicity-relevant aggregate surfaces, rather than achieving complete depolymerization, may represent a promising therapeutic strategy.

Keywords: Amyloid aggregate; Amyloid-β42; EGCG; Interfacial passivation; Molecular dynamics simulation; Oligomer toxicity; Oscillating electric field

DOI: https://doi.org/10.1016/j.ijbiomac.2026.154811

Brain. 2026 Oct 14. pii: awag356. [Epub ahead of print]

Extracellular vesicle α-synuclein topology reveals disease-associated conformers in brain and blood.

Suman Dutta, Amin Atashgaran, Anis Sahoo, Stelios Chatzimichail, Achillefs N Kapanidis, George K Tofaris.

Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are unified by pathological α-synuclein (αSyn) aggregation, yet diverge in terms of the cellular distribution of pathology and clinical phenotype. Extracellular vesicles (EVs) have emerged as potential mediators or biomarkers of αSyn pathology, but whether their molecular constituents in the brain reflect disease-specific processes or conformations remains unknown. Here, we combined EV isolation, electrochemiluminescence, quantitative mass spectrometry and nanoscale single-vesicle imaging by direct stochastic optical reconstruction microscopy (dSTORM) to map the topology, epitope exposure and cellular origin of αSyn in EVs isolated from post-mortem PD, DLB, MSA, and healthy control (HC) brains and assessed the tractability of these molecular signatures in blood. Proteomics and immunoblotting of EV lysates isolated from human brains confirmed that they were highly purified and derived from neurons and glial cell subtypes. Across diseases, αSyn association with EVs exhibited distinct patterns: In PD and DLB, both total αSyn levels normalised to CD81 and the percentage of neuronal (L1CAM+) EVs with aggregated αSyn as detected by aggregate-preferring antibodies, were increased, whereas in MSA, aggregated αSyn was detected primarily in neuronal and to a lesser extent glial EV subpopulations without an increase in total EV-associated αSyn. Further epitope mapping by dSTORM identified a distinct αSyn conformational arrangement, as detected by antibodies against an epitope spanning αSyn residues 34-45, that was enriched on the surface of L1CAM+ EVs in MSA compared to PD. This N-terminal immunoreactive conformer was tractable in serum and enriched on the surface of L1CAM+ EVs from MSA compared to PD patients or controls. Collectively, our findings suggest that the epitope accessibility and topology of EV-associated αSyn proteoforms, rather than their abundance alone, discriminate synucleinopathy subtypes, offering a framework for a blood-based conformational stratification of these disorders.

Keywords: alpha-synuclein; biomarkers; dSTORM; dementia; extracellular vesicles; synucleinopathies

DOI: https://doi.org/10.1093/brain/awag356

J Pept Sci. 2026 Dec;32(12): e70140

Inhibitory Activity of Red Panda Islet Amyloid Polypeptide on Human IAPP Aggregation.

Lauren Phillips, Elizabeth L Moffet, Judah Mayfield, Eden L Jonick, Luiza A Nogaj, David A Moffet.

Human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-secreted with insulin from pancreatic β-cells, undergoes self-assembly into cytotoxic amyloid fibrils in the pathogenesis of type 2 diabetes (T2D). The resulting islet amyloid deposits are implicated in progressive β-cell dysfunction and loss, making hIAPP aggregation an attractive therapeutic target. Nonhuman islet amyloid polypeptide (IAPP) orthologs have recently emerged as a valuable source of mechanistic insight, with several variants-including raccoon and chicken IAPPs-demonstrating the capacity to inhibit hIAPP fibril formation. Here, the biophysical characterization of red panda (Ailurus fulgens) IAPP (rpIAPP) and its effects on hIAPP aggregation are reported. Using thioflavin T fluorescence assays, circular dichroism spectroscopy, and atomic force microscopy, red panda IAPP is found to inhibit hIAPP fibrillation at substoichiometric concentrations, with significant inhibitory activity observed at molar ratios as low as 1:0.5 (hIAPP:rpIAPP). These results position red panda IAPP as one of the more potent nonhuman IAPP inhibitors characterized to date and support its further evaluation as a scaffold for the rational design of peptide-based therapeutics targeting T2D-associated amyloidogenesis.

Keywords: IAPP; amyloid aggregation; atomic force microscopy; circular dichroism; inhibitor; islet amyloid polypeptide; red panda; thioflavin T; type 2 diabetes

DOI: https://doi.org/10.1002/psc.70140

Front Mol Neurosci. 2026 ;19 1965177

From dynamic condensates to pathological assemblies: the phase behavior of tau and α-synuclein.

Suelen Camargo, Kevin Novelo, Scott D Ryan.

Neurons rely on precise protein folding, trafficking, and turnover to maintain synaptic function. Disruption of proteostasis promotes misfolded proteins that impair axonal transport, mitochondrial function, and signalling, contributing to neuronal loss. Although neurodegeneration has traditionally focused on stable amyloid deposits, many disease-associated proteins contain intrinsically disordered regions (IDRs) that can organize through liquid-liquid phase separation (LLPS). LLPS concentrates proteins and nucleic acids into dynamic condensates that regulate cellular processes, but these adaptive interactions can also promote condensate aging and less reversible, aggregation-prone states. Here, we review how sequence-encoded properties of tau and α-synuclein (α-syn) link physiological condensation to pathological protein assembly, while emphasizing that LLPS and amyloid formation are related but not obligatorily linked.

Keywords: LLPS; amyloid aggregation; amyloid generation; biomolecular condensates; synuclein alpha; tau

DOI: https://doi.org/10.3389/fnmol.2026.1965177

medRxiv. 2026 Sep 29. pii: 2026.09.22.26363432. [Epub ahead of print]

Gantenerumab reduces brain amyloid-β proteoforms: Biochemical evaluation in dominantly inherited Alzheimer disease.

Dominantly Inherited Alzheimer Network Observational Study

Therapeutic strategies targeting amyloid-β (Aβ) in Alzheimer disease (AD) include antibodies directed against fibrillar amyloid plaques or soluble amyloid-β (Aβ) species, yet how these approaches reshape brain pathology remains poorly understood. Postmortem neuropathological assessment is crucial for evaluating the degree of Aβ removal, providing information and context that fluid biomarkers and positron emission tomography (PET) alone cannot, and guiding development of more effective disease modifying therapies for AD. In this study, using high resolution mass spectrometry we quantitatively measured Aβ and tau proteoforms in postmortem brain tissue homogenates to evaluate the impact of long-term treatment with anti-Aβ monoclonal antibodies gantenerumab or solanezumab in a clinical trial of dominantly inherited Alzheimer disease (DIAD). Symptomatic DIAD participants who had been treated for ∼ 4 years with anti-Aβ monoclonal antibodies (gantenerumab, n=4 or solanezumab, n=4) were compared with untreated, symptomatic DIAD mutation carriers (n=40) and with age-relevant non-DIAD controls with modest or no plaque pathology (n=18). Consistent with antemortem Aβ-PET findings in the clinical trial, gantenerumab-treated participant samples showed significantly lower levels of specific Aβ proteoforms (Aβ 42 , Aβ 40 ) in the insoluble plaque associated pool (range: 60-80 % reduction); they also showed lower levels of post-translationally modified Aβ proteoform Aβ 3pGlu in both the insoluble and soluble pool, compared to untreated DIAD participants, but without reaching the levels found in non-DIAD controls. Samples from gantenerumab-treated participants also showed regionally lower amounts of insoluble phosphorylated tau species (pT181, pT205, pT208) and MTBR tau species (354-369, 306-317, 299-317) without apparent differences in insoluble total tau levels. In contrast, brain tissue samples from solanezumab-treated participants did not show significant differences overall in soluble or insoluble levels of Aβ and tau proteoforms in comparison to those from non-treated DIAD individuals. These findings support that amyloid targeting treatment (ATT) with gantenerumab, an antibody that targets fibrillar Aβ, can remove insoluble Aβ from the DIAD brain and also mitigate "downstream" biochemical and pathophysiological changes associated with AD.
Key Summary: Question: How do amyloid targeting treatments (ATT) affect the Alzheimer disease (AD)-related brain pathologies of soluble and aggregated amyloid-β and tau proteoforms in postmortem tissue?Background: Extracellular amyloid plaques and neurofibrillary tangles (NFTs) are the primary pathological hallmarks of AD. For the past three decades, active and passive immunization against cerebral amyloid-β (Aβ) has constituted one of the primary avenues of disease-modifying intervention in AD. Recently, passive immunizations using anti-Aβ targeting antibodies have demonstrated slowing of cognitive decline in sporadic AD and possibly in dominantly inherited AD (DIAD). In these clinical trials, target engagement has been inferred from Aβ-positron emission tomography (PET) and/or biofluid biomarkers during life. However, to confirm evidence of target engagement more directly, identify which pathological proteoforms are affected, quantify the dose dependent treatment effects of these treatments, and begin to evaluate their putative downstream effects on AD pathophysiology, quantitative biochemical comparisons of amyloid plaques and tau pathology (soluble and insoluble Aβ and tau species) in postmortem brain tissue of treated and untreated AD are needed.Findings: In this study, using high resolution mass spectrometry we measured the soluble and insoluble Aβ and tau proteoforms in the postmortem brain tissue homogenates from DIAN-TU-001 trial participants who were symptomatic and had been treated for ∼ 4 years with gantenerumab (n=4) or solanezumab (n=4), two antibodies that bind to insoluble and soluble Aβ, respectively. Intervals between treatment discontinuation and death ranged from 5 months to 3 years. Comparisons were made with postmortem brain tissue samples from untreated, symptomatic DIAD participants of the DIAN-Obs study (n=40) and from age-relevant, cognitively normal, non-DIAD controls with or without only modest burdens of diffuse Aβ plaques (n=18). Consistent with antemortem Aβ-PET findings in the clinical trial, gantenerumab significantly decreased specific Aβ (Aβ 42 , Aβ 40 ) proteoforms in the insoluble plaque associated pool (range: 60-80% reduction) compared to the untreated DIAD participants, but without reaching the levels found in the non-DIAD controls. Samples from gantenerumab treated participants also showed significantly lower amount of post-translationally modified Aβ (Aβ 3pGlu ) and regionally lower insoluble phosphorylated tau species (pT181, pT205 and pT208), without apparent differences in insoluble total tau levels. In contrast, solanezumab treatment did not show significant effect on the soluble or insoluble levels of Aβ and tau proteoforms in comparison to samples from non-treated DIAD individuals. Significance: These findings support that ATT with gantenerumab, an antibody that targets fibrillar Aβ, can remove insoluble Aβ from the DIAD brain and also mitigate "downstream" biochemical and pathophysiological changes associated with AD.

DOI: https://doi.org/10.64898/2026.09.22.26363432

Phys Chem Chem Phys. 2026 Oct 12.

From condensates to fibrils: polyphosphate-regulated phase separation of p53.

Narendran Sekar, Hema Chandra Kotamarthi, Swathi Sudhakar.

Protein aggregation is widely associated with neurodegenerative disorders, but increasing evidence suggests that similar misfolding phenomena also contribute to cancer. Although p53 aggregation is commonly associated with oncogenic mutations, wild-type p53 can also misfold under cellular stress. Here, we show that the endogenous polyanion polyphosphate regulates the phase behaviour and aggregation of wild-type p53 in a pH-dependent manner. Using thioflavin T kinetics together with optical and electron microscopy, we demonstrate that acidic conditions promote polyphosphate-driven coacervation of p53, leading to the formation of multicoacervate condensates. These protein-rich condensates locally concentrate p53 and accelerate fibril nucleation and maturation into dense fibrillar networks. In contrast, at neutral pH, p53 remains soluble and non-amyloidogenic, consistent with the absence of phase separation. Together, our findings reveal a phase separation-assisted pathway for p53 fibrillization under acidic stress and highlight polyphosphate as an important regulator of p53 aggregation.

DOI: https://doi.org/10.1039/d6cp02900k

J Alzheimers Dis Rep. 2026 Jan-Dec;10:10 25424823261449500

Spermidine protects mitochondria against amyloid-β oligomers.

Drake Mosca, Ekaterina Parfenova, Yuan Bie, Anthony Mutsaers, Paul A Spagnuolo.

Background: Alzheimer's disease (AD) is a neurodegenerative condition characterized by amyloid-β (Aβ) plaques in the brain. In early pathological conditions, Aβ oligomers localize in mitochondria to promote disease progression by causing mitochondrial dysfunction.
Objective: Establish a robust AD pathological in vitro model and assess the therapeutic effect of spermidine (SPD) against extracellular Aβ oligomers.
Methods: In this study, high-resolution respirometry, flow cytometry, and immunoblotting techniques were used to characterize the negative effects of Aβ oligomer localization in mitochondria and assess the potential neuroprotective effects of SPD.
Results: Oligomeric Aβ accumulates in and causes mitochondrial dysfunction, as evidenced by increased mitochondrial superoxide production, decreased mitochondrial mass, and decreased maximal mitochondrial respiration and spare reserve capacity. SPD, an endogenously produced polyamine that can also be provided through exogenous supplementation, improved these markers and protected mitochondria of oligomer-treated cells.
Conclusions: SPD ameliorated mitochondrial dysfunction caused by Aβ oligomers in vitro.

Keywords: Alzheimer's disease; Aβ oligomers; mitochondria; spermidine

DOI: https://doi.org/10.1177/25424823261449500

J Chem Phys. 2026 Oct 14. pii: 144904. [Epub ahead of print]165(14):

Modulators selectively reshape α-synuclein phase transitions.

Holly Masson, Massimiliano Paesani, Ioana M Ilie.

Protein phase transitions govern numerous diseases, including neurodegenerative disorders. In Parkinson's disease, distinct species of the protein α-synuclein undergo phase transitions from disordered to ordered β-rich states. The emerging species and transitions between them can be reshaped by modulators, e.g., small molecules, peptides or antibodies. Here, we use coarse-grained simulations to understand the effect of modulators on the thermodynamics and kinetics of α-synuclein phase transitions. Each protein is represented as a morphing particle that transforms from a soft sphere (disordered) to a hard spherocylinder (β-rich). Modulators are modeled as soft isotropic particles mimicking peptides. Purely repulsive modulators do not alter the final outcome; that is, fibrils form following the same mechanisms independently of the modulator concentration. Attractive interactions toward the disordered protein dose-dependently slow down fibrillization by stabilizing intermediate species, including persistent disordered heteroclusters. Specific attraction to the β-rich state shortens fibrils through direct modulator surface "capping" that introduces kinetic barriers to monomer templating at the fibril ends and inhibits fibril elongation. Overall, these results link modulator properties and environmental conditions to nucleation, fibril elongation, and off-pathway trapping, providing a quantitative roadmap for designing interventions that redirect phase transitions toward desirable endpoints.

DOI: https://doi.org/10.1063/5.0354094

Alzheimers Dement. 2026 Oct;22(10): e71907

Dementia with Lewy bodies and amyloid pathology: Eligible for anti-amyloid treatment or not?

Lieza G Exalto, Juliette L van Alphen, Frederik Barkhof, Charlotte Teunissen, Everard G B Vijverberg, Dag Aarsland, Afina W Lemstra.

In the future, treatment of dementia will be personalized, targeted to contributing pathologies, rather than the clinical syndrome. Anti-amyloid drugs for Alzheimer's disease are the first approved drugs; however, the impact of co‑pathology on the treatment effects remains incomplete. Currently, only patients with a clinical diagnosis of Alzheimer's disease are eligible for these new drugs, but could they also be beneficial when amyloid is present in other neurodegenerative diseases? For example, roughly 50% of patients with dementia with Lewy bodies are amyloid-positive. In this perspective, we discuss the theoretical benefits and challenges of anti-amyloid drugs in patients with a clinical diagnosis of dementia with Lewy bodies and concomitant Alzheimer's disease pathology. We show that a significant portion of newly diagnosed dementia with Lewy bodies patients could be eligible. We advocate for the systematic collection of efficacy and safety data using innovative strategies to achieve adequate statistical power.

Keywords: anti‐amyloid drugs; appropriate use criteria; dementia with Lewy bodies

DOI: https://doi.org/10.1002/alz.71907