bims-amyloi 2026-08-23 papers

Issue of 2026–08–23
eight papers selected by
Alexander Röntgen, University of Cambridge

Protein Sci. 2026 Sep;35(9): e70754

Multimerization of a rationally designed nanobody for enhanced avidity toward Aβ42 oligomers.

Magdalena Nowinska, Elijah Suh, Casey Mogilevsky, Michele Vendruscolo.

Alzheimer's disease affects tens of millions of people worldwide and is associated with the self-assembly of the Aβ42 peptide into amyloid aggregates. Among the species formed during this process, soluble oligomeric intermediates are the most closely linked to neurotoxicity and are therefore an attractive target for both therapeutic and diagnostic strategies. Their conformational heterogeneity and transient nature, however, have so far hindered the development of reagents that recognize them selectively, and no fully quantitative biomarker of Aβ42 oligomers is widely available. To address this problem, we use a rationally designed conformation-specific single-domain antibody, DesAbO, which binds selectively to Aβ42 oligomers. By using enzyme-linked immunosorbent assay, we show that encoding self-assembling multimerization domains in the DesAbO plasmid yields multimeric variants with increased avidity toward Aβ42 oligomers. In aggregation assays, the multimeric variants inhibited Aβ42 aggregation at concentrations at which the monomeric form was no longer effective, with the SB175 trimer performing best. These results show how multimerization can be used to enhance the recognition of Aβ42 oligomers and offer a route toward diagnostic and therapeutic agents for Alzheimer's disease and other protein misfolding disorders.

Keywords: Alzheimer’s disease; Aβ42 oligomers; avidity; multivalency; nanobodies; protein aggregation

DOI: https://doi.org/10.1002/pro.70754

Methods Mol Biol. 2026 ;3035 437-446

Imaging and Characterization of Ganglioside-Induced Amyloid Fibril Formation.

Teruhiko Matsubara.

High-density nanoclusters of gangliosides in membrane rafts interact with amyloid β protein (Aβ), which induces toxic Aβ aggregation. This chapter describes how to generate, detect, and assess the Aβ aggregates induced by ganglioside-containing liposomes and planar lipid bilayers.

Keywords: Amyloid β protein; Ganglioside cluster; Langmuir trough; Membrane raft; Thioflavin T; Topography

DOI: https://doi.org/10.1007/978-1-0716-5288-6_29

Chemphyschem. 2026 Aug 27. 27(16): e70538

Membrane Complexity and Phase Behavior Dictate the Stability of Membrane-Inserted Aβ42 Hexamers.

Bastian Ferdinand Bundschuh, Franziska Kley, Yu Wang, Birgit Strodel.

Protein-membrane interactions are vital to Alzheimer's pathogenesis, as lipid environments modulate both the aggregation and toxicity of amyloid-β (Aβ) peptides. Using atomistic molecular dynamics simulations, this study investigates the stability of an NMR-derived hexameric Aβ42 β-barrel in aqueous solution, a fluid 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer, and a complex neuronal membrane. While the hexamer is unstable and conformationally heterogeneous in water, lipid environments provide essential structural reinforcement. Notably, the multicomponent neuronal membrane offers superior stabilization compared to POPC, supporting the β-barrel in a stable transmembrane conformation. This superior stability is driven by the rigid scaffolding of the liquid-ordered phase alongside specific electrostatic anchoring between the ethanolamine headgroups of the POPE component and the acidic Aβ42 residues E22/D23. We characterize a reciprocal relationship where the membrane stabilizes the β-barrel architecture, while the peptide induces localized lipid disorder and flip-flop translocation. Our findings demonstrate how membrane complexity and phase behavior dictate the stability of toxic Aβ42 oligomers, offering key insights into the membrane-mediated mechanisms of neurotoxicity.

Keywords: β‐barrel; alzheimer’s disease; amyloid‐β; molecular dynamics; neuronal membrane

DOI: https://doi.org/10.1002/cphc.70538

Bull Math Biol. 2026 Aug 20. pii: 162. [Epub ahead of print]88(9):

Metal-Ion-Mediated Amyloid- β Aggregation in Alzheimer's Disease: A Mathematical Model of Chelation and Inhibitory Therapies.

Shantia Yarahmadian, Yasser Alzahrani, Vaghawan Prasad Ojha.

We develop a novel, comprehensive, and rigorously validated mathematical framework to investigate the kinetics of amyloid- β (A β ) aggregation in the presence of biologically relevant metal ions, chelating agents, and inhibitor drugs. Building upon and extending existing aggregation models, our approach integrates metal-assisted aggregation, A β self-assembly, and therapeutic interventions within a unified and mechanistically consistent formulation. The model captures the microscopic reaction pathways governing A β dynamics and explicitly incorporates the catalytic roles of copper, zinc, and iron ions-key contributors to neurotoxic plaque formation in Alzheimer's disease. Distinctively, the framework combines dual therapeutic strategies: (i) metal chelation therapy, which sequesters free metal ions, and (ii) direct inhibition of A β aggregation. Numerical simulations across multiple kinetic regimes reveal how these interventions modulate aggregation pathways, both independently and synergistically. To further validate the model, we perform a quantitative comparison with experimental data by reconstructing aggregate morphology distributions and benchmarking them against reported AFM measurements. The model successfully captures key experimental features, including peak structure and metal-dependent heterogeneity, thereby demonstrating its predictive capability. Overall, this work provides an extended and unified modeling platform that advances the quantitative understanding of metal-mediated amyloid aggregation and offers a predictive tool for evaluating and optimizing therapeutic strategies for Alzheimer's disease.

Keywords: A β ; Alzheimer’s disease (AD); Chelation therapy

DOI: https://doi.org/10.1007/s11538-026-01732-1

Neurobiol Dis. 2026 Aug 17. pii: S0969-9961(26)00321-9. [Epub ahead of print] 107576

PrPC limits APP delivery to the plasma membrane and alters its processing to facilitate aβ release.

Nikita Mehta, Sungro Jo, Stanislau Smirnou, Gopal Thinakaran, James A Mastrianni.

Several lines of evidence suggest that the cellular isoform of prion protein (PrPC) plays one or more roles in Alzheimer's Disease (AD). We previously found, in mouse neuroblastoma N2a cells that express human APP carrying the Swedish mutation (N2a-APPswe), that PrPC expression correlated with the secretion of Aβ42 peptide, the product of proteolytic processing of the amyloid precursor protein (APP) that is central to AD. To determine whether PrPC modulates APP processing to affect Aβ42 release and if any effect of PrPC is selective for APPswe, we applied the MesoScale Discovery (MSD) platform to assess APP processing and Aβ secretion before and after siRNA-induced knockdown of PrPC in APPswe and wild-type APP (APPwt) N2a cells. We found that PrPC knockdown reduced the major isoforms of secreted Aβ peptides in both cell lines (with the exception of Aβ42 in N2a-APPwt cells) in the absence of a reduction in either APP expression or enhanced Aβ degradation. Additionally, the soluble ectodomain of β-secretase cleavage (sAPPβ) was reduced in both cell lines whereas the ectodomain of α-secretase cleavage (sAPPα) was increased only in N2a-APPwt cells. PrPC overexpression led to an increase in Aβ42 in HEK cells and sAPPβ in both N2a cells and HEK cells expressing APPswe, confirming that PrPC promotes the amyloidogenic processing pathway independent of cell type. Biotinylation and immunofluorescence studies in the N2a cell lines revealed an increase in APP labeling at the plasma membrane, an increase in APP endocytosis, and an accumulation of APP C-terminal fragments (CTFs) after PrPC knockdown. We propose that PrPC limits delivery of APP to the plasma membrane, which acts to promote the amyloidogenic pathway by increasing its exposure to BACE1 within early secretory compartments.

Keywords: Alzheimer's disease; Amyloid precursor protein (APP); Amyloid-beta (aβ); Prion; Prion protein (PrP); Protein processing

DOI: https://doi.org/10.1016/j.nbd.2026.107576

Mol Biomed. 2026 Aug 20. pii: 145. [Epub ahead of print]7(1):

Pathological depositions in human disease: converging mechanisms in atherosclerosis, Alzheimer's disease, and related disorders.

Louis Ragolia.

Pathological deposition of endogenous material within tissues represents a central, unifying mechanism across a broad spectrum of prevalent human diseases. Atherosclerosis and Alzheimer's disease (AD) exemplify this paradigm: atherosclerosis is driven by subendothelial accumulation of apolipoprotein B-containing lipoproteins, cholesterol crystals, and hydroxyapatite, while AD is characterized by cerebral deposition of misfolded amyloid-β (Aβ) and/or hyperphosphorylated tau. Emerging evidence implicates substantial lipid dyshomeostasis in AD pathogenesis, including lipid-droplet-accumulating microglia and widespread lipidomic disruption, blurring the categorical boundary between "lipid" and "protein" deposition diseases. Apolipoprotein A-I (apoA-I) dysfunction bridges both domains: post-translational modifications and point mutations impair reverse cholesterol transport in atherosclerosis and simultaneously promote apoA-I amyloid fibril formation in systemic amyloidosis. Across atherosclerosis, AD, systemic amyloidoses, immune complex-mediated nephropathies, crystal arthropathies, and lysosomal storage disorders, shared pathophysiologic processes emerge: production-clearance imbalance, conformational transitions favoring aggregation or crystallization, microenvironmental modulation by extracellular matrix components, and chronic sterile inflammatory responses driven by NLRP3 inflammasome activation. In this review, we synthesize deposition biology using atherosclerosis and AD as primary paradigms, integrate mechanistic insights from related disorders, highlight convergent molecular pathways including NLRP3, proteostasis, and glymphatic clearance, and discuss diagnostic and therapeutic strategies. A conceptual framework unifying these conditions as variations on a common deposition theme is proposed to guide broadly applicable precision therapies.

Keywords: Alzheimer’s disease; Apolipoprotein A-I; Atherosclerosis; Lysosomal storage disorders; NLRP3 inflammasome; Pathological deposition

DOI: https://doi.org/10.1186/s43556-026-00552-y

mBio. 2026 Aug 17. e0083126

AI-designed prion-capping proteins provide evidence that prion fibril ends are replication-competent surfaces that contribute to prion seeding activity and infectivity.

Jessy A Slota, Matthew Kirby, Aidan Van Den Driessche, Dominic M S Kielich, Lise Lamoureux, Daniel R Beniac, Christine Layne, Melissa Poirier, Jörg Stetefeld, Stephanie A Booth, Ben A Bailey-Elkin.

End-elongation of amyloid fibrils is a prevailing theory to explain prion replication, but direct experimental evidence for this phenomenon is limited by the lack of research tools. To serve as molecular probes for prion fibril termini, here, we designed protein binders against high-resolution structures of infectious prion fibrils using a diffusion-based design model. By generating protein scaffolds around short β-strand segments from terminal prion rungs, we designed β-hairpin-interfacing proteins that cap prion fibrils, which we termed PRICAPs. We validated that PRICAPs exhibit binding to prion fibril termini and confirmed the role of prion fibril ends in replication by demonstrating that PRICAPs inhibit prion seeding activity and attenuate prion replication in organotypic cerebellar slice cultures. Collectively, these findings describe a class of prion-capping protein that can be used to probe prion fibril termini and verify that these surfaces contribute to prion replication and infectivity.
IMPORTANCE: Prions replicate by templating the misfolding of native proteins; however, direct evidence identifying the precise sites of replication has remained limited. Here, we address this gap by developing a new class of rationally designed protein tools that specifically bind and cap the ends of infectious prion fibrils. Using these probes, we demonstrate that fibril termini are replication-competent surfaces required for prion seeding and propagation. By inhibiting these sites, our designed proteins markedly reduce prion replication in a disease-relevant ex vivo system, providing functional validation of the end-elongation model. Beyond resolving a fundamental question in prion biology, this work establishes a generalizable strategy for targeting amyloid fibril ends with high specificity. These findings have broad implications for understanding protein aggregation in neurodegenerative diseases and open new avenues for the development of therapeutics that selectively disrupt pathogenic amyloid propagation.

Keywords: Creutzfeldt-Jakob disease; RFdiffusion; amyloid; prion

DOI: https://doi.org/10.1128/mbio.00831-26

medRxiv. 2026 Aug 05. pii: 2026.08.03.26359636. [Epub ahead of print]

Antemortem α-Synuclein levels from neuron-derived extracellular vesicles identify Lewy Body pathology in Parkinson's Disease and Alzheimer Disease.

Tamil Iniyan Gunasekaran, Dolly Reyes-Dumeyer, Yian Gu, Olga Volpert, Doug Beauregard, Lammert Albers, Andrew Teich, Lawrence S Honig, Richard Mayeux, Erez Eitan, Badri N Vardarajan.

Importance: Alzheimer disease (AD) is frequently accompanied by co-pathologies such as Lewy bodies, intracellular protein aggregates consisting of misfolded α-synuclein, ubiquitin and several other proteins. These aggregated proteins contribute to the pathological and clinical heterogeneity of AD and are associated with a more rapid progression. Cerebrospinal fluid (CSF) measurement of aggregated α-synuclein or skin biopsy histochemistry are the current biomarkers for Lewy body pathology in individuals with Parkinson's disease and related synucleinopathies but are invasive, not easily scalable for large studies or practical in clinical practice. Neuron-derived extracellular vesicles (nEVs) provide a feasible and tolerable alternative to detect Lewy body pathology. nEVs exit across the blood-brain barrier and deliver neuron-derived proteins into the systemic circulation, offering direct access to brain-level protein concentrations from peripheral blood, not afforded by conventional plasma biomarkers.
Objective: To use nEVs extracted from plasma to measure brain-derived α-synuclein levels as a clinical biomarker of Lewy body pathology and synucleinopathy across clinically and pathologically characterized cohorts.
Design Setting and Participants: This multicohort observational study evaluated plasma nEV-derived α-synuclein levels in 1,304 individuals, including 794 (61%) individuals without dementia, 469 (36%) individuals with AD, and 41 (3%) individuals with PD across four cohorts. Postmortem validation was performed from autopsy data in 127 individuals, including 96 (76%) individuals without, and 31 (24%) with, Lewy body pathology. Cerebrospinal fluid (CSF) α-synuclein seed amplification assay data were available in a small subset of 54 (4.1%) of the group. Amyloid positron emission tomography (PET) data were available in 901(69.1%) of the total group.
Exposure: Clinical diagnosis, AD biomarker positivity, Lewy body pathology, CSF α-synuclein seed assay status, and amyloid PET positivity.
Main Outcomes and Measures: Plasma nEV-derived α-synuclein levels normalized to CD9 and assessed in relation to clinical diagnosis, AD biomarker status, neuropathologically confirmed Lewy body pathology, CSF seed assay results, and amyloid PET positivity.
Results: Compared with controls, plasma α-synuclein levels from nEVs were significantly elevated among individuals with PD (controls mean 0.51, SD=0.24 vs PD mean=0.69, SD=0.23, P =8.66×10 - □). nEV-derived α-synuclein levels were also significantly higher in P-tau181 and P- tau217 positive individuals with and without cognitive impairment compared to P-tau negative individuals. Elevated nEV-derived α-synuclein levels were subsequently validated in individuals with postmortem Lewy body pathology (28.6% higher mean levels, P =0.02). Among 54 individuals with CSF α-synuclein seed amplification assay, 8 (15%) were positive and showed a 18.2% increase in mean nEV α-synuclein levels compared to individuals with negative α- synuclein seed amplification. nEV-derived α-synuclein levels were also significantly elevated in amyloid PET positive individuals with and without dementia (5.8% higher mean levels, P =8.50E-03) and clinical AD (9.3% higher mean levels, P =6.38E-12).
Conclusions and Relevance: Plasma α-synuclein levels from nEVs likely reflect underlying synuclein pathology in the brain and have potential as a blood-based biomarker for detecting Lewy body pathology in PD and in AD and related dementias. nEVs cross the blood-brain barrier and carry neuron-derived cargo directly into the bloodstream, thus providing a unique window into brain α-synuclein levels that is not accessible through conventional plasma biomarkers.

DOI: https://doi.org/10.64898/2026.08.03.26359636