bims-amyloi 2026-09-06 papers

bims-amyloi

Biomed News

on Amyloid

Issue of 2026–09–06
seventeen papers selected by
Alexander Röntgen, University of Cambridge

Calcium Reshapes Aβ Aggregation at Anionic Lipid Membranes.
Targeting of α-Syn Condensate Fluidity by Natural Polyphenols to Retard the Amyloid Transition and Ameliorate α-Syn-Caused Neurotoxicity.
Protein Recognition and Amyloid Remodeling Governed by Paddlewheel Diruthenium Coordination Chemistry.
Biphasic Role of β-Cyclodextrin in Anionic Surfactant-induced Lysozyme Aggregation and Refolding.
Hydration water dynamics in amyloid-β aggregates using deuterium and oxygen-17 solid-state NMR spectroscopy.
Protein Aggregates as Drivers of Receptor Clustering and Pathological Signaling: A Framework Linking Extracellular Amyloid-β to Tau Dysregulation.
Molecular Glue Degraders Enhance CAPRIN1-Dependent Lysosomal Degradation of APP and Reduce Amyloid β in Alzheimer's Disease.
Triprolidine Interferes with α-Synuclein Fibrillation and Remodels Aggregate Structure via Conformational Modulation.
Osmolytes suppress liquid‒liquid phase separation and the aggregation of Tau.
N-Terminal Chirality and Sequence Variations Modulate the Conformational Landscape of Amyloid-Beta 42.
Impact of Phosphorylation on the Conformational Landscape and Aggregation Behavior of Aβ40: A Comprehensive Computational Study.
Mechanistic Characterization of NABi as a Selective Inhibitor of SOD1G93A Aggregation: Structural Basis and Therapeutic Implications for ALS.
Tiny Droplets, Large Insights: Studying Peptide Aggregation with Droplet-Based Microfluidics Hyphenated with Ion Mobility Mass Spectrometry.
Conformational Features of Aβ25-35 and Its Mutants Suggest Toxic Structural Determinants: Insights from REST2 Simulations.
Changes in five cerebrospinal fluid and three plasma Alzheimer's disease biomarkers across increasing brain amyloid-beta and tau pathology burden.
Rebalancing α-Synuclein Clearance: Novel Therapeutic Frontiers in Parkinson's Disease.
Colorimetric gold nanosensors for monitoring protein aggregation: implications for Alzheimer's disease.

J Phys Chem B. 2026 Sep 03. 130(35): 8770-8781

Calcium Reshapes Aβ Aggregation at Anionic Lipid Membranes.

Meenal Jain, Silvina Matysiak.

Dysregulated calcium homeostasis is a hallmark of neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. In Alzheimer's disease (AD), the aggregation of amyloid beta (Aβ) peptides at neuronal membranes is shown to be modulated by the presence of Ca2+ ions, yet the molecular mechanism by which Ca2+ reshapes Aβ aggregation at anionic membrane surfaces remains poorly understood. To address this knowledge gap, we employed coarse-grained molecular dynamics simulations to investigate the aggregation of the model amyloidogenic K16LVFFAE22 fragment of Aβ (Aβ16-22), on a mixed bilayer composed of 30% anionic phosphatidylserine (PS) and 70% zwitterionic phosphatidylcholine (PC) (30% POPS, 70% POPC) in the presence of Ca2+ ions. We find that Ca2+ ions screen the surface charge and reduce hydrophobic packing defects at the membrane surface. Since peptide binding is primarily driven by electrostatic interactions between positively charged residues and anionic lipids, followed by hydrophobic interactions, these Ca2+-induced changes delay peptide adsorption onto the bilayer, promoting the formation of larger aggregates in solution that subsequently adsorb as preformed aggregates. This is in contrast with the no-Ca2+ condition, where peptides bind earlier as small oligomers and aggregate on the bilayer. Following adsorption, PS-Ca2+-PS ionic bridges rapidly condense PS lipids around peptide aggregates and reduce their lateral mobility. This leads to larger, less ordered aggregates with shallower insertion and hydrophobic residues exposed to the solution, a structural feature associated with seeding-active aggregates. These findings align with Western blot analyses showing enhanced Aβ aggregation with Ca2+ ions and provide a molecular basis for the observed aggregation behavior. Together, our results provide mechanistic insight into how calcium alters the membrane-mediated aggregation pathway of amyloidogenic peptides, potentially informing therapeutic strategies against amyloid pathology.

DOI: https://doi.org/10.1021/acs.jpcb.6c02606
J Agric Food Chem. 2026 Aug 26. 74(33): 26183-26195

Targeting of α-Syn Condensate Fluidity by Natural Polyphenols to Retard the Amyloid Transition and Ameliorate α-Syn-Caused Neurotoxicity.

Fengshuo Fan, Bingkuan Xu, Lizhu Zhang, Yuelin Liu, Zhenchao Li, Yinghui Liu, Ruyue He, Lingjun Zheng, Haijia Yu.

  The key pathology of Parkinson's disease (PD) is the presence of Lewy bodies, which contain aggregated α-synuclein (α-Syn). Recent studies revealed that liquid-liquid phase separation (LLPS) is critical for α-Syn aggregation. This study investigates the regulatory effects of three food-related natural polyphenols on α-Syn LLPS and amyloid transition. We discovered that, rather than epigallocatechin gallate (EGCG) and gallic acid (GA), tannic acid (TA) dynamically regulates α-Syn LLPS by increasing α-Syn mobility within the condensates. TA promotes α-Syn condensate fusion but retards the liquid-to-solid phase transition, inhibiting α-Syn aggregation. Further studies showed that TA strongly blocks α-Syn seed-induced aggregation in neuronal cells and exerts neuroprotective effects against α-Syn in Caenorhabditis elegans. Our findings demonstrate that the regulation of LLPS-driven α-Syn amyloid aggregation by small molecules differs from that of nucleation-dependent deposition, providing new insights into targeting α-Syn phase separation in the treatment of PD and other protein aggregation-related diseases.

Keywords:  Parkinson’s disease (PD); amyloid aggregation; phase separation; polyphenol; α-synuclein

DOI:  https://doi.org/10.1021/acs.jafc.5c17436
Inorg Chem. 2026 Aug 31. 65(34): 19953-19964

Protein Recognition and Amyloid Remodeling Governed by Paddlewheel Diruthenium Coordination Chemistry.

Sara La Manna, Daniele Florio, Giarita Ferraro, Maria Rosaria Policino, Filomena Altieri, Aarón Terán, Santiago Herrero, Antonello Merlino, Daniela Marasco.

Paddlewheel diruthenium (Ru2) complexes are promising modulators of protein aggregation due to their tunable coordination chemistry and dual-action properties. Here, we investigate the interaction of five Ru2 complexes with hen egg white lysozyme (HEWL), an amyloid model, to elucidate their antiaggregation capabilities. High-resolution X-ray crystallography shows that all complexes preferentially bind to Asp119 and, in some cases, Asp101, through coordination to the Ru2 core while preserving the overall protein fold. Both covalent and noncovalent interactions are observed, depending on ligand environment and steric effects. Solution studies confirm the formation of HEWL-Ru2 adducts under both neutral and acidic conditions. Functional assays demonstrate that all Ru2 complexes effectively inhibit HEWL fibrillogenesis, as indicated by reduced ThT fluorescence and the absence of large aggregates in dynamic light scattering measurements. Disaggregation of preformed fibrils was more variable, with the complex bearing vacant axial sites showing the highest activity. Circular dichroism and scanning electron microscopy analyses reveal that these compounds redirect aggregation toward noncanonical morphologies rather than fully dissolving fibrils. Cytotoxicity assays confirm reduced HEWL-induced cellular toxicity. Overall, our findings establish a correlation between ligand composition, coordination behavior, protein binding, and antiamyloid activity, providing a framework for designing Ru2-based multifunctional modulators of protein aggregation.

DOI: https://doi.org/10.1021/acs.inorgchem.6c02947
J Oleo Sci. 2026 ;75(9): 1085-1095

Biphasic Role of β-Cyclodextrin in Anionic Surfactant-induced Lysozyme Aggregation and Refolding.

Ajamaluddin Malik, Abdulaziz Alamri, Javed Masood Khan, Md Tabish Rehman, Mohammad Shamsul Ola, Hamza Odeibat.

  This study explores the role of β-cyclodextrin (β-CD) on the aggregation and refolding of hen egg white lysozyme (HEWL) induced by an anionic surfactant, i.e., sodium dodecylbenzenesulfonate (SDBS). Different biophysical techniques (Spectrophotometer, Flurometer, and Circular Dichroism) were employed to measure the conformational changes and aggregation propensity. UV-Vis spectroscopy revealed a biphasic turbidity response: initial β-CD concentrations (<0.4 mM) enhanced HEWL aggregation, whereas higher concentrations (>0.4 mM) solubilized the SDBS-induced aggregates, thereby restoring a native-like HEWL structure. Intrinsic fluorescence and circular dichroism analyses indicated that β-CD mitigated SDBS-induced structural disruptions, facilitating HEWL refolding. Thioflavin T assays confirmed the formation of amyloid-like fibrils in the SDBS-HEWL complex, which were solubilized upon addition of higher β-CD concentration, correlating with a decrease in turbidity,the regain of tertiary and secondary structure. Right-angle light scattering kinetic measurements supported these findings, showing rapid aggregate solubilization at higher β-CD concentrations. The study suggests that β-CD forms inclusion complexes with SDBS, thereby reducing its availability to interact with HEWL and mitigating aggregation, while promoting refolding. These findings underscore the potential of β-CD as a chemical chaperone in modulating protein aggregation, with implications for the formulation of therapeutic proteins and the understanding of protein misfolding diseases.

Keywords:  HEWL; SDBS; aggregation; amyloid; surfactant; β-cyclodextrins

DOI:  https://doi.org/10.5650/jos.ess25193
J Chem Phys. 2026 Sep 07. pii: 095101. [Epub ahead of print]165(9):

Hydration water dynamics in amyloid-β aggregates using deuterium and oxygen-17 solid-state NMR spectroscopy.

Bailey Frazier, Sommer Vanden Heuvel, Kusum Yadav, Bangyan Fu, Sarah A Zimmermann, Riqiang Fu, Crystal Vander Zanden, Dmitry Ostrovsky, Liliya Vugmeyster.

The dynamics of water molecules in the hydration shells of solid-like amyloid-β (Aβ) aggregates, key players in neurodegeneration, can play an important role in regulating aggregation and neurotoxicity. This study focuses on identifying the main motional modes of water in Aβ fibrils and oligomers formed from the native Aβ1-40 peptide or the toxic, yet naturally occurring, pyroglutamate-3 (PE) post-translational modification. The oligomers and fibrils were hydrated with either D2O or H217O enriched water for quantitative analysis of the dynamics of protein-bound and remote layers, using 2H and 17O solid-state NMR spectroscopy in the 300-170 K temperature range. Line shape and relaxation measurements, spanning laboratory and rotating frame relaxation, provide complementary assessment of motions in the protein-bound and remote layers, sensing different amplitudes and time scales. The comparison of the water dynamics between all of the Aβ species and a previously characterized globular protein indicates distinct differences. In particular, the general trend is the enhancement of water dynamics in the oligomers compared to fibrils, with the PE oligomer in the lead.

DOI: https://doi.org/10.1063/5.0349500
ACS Chem Neurosci. 2026 Sep 02. 17(17): 3150-3155

Protein Aggregates as Drivers of Receptor Clustering and Pathological Signaling: A Framework Linking Extracellular Amyloid-β to Tau Dysregulation.

Renan C Ratis, Juliana S Bonini, Angelica B W Bold.

  Extracellular protein aggregates have long been viewed primarily as toxic deposits, yet this framing fails to explain a critical clinical observation: removal of amyloid-β oligomers does not halt or reverse Alzheimer's disease progression. Here, we propose that this paradox reflects the emergence of a self-sustaining intracellular signaling state, initiated by aggregate-driven receptor clustering but capable of persisting independently of the original extracellular trigger. We argue that oligomeric assemblies act as multivalent scaffolds that cross-link cell-surface receptors, inducing nanoscale clustering and the formation of signaling-competent membrane platforms. In Alzheimer's disease, this mechanism links amyloid-β to a receptor complex involving PrPc and mGluR5, leading to Fyn activation and downstream tau hyperphosphorylation. Critically, redistributed tau enhances Fyn recruitment to postsynaptic compartments, establishing a positive feedback loop in which kinase activity and tau pathology become mutually reinforcing, and progressively decoupled from the initiating amyloid signal. This self-amplifying circuit provides a mechanistic basis for the limited efficacy of amyloid-targeted therapies and reframes the therapeutic window problem in neurodegeneration. Beyond Alzheimer's disease, we propose that clustering-driven feedback loops may represent a generalizable principle in proteinopathies involving extracellular or membrane-associated aggregates─such as α-synuclein─though the applicability of this principle appears to depend on whether the aggregating protein directly engages cell-surface receptor systems. This framework shifts the focus from aggregate burden to membrane organization and feedback topology as determinants of disease progression, and identifies the tau-Fyn feedback loop as a candidate therapeutic target in proteinopathies.

Keywords:  beta-amyloid; lipid raft; neurons; positive feedback; proteinopathy

DOI:  https://doi.org/10.1021/acschemneuro.6c00331
Adv Sci (Weinh). 2026 Sep 01. e77575

Molecular Glue Degraders Enhance CAPRIN1-Dependent Lysosomal Degradation of APP and Reduce Amyloid β in Alzheimer's Disease.

Sunghan Jung, Xu Wang, Bin Liu, Raktim Roy, Nancy Jaiswal, Ratan K Rai, Yuichiro Takagi, Cen Gao, Lifan Zeng, Ho-Yin Lo, Reagan K Wohlford, Ryan K Higgins, Bruce T Lamb, Anantha Shekhar, Anita C Bellail, Chunhai Hao.

  The amyloid cascade involving the production and deposition of amyloid β (Aβ) peptides derived from amyloid precursor protein (APP) is a leading hypothesis in the pathogenesis of Alzheimer's disease (AD). However, disease-modifying therapies targeting this cascade remain an unmet challenge. Here, we identify small molecules that degrade APP and reduce Aβ production through a targeted protein degradation strategy. Using genetically engineered APP cell models and induced pluripotent stem cell (iPSC)-derived neurons from patients with AD, we demonstrate that cytoplasmic activation/proliferation-associated protein 1 (CAPRIN1) is expressed in neurons and physically interacts with APP. Screening of a CAPRIN1-targeted compound library identified compound 0043, which promotes intracellular APP degradation and reduces extracellular Aβ release. Structure-activity relationship optimization of 0043 derivatives yielded compound 0152 with improved potency and blood-brain barrier permeability. In AD iPSC-derived neurons, these compounds enhance CAPRIN1-APP interactions and promote CAPRIN1-dependent APP degradation through the endolysosomal pathway. CAPRIN1 is predominantly expressed in neurons in AD postmortem brains and iPSC-derived brain organoids. Systemic administration of compound 0152 significantly reduced APP levels, Aβ production, and amyloid burden in 5xFAD mice. These findings establish CAPRIN1-dependent, lysosome-targeted molecular glue degraders as a potential APP-targeted therapeutic strategy for AD.

Keywords:  Alzheimer's disease; amyloid precursor protein; amyloid β plaque; induced pluripotent stem cell; molecule glue degrader

DOI:  https://doi.org/10.1002/advs.77575
Biochemistry. 2026 Aug 27.

Triprolidine Interferes with α-Synuclein Fibrillation and Remodels Aggregate Structure via Conformational Modulation.

Md Nadir Hassan, Murtaza Hussain, Faisal Nabi, Devendra Singh, Sumbul Yasmeen, Md Sharique Zafar, Irum Rizvi, Syed Mohammad Zakariya, Waseem A Siddiqui, Vladimir N Uversky, Rizwan Hasan Khan.

Parkinson's disease (PD) is characterized by the pathological aggregation of α-synuclein (α-syn) into β-sheet-rich fibrils, contributing to neuronal toxicity and oxidative stress. In this study, we investigated the inhibitory and disaggregating effects of Triprolidine (TC) on α-syn fibrillation through a combined experimental and computational approach. Biophysical assays, including ThT assay, DLS, and ANS assays, demonstrated that TC inhibits α-syn fibrillation in a concentration-dependent manner (IC50 ≈ 255 μM), disrupts preformed fibrils, and maintains the protein's native form. CD data further revealed that TC prevents the transition of α-syn to its toxic β-sheet-rich form and facilitates partial structural reversal during disaggregation. To elucidate the molecular mechanism of inhibition, we performed all-atom molecular dynamics (MD) simulations followed by Markov State Model (MSM) construction. The simulations revealed that TC binding remodels the conformational landscape of α-syn by stabilizing compact, disordered states and reducing the population of β-sheet-prone intermediates, particularly in the aggregation-prone NAC region. MSM analysis identified metastable states with diminished aggregation potential and reduced inter-residue contact probability, offering mechanistic insights into how TC interferes with early nucleation events. TC attenuates seeded fibrillation in a concentration-dependent manner too. Complementary cellular assays, including MTT and hemolytic assays, confirmed a significant reduction in α-syn-induced cytotoxicity upon TC treatment, with a decrease in ROS levels as confirmed by the DCFH-DA assay. Together, these findings demonstrate that TC modulates both the structural dynamics and functional toxicity of α-synuclein, and highlight its potential as a promising chemical modulator for further investigation in PD-related protein aggregation.

DOI: https://doi.org/10.1021/acs.biochem.6c00571
Biochimie. 2026 Sep 01. pii: S0300-9084(26)00207-5. [Epub ahead of print]

Osmolytes suppress liquid‒liquid phase separation and the aggregation of Tau.

Jingye Lin, Zongbao Wang, Chenxi Liu, Yiwen Hua, Sen Li.

  Tau liquid-liquid phase separation (LLPS) is increasingly recognized as an early event that promotes pathological aggregation in Alzheimer's disease and other tauopathies. Osmolytes are natural chemical chaperones that stabilize protein conformations, yet their effects on Tau phase behavior remain poorly understood. Here, we show that sucrose, trehalose, glucose, maltose, and betaine suppress Tau LLPS and dissolve preformed Tau droplets, shifting the equilibrium toward soluble monomers in vitro. Among the five osmolytes, trehalose and glucose exhibited the strongest inhibitory effects on Tau LLPS. They also suppressed the liquid-to-solid phase transition of Tau droplets, as evidenced by reduced Thioflavin T (ThT) fluorescence, inhibition of fibril formation observed by transmission electron microscopy (TEM), and improved condensate dynamics in fluorescence recovery after photobleaching (FRAP) assays performed in okadaic acid-treated cells. These results indicate that osmolytes interfere with multiple stages of Tau phase transition-from initial condensate formation to pathological maturation and fibrillization. Our findings establish osmolytes as effective modulators of Tau phase behavior and provide mechanistic insights into the physicochemical regulation of Tau phase transitions.

Keywords:  Alzheimer's disease; Liquid‒liquid phase separation; Osmolytes; Protein stability; Tau protein aggregation

DOI:  https://doi.org/10.1016/j.biochi.2026.08.019
J Chem Inf Model. 2026 Aug 24. 66(16): 10156-10167

N-Terminal Chirality and Sequence Variations Modulate the Conformational Landscape of Amyloid-Beta 42.

Qiang Zhu, Haibo Yu.

Amyloid beta (Aβ), one of the hallmark proteins of Alzheimer's disease (AD), aggregates into plaques that are strongly linked to cognitive decline and neuronal death. Reducing its aggregation propensity may provide a strategy to slow the progression of AD. While chirality modulation has emerged as an innovative approach to disrupt this process, research has primarily focused on alterations at the Cα position, often overlooking the impact of the second chiral center, such as the Cβ atom of threonine. Furthermore, the underlying mechanisms governing these chiral effects remain elusive. Given the intrinsically disordered nature of the Aβ peptide, we employed temperature-replica exchange molecular dynamics simulations to explore its rugged conformational landscape. We considered sequence mutations (A2T and A2V), N-terminal chirality inversion of the first six residues (A2V1-6D and WT1-6D), and alteration of the second chiral center (Cβ) of threonine (A2TCβ). By analyzing the effect size and population change induced by these mutations and chiral modulation, we concluded that the modulation at the N-termini is not confined locally but also exerts specific effects on the central hydrophobic core (CHC) region. Inspection of their free energy landscape and representative structures reveals that the protective or pathogenic effects of these variants correlate with their similarity to the wild type ensemble. Beyond these static thermodynamics analyses, a direct connection to phase transitions was made by estimating heat capacity as a function of temperature. Both analyses predict that A2TCβ may exert a pathogenic effect, in contrast to the protective nature of A2T. These findings offer a deeper understanding of the effects of site-specific mutations and chirality and shed light on the development of advanced therapeutic strategies for AD.

DOI: https://doi.org/10.1021/acs.jcim.6c01001
J Phys Chem B. 2026 Sep 03. 130(35): 8782-8793

Impact of Phosphorylation on the Conformational Landscape and Aggregation Behavior of Aβ40: A Comprehensive Computational Study.

Zaihang Ye, Chen Wang, Bin Tu, Yanlian Yang, Qiaojun Fang.

Phosphorylation of amyloid-β (Aβ40) at Ser8 and Ser26 exerts opposing effects on fibril formation: Ser8 phosphorylation promotes aggregation, whereas Ser26 phosphorylation strongly inhibits it. Using replica exchange with solute tempering (REST2) simulations and coarse-grained modeling, we reveal the atomic-level mechanisms underlying these effects. Ser26 phosphorylation forms a highly stable pS26-K28 salt bridge that competes with and disrupts the native E22/D23-K28 interaction required for hairpin formation and fibrillization, yielding a compact, globular conformation that is aggregation-incompetent. In contrast, Ser8 phosphorylation stabilizes the hairpin structure with a preformed N-terminal attachment (the S* structure) via pS8-K16/K28 salt bridges, lowering the entropic barrier for N-terminal alignment. This mechanism aligns with experimental observations that pS8 fibrils gain stability due to N-terminal incorporation into the fibril core, thereby promoting fibrillization. Together, these results demonstrate that monomeric conformational landscapes directly encode aggregation propensity, providing a mechanistic framework for understanding how post-translational modifications modulate amyloid assembly pathways.

DOI: https://doi.org/10.1021/acs.jpcb.6c02971
ACS Chem Neurosci. 2026 Sep 02. 17(17): 3156-3168

Mechanistic Characterization of NABi as a Selective Inhibitor of SOD1G93A Aggregation: Structural Basis and Therapeutic Implications for ALS.

Min-Kyung Nam, Yeram Oh, Yemi Choi, Jieun Lee, Gi Heon Jeong, Sangjun Park, Seung-Ah Yoo, Moonseok Kim, Seongman Kang, Hyangshuk Rhim.

  Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, with familial ALS (fALS) frequently caused by mutations in Cu/Zn superoxide dismutase (SOD1). The G93A mutation, one of the most aggressive forms, promotes the formation of cytotoxic protein aggregates through cross-β-sheet structures, leading to neuronal dysfunction and death. In this study, we investigated the therapeutic potential of NABi (natural Aβ binder and Aβ-aggregation inhibitor), a stable small engineered protein composed of the N-terminal 90 amino acids of SOD1, originally developed to target amyloid-β aggregation in Alzheimer's disease. Given the shared β-sheet-rich aggregation mechanisms between amyloid-β and mutant SOD1 proteins, we hypothesized that NABi could serve as a dual-action therapeutic for both diseases. Through an integrated approach involving structural, biochemical, and cellular analyses, we demonstrate that NABi exhibits a 4-fold greater binding affinity for SOD1G93A compared to SOD1WT, selectively targeting the mutant protein via specific hydrophobic interactions. Structural modeling using AlphaFold2 reveals that the G93A mutation exposes hydrophobic residues that create an optimal binding interface for NABi. Functionally, NABi effectively inhibits SOD1G93A aggregation, as demonstrated by filter trap assays and immunofluorescence microscopy, while maintaining the protein in a soluble, nontoxic state. Importantly, coexpression of NABi reduces SOD1G93A-induced cytotoxicity by approximately 4-fold, significantly enhancing neuronal survival. These findings establish NABi as a promising therapeutic candidate for SOD1G93A-associated familial ALS, demonstrating its capacity to selectively target pathological protein conformations while preserving normal cellular function. Our results support the development of NABi as an innovative pan-therapeutic approach targeting shared aggregation pathways across multiple neurodegenerative diseases.

Keywords:  Amyotrophic lateral sclerosis; NABi; SOD1G93A; aggregation inhibitor; neurodegenerative diseases; protein aggregation; therapeutic peptide; β-sheet inhibitor

DOI:  https://doi.org/10.1021/acschemneuro.5c00977
Anal Chem. 2026 Sep 01. 98(34): 25463-25476

Tiny Droplets, Large Insights: Studying Peptide Aggregation with Droplet-Based Microfluidics Hyphenated with Ion Mobility Mass Spectrometry.

Ariadni Geballa-Koukoula, Iuliia Stroganova, Hannah Willenberg, Kevin Hes, Emily E Kempa, Perdita E Barran, Aigars Piruska, Wilhelm T S Huck, Anouk M Rijs.

Peptide and protein aggregation are hallmarks of numerous neurodegenerative diseases. However, the structural characterization of oligomeric intermediates remains challenging due to their low abundance, heterogenic nature, and complexity of coinciding and transient reaction networks. Confining reactions to microenvironments, such as picoliter droplets in droplet-based microfluidics (DBMFs), simplifies these networks, thereby enabling high-throughput analysis and controlled reaction kinetics. This study explores the integration of DBMF with ion mobility mass spectrometry (IM-MS) to probe the aggregation kinetics in droplets. We address key technical challenges, including interference from the dispersed phase, surfactant, and DBMF device material, followed by optimization strategies for droplet generation and surfactant concentration to reduce the level of contamination. Furthermore, we investigate instrumentation-based influences on ionization to improve the signal stability. Using model peptides, bradykinin, leucine-enkephalin, and the aggregation-prone segment Ac-PHF6-NH2 from the tau protein, we demonstrated the successful development of a sensitive method. Additionally, using the Ac-PHF6-NH2 peptide, oligomeric transient species were probed and characterized by their IM and m/z values. This work demonstrates the potential of DBMF-IM-MS to study peptide aggregation in confined environments, providing insights into the formation of oligomeric species and laying the groundwork for studies on larger proteins and the development of therapeutic agents targeting aggregation using multichannel devices.

DOI: https://doi.org/10.1021/acs.analchem.6c05360
J Phys Chem B. 2026 Sep 03. 130(35): 8855-8866

Conformational Features of Aβ25-35 and Its Mutants Suggest Toxic Structural Determinants: Insights from REST2 Simulations.

Yuxiang Mo, Yonghui Hou, Rui Su, Zhijing Huang, Guoning Tang, Liang Du, Yan Lu.

The Aβ25-35 fragment is the shortest proteolytic fragment retaining the core neurotoxicity of full-length Alzheimer's amyloid-β (Aβ). To elucidate the structure-neurotoxicity relationships, we performed replica exchange with solute tempering 2 (REST2) simulations on wild-type (WT), N27A (less toxic), and M35A (more toxic) Aβ25-35 hexamers in explicit solvent. Our simulations show that N27A, WT, and M35A hexamers predominantly adopt 4-stranded, 6-stranded, and 5-stranded β-barrels, respectively, driven by hydrophobic interactions within residues I30-G33. Hydrogen bond counts and binding energies for adjacent peptide contacts and peptide-water interactions indicate that both β-barrel disassembly propensity and N-terminal hydration (residues G25-K28) correlate with the cytotoxicity trend (N27A < WT < M35A). Integrating our findings with established membrane damage mechanisms, we propose that (I) the disassembly propensity of dominant β-barrels governs their transition from off-pathway states to cytotoxic oligomers, and (II) N-terminal domain exposure (G25-K28) in on-pathway intermediates modulates peptide-membrane interactions. To reduce Aβ25-35 oligomeric toxicity, we recommend inhibiting hydrophobic core residues (A30-G33) to suppress aggregation and modulating N-terminal contacts to limit solvent exposure and membrane binding. Our simulations provide new insights into WT and mutant Aβ25-35 cytotoxicity and suggest therapeutic strategies for its attenuation.

DOI: https://doi.org/10.1021/acs.jpcb.6c04178
Acta Neuropathol. 2026 Sep 03. pii: 28. [Epub ahead of print]152(1):

Changes in five cerebrospinal fluid and three plasma Alzheimer's disease biomarkers across increasing brain amyloid-beta and tau pathology burden.

Andrea Mastrangelo, Simone Baiardi, Edoardo Ruggeri, Giuseppe Mario Bentivenga, Claudia Marina Vargiu, Angela Mammana, Marco Sbriccoli, Barbara Polischi, Benedetta Carlà, Sabina Capellari, Piero Parchi.

  Neuropathological validation studies of pathology-specific biomarkers for neurodegenerative diseases are essential but are often limited by long sampling-to-death intervals and the lack of semi-quantitative pathology measures. We assessed the associations of five cerebrospinal fluid (CSF) (Aβ42/Aβ40, p-tau181, p-tau217, Aβ42/p-tau181 and Aβ42/p-tau217) and three plasma (p-tau217, p-tau217/Aβ42 and Aβ42/Aβ40) biomarkers with post-mortem Aβ and tau pathology burden in 250 participants with ante-mortem CSF (n=230) and/or plasma (n=101), affected by prion (n=162) or non-prion diseases (n=88). Aβ and tau burden were scored across nine and six brain areas, respectively. We assessed the earliest biomarker changes across quartiles of Aβ and tau pathology burden and the discriminatory performance at progressively higher pathology thresholds using multivariable linear regression and sequential ROC analyses. Analyses on p-tau markers were restricted to non-prion participants. The median sampling-death interval was 1.5 months for CSF and 1 month for plasma. CSF Aβ42/Aβ40 decreased at the second quartile of Aβ burden (p<0.001), whereas p-tau181 (p<0.01) and p-tau217 (p<0.001) increased only from the third quartile. CSF Aβ42/Aβ40 achieved its highest accuracy at low/intermediate Aβ burden (AUC 0.984), while CSF p-tau and derived ratios performed best at advanced Aβ (AUCs 0.889 to 0.980) and intermediate tau pathology stages (AUCs 0.949 to 0.995). CSF p-tau217 and Aβ42/p-tau217 consistently showed higher accuracy than their p-tau181 counterparts across Aβ and tau pathology scores. Plasma p-tau217 and p-tau217/Aβ42 significantly increased in the highest Aβ and tau burden quartiles, where they achieved their best performance (AUCs 0.893 to 0.928). These findings support a sequential model of biomarker changes across the Alzheimer's disease neuropathological continuum. CSF Aβ42/Aβ40 best reflects low/intermediate Aβ burden, while CSF p-tau markers are more closely related to high Aβ and intermediate tau load. Plasma markers primarily identify advanced Aβ and tau pathology burden. Notably, current fluid biomarkers do not capture the earliest phases of Aβ deposition.

Keywords:  Autopsy; Diagnosis; Neurodegenerative diseases; Neuropathology; Staging; Validation

DOI:  https://doi.org/10.1007/s00401-026-03076-5
Neuromolecular Med. 2026 Aug 31. pii: 51. [Epub ahead of print]28(1):

Rebalancing α-Synuclein Clearance: Novel Therapeutic Frontiers in Parkinson's Disease.

Maryam Jabeen, Huma Hameed, Syed Muhammad Ahmad, Tehreem Mushtaq, Mahtab Ahmad Khan, Anam Hameed.

  Parkinson's disease (PD), the second most common neurodegenerative condition, develops because of abnormal protein misfolding and aggregation of α-synuclein with its subsequent intercellular spread. Such pathological changes lead to disruption of neuronal homeostasis and contribute to neuronal degeneration. During normal conditions, α-synuclein clearance is controlled by different types of lysosomal degradation, namely, macro autophagy, chaperone-mediated autophagy (CMA), micro autophagy, and the ubiquitin-proteasome system. Malfunction of these systems results in increased α-synuclein secretion due to exosome-dependent, direct, and damage-induced mechanisms, which, in turn, promotes enhanced intercellular propagation, inflammation, mitochondrial dysfunction, blood-brain barrier leakage, and neuronal cell death. Although several approaches targeting α-synuclein clearance have shown biological activity in preclinical or early clinical studies, consistent disease-modifying efficacy has not yet been established, owing to challenges including target specificity, blood brain barrier penetration, biological heterogeneity, and the limited sensitivity of clinical endpoints. Recent research indicates that successful treatment is more related to restoring the balance of these two processes than to manipulating one of them.In this review, it is proposed that a systems-level approach can be taken where PD is understood as a disease characterized by the imbalance in proteostasis. Potential treatment modalities include small molecules targeting lysosome function (ambroxol, rapamycin, TFEB activators), CMA enhancers, gene therapy, and antibodies against extracellular α-synuclein. Furthermore, new modalities like molecular glue degraders, allostery-based stabilization of α-synuclein tetramers, engineered decoy particles, and bispecific antibodies represent some other possible routes towards multimodal disease modification.

Keywords:  Autophagy; Extracellular Propagation; Lysosomal Dysfunction; Nanoparticles; Parkinson’s Disease; α-Synuclein

DOI:  https://doi.org/10.1007/s12017-026-08948-3
Chem Commun (Camb). 2026 Sep 01.

Colorimetric gold nanosensors for monitoring protein aggregation: implications for Alzheimer's disease.

Célia Sahli, Haining Zhu, Kenry.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. It remains a major public health challenge due to the lack of early diagnostic tools and effective disease-modifying therapies. Molecularly, AD is characterized by extracellular amyloid-β (Aβ) plaques and intracellular Tau tangles, as well as soluble oligomers that are likely the neurotoxic species. However, the transient and heterogeneous nature of these oligomers makes them difficult to detect using conventional biosensing approaches. Nanomaterial-based colorimetric biosensors have emerged as promising platforms for detecting protein aggregates and discovering aggregation inhibitors. Specifically, the localized surface plasmon resonance properties of metallic nanomaterials can enable rapid, label-free, and visually detectable colorimetric sensing of molecular interactions. These features can be leveraged to monitor protein aggregation processes in real time and achieve high-throughput screening of aggregation inhibitors, which may collectively enable early detection and timely intervention of AD progression. This Review Article presents the design and engineering of gold-nanomaterial-based colorimetric biosensors for monitoring protein aggregation and highlights the current challenges and emerging opportunities for applying these nanosensors to combat AD.

DOI: https://doi.org/10.1039/d6cc02973f