bims-amyloi 2026-10-25 papers

bims-amyloi

Biomed News

on Amyloid

Issue of 2026–10–25
sixteen papers selected by
Alexander Röntgen, University of Cambridge

Investigating Structural Heterogeneities of Amyloid Aggregates with Spatially Resolved Infrared Spectroscopy.
Monitoring amyloid formation from natively folded proteins to amyloid fibrils by NMR spectroscopy.
Aβ17-22 Derived Hexapeptide Segment Inhibits Islet Amyloid Polypeptide (IAPP) Aggregation and Attenuates Cytotoxicity.
The morphology of α-synuclein fibrils changes during formation, storage, and upon exposure to ligands.
Aβ-42 Side Chain Deamidation at Q15 or N27 Modulates Protein Aggregation and Alters Microglial Cytokines and CD68.
Imaging nanoscopic co-assemblies of α-synuclein and Tau in human samples.
Binding without Docking: Small-Molecule Binding Paths on Disordered Proteins.
Heterogeneous amyloid β dimerization revealed by single-molecule FRET and MD simulation.
Residue-Resolved Mapping of Heterogeneous Structural Organization during Native-to-Amyloid Transition of an Amyloidogenic Protein.
De novo formation of familial Alzheimer's disease-relevant Aβ strains occurs exclusively in the human brain.
Influence of Temperature and Osmolytes on Conformational Dynamics of Alpha Synuclein.
Cryo-EM advances in TDP-43 amyloid fibrils structure determination.
Formation mechanism of mung bean protein amyloid fibril hydrogels via acidic heating.
Impact of Lipid Composition and Synergistic Effect on Aβ42 Oligomer-Induced Changes in Membrane Conductance and Microviscosity.
NMR characterization of Tacrine in aqueous solution and insights into its interaction with amyloid-β1-40 aggregates revealed by STD.
Discovery of a BBB-Penetrant Lanosterol Derivative as an Aβ Aggregation Inhibitor for Alzheimer's Disease.

Acc Chem Res. 2026 Oct 20. 59(20): 3294-3307

Investigating Structural Heterogeneities of Amyloid Aggregates with Spatially Resolved Infrared Spectroscopy.

Divya Baghel, Ayanjeet Ghosh.

The aggregation of proteins into fibrillar amyloids is central to the pathology of neurodegenerative disorders. However, the relationship between the structure of amyloid aggregates and disease progression remains incompletely understood, in part because amyloid systems are intrinsically heterogeneous: structurally distinct species coexist at every stage of aggregation, and conventional ensemble-averaged methods cannot always resolve them. This Account describes how infrared spectroscopy can be coupled to different imaging modalities to resolve this heterogeneity at multiple length scales: from single-aggregate level to amyloid species in diseased brain tissues. Our findings demonstrate that (i) early stage tau fibrils exhibit pronounced structural polymorphism without morphological differences, converging to a single dominant conformation upon maturation that unexpectedly includes antiparallel β-sheet structure; (ii) Aβ42 oligomeric heterogeneity propagates through protofibrils into fibrils, where structurally distinct domains coexist along a single fibril, demonstrating that amyloid fibrils can deviate significantly from the canonical parallel cross-β architecture; (iii) Aβ(16-22) fibrils undergo a parallel-to-antiparallel β-sheet transition during maturation through disordered intermediates without morphological change, providing direct evidence of spontaneous structural reorganization in fibrillar species. Beyond single-protein systems, (iv) Aβ42 forms structurally distinct mixed polymorphs when aggregated with sequentially or structurally heterotypic seeds and when coaggregated with α-synuclein, establishing heterotypic interactions as an underappreciated source of aberrant aggregate structures; (v) coaggregation of Aβ with the islet amyloid polypeptide (IAPP) from the monomeric state produces a unique heterotypic polymorph in which both peptides adopt non-native structures, whereas cross-seeding with preformed IAPP fibrils yields predominantly homotypic Aβ aggregates, demonstrating that conformational flexibility at the monomeric stage is required for heterotypic fibril formation. These molecular-level findings are complemented by tissue-scale evidence: (vi) discrete frequency IR imaging reveals that amyloid plaques in AD brain exhibit chemical and structural heterogeneities not reflected in morphology, consistent with in vitro observations; and (vii) optical photothermal infrared (O-PTIR) spectroscopic imaging of vascular amyloid deposits in cerebral amyloid angiopathy (CAA) reveals a disease-stage-dependent increase in antiparallel β-sheet content that correlates specifically with colocalized lipids, recapitulated in vitro by coaggregating Aβ40 with lipid extracts. Collectively, these findings support the view that structural heterogeneity is not merely an artifact of in vitro conditions but a property that can persist in human brain tissues and illustrate how spatially resolved IR spectroscopy can complement cryogenic electron microscopy (cryo-EM) and solid-state NMR in the study of amyloid pathology.

DOI: https://doi.org/10.1021/acs.accounts.6c00390
Biophys Chem. 2026 Oct 15. pii: S0301-4622(26)00156-0. [Epub ahead of print]340 107723

Monitoring amyloid formation from natively folded proteins to amyloid fibrils by NMR spectroscopy.

Jyoti Singh, Tejaswini Pradhan.

  Amyloids are insoluble protein aggregates that arise through protein misfolding and are associated with numerous neurodegenerative disorders, systemic amyloidosis, and other human diseases. Nuclear magnetic resonance (NMR) spectroscopy, encompassing both solution-state and solid-state approaches, offers unique capabilities to investigate each stage of the complex amyloid formation pathway, from soluble monomeric precursors through transient intermediate states and oligomeric assemblies to highly ordered mature fibrils. This residue-specific and atomic-level characterization of the aggregation process is difficult to achieve using other biophysical techniques. NMR is particularly well suited for elucidating the mechanisms of amyloid formation because it provides detailed structural and dynamic information across multiple aggregation states at molecular resolution. This review highlights the application of solution-state and solid-state NMR methods in characterizing the conversion of natively folded amyloidogenic proteins into amyloid fibrils, with particular emphasis on the identification and characterization of transient intermediates, including both observable and "invisible" species, high-molecular-weight oligomers, and insoluble fibrillar aggregates. Representative examples of natively folded amyloidogenic precursor proteins are discussed, together with an overview of the NMR method used to elucidate their misfolding and aggregation mechanisms. Collectively, these studies demonstrate the power of NMR spectroscopy in providing mechanistic and structural insights into amyloid formation at residue-level resolution.

Keywords:  Aggregation; Amyloid fibrils; Intermediate states; NMR spectroscopy; Oligomers; Transient state

DOI:  https://doi.org/10.1016/j.bpc.2026.107723
Biochemistry. 2026 Oct 20. 65(20): 3226-3235

Aβ17-22 Derived Hexapeptide Segment Inhibits Islet Amyloid Polypeptide (IAPP) Aggregation and Attenuates Cytotoxicity.

Subhadip Jana, Sk Rajibul Haque, Loganathan Palanikumar, Gabriel D Verley, Rudra Shankar Das, Sagarika Patra, Mazin Magzoub, Debabrata Maity.

Misfolding and aggregation of islet amyloid polypeptide (IAPP) are associated with the decline of β-cells in type 2 diabetes (T2D). Design of short peptide-based inhibitors of β-sheet-rich amyloid plaque formation is challenging due to the dynamic nature of the amyloid species. The key sequences involved in cross-amyloid interactions shed light on the design of peptide-based inhibitors. Amyloid-β peptide (Aβ) has nearly 50% similarity and 25% identity with IAPP sequences, and their cross-interactions have been suggested to link T2D pathogenesis with Alzheimer's disease (AD). Here, we show that a short anionic amphiphilic hexapeptide (DM-P02) containing the Aβ domain (Leu17-Glu22) effectively suppresses aggregation and oligomerization of IAPP by predominantly interacting with its cationic N-terminus. DM-P02 also binds strongly to IAPP in pancreatic β-cell lines, as confirmed by confocal imaging, and protects them from IAPP aggregation-associated cytotoxicity. Our study underlines the therapeutic potential of short peptides for developing anti-amyloid agents.

DOI: https://doi.org/10.1021/acs.biochem.6c00469
Org Biomol Chem. 2026 Oct 19.

The morphology of α-synuclein fibrils changes during formation, storage, and upon exposure to ligands.

Timothy S Chisholm.

Protein fibrils are pathological hallmarks of many neurodegenerative diseases, including Parkinson's disease. The preparation of α-synuclein (αSyn) fibrils in vitro is widely used in research relating to these conditions. However, αSyn fibrils exhibit substantial structural polymorphism. How fibril morphology evolves during formation, storage, or in the presence of small molecule ligands is poorly understood. Here, the evolution of αSyn fibril morphology was investigated using fluorescence assays, circular dichroism, transmission electron microscopy, and ligand profiling. Fibril morphology was found to evolve continuously during both aggregation of αSyn and subsequent storage, even at -79 °C. The inclusion of ligands, such as Thioflavin X, during aggregation affected both the reaction kinetics and the fibril morphologies formed. The addition of ligands to pre-formed fibrils also produced changes in fibril morphology. As different fibril morphologies exhibit distinct properties, more careful characterization and controls are required to ensure reproducibility and reliable interpretation of results. Additionally, these findings suggest the potential to use ligands to remodel fibril structure, possibly allowing for pathological morphologies to be converted to less pathological forms.

DOI: https://doi.org/10.1039/d6ob00760k
ACS Chem Neurosci. 2026 Oct 21. 17(20): 3421-3430

Aβ-42 Side Chain Deamidation at Q15 or N27 Modulates Protein Aggregation and Alters Microglial Cytokines and CD68.

Martin N Griffin, Daniel M Dinakarapandian, Chenxing Li, Pranay Ramaswamy, Sia J Saheba, Janie Lee, Tarunya Rao Sudarshan, Maria Sajimon, Christopher J Wheeler, Jevgenij A Raskatov, Anant K Paravastu, Levi B Wood.

  The progressive aggregation of amyloid beta (Aβ) monomers into oligomers is a critical factor in Alzheimer's disease (AD) pathogenesis. Although mutated forms of Aβ have been shown to display altered aggregation dynamics, the specific effects of deamidated Aβ on microglial function remain understudied. Our research group previously found that the deamidated variant Aβ-42-N27D modified Aβ aggregation, reduced neurotoxicity, and reduced microglial reactivity, but the impact of Aβ-42 side chain deamidation in general on such parameters remained unclear. Here, we expanded on our prior work by investigating how two site-specific Aβ-42 mutations (Q15E & N27D), where neutral amide side chains are replaced with negatively charged carboxylic acids, affect aggregation and microglial immune response using a mouse microglial cell line. Size exclusion chromatography, Thioflavin T fluorescence, circular dichroism, and dynamic light scattering revealed that Aβ-42-Q15E and Aβ-42-N27D exhibit reduced aggregation compared to Aβ-42 wild type (WT). Multiplexed analysis of 8 microglial cytokines secreted into the culture medium revealed that Aβ-42-Q15E and Aβ-42-N27D decrease the expression of inflammatory cytokines such as IL-6, IP-10, and MIP-1α relative to Aβ-42-WT. Immunocytochemistry revealed that Aβ-42-Q15E and Aβ-42-N27D decrease CD68 expression and intracellular Aβ labeling relative to Aβ-42-WT. These findings demonstrate that deamidation significantly alters Aβ-42 aggregation and microglial activation, suggesting structural modifications to Aβ-42 modulate inflammatory signaling in AD. This work provides a foundation for future studies on Aβ-42 post-translational modifications as potential therapeutic targets in AD.

Keywords:  Alzheimer’s disease; aggregation; amyloid beta; cytokines; inflammation; protein deamidation

DOI:  https://doi.org/10.1021/acschemneuro.6c00024
Nat Commun. 2026 09 18. pii: 10951. [Epub ahead of print]17(1):

Imaging nanoscopic co-assemblies of α-synuclein and Tau in human samples.

Yu P Zhang, Amber Wallis, Clara Obensa Bertroli, Cherida Zhang, Melanie Burke, Florence Layburn, Evgeniia Lobanova, Martin Furlepa, Shekhar Kedia, Yuhao Cui, Prasanna Suresh, Woo Suk Yang, Annelies Quaegebeur, Tim Bartels, Caroline H Williams-Gray, David Klenerman.

α-synuclein (αS), amyloid-β (Aβ), and Tau aggregates are hallmarks of many neurodegenerative diseases, yet the prevalence and nature of their nanoscopic co-assemblies remain poorly understood. Here, we adapt a single-molecule pull-down (SiMPull) assay to profile αS, Aβ, and Tau co-assemblies across post-mortem brain tissue homogenates, soluble brain fractions, human serum, cerebrospinal fluid, and saliva. We show that αS-Tau co-assemblies are abundant across all sample matrices, accounting for ~10-70% of total αS aggregates in both Parkinson's disease (PD) and control samples. Notably, αS-Tau co-assemblies in soluble brain fractions from controls exhibit higher Proteinase K (PK) resistance than those from PD cases. Biophysically, Tau accelerates αS aggregation in simple in vitro systems, but this effect is suppressed in complex environments. Together, this work establishes a framework for probing co-assemblies, revealing that αS-Tau species possess heterogeneous biophysical features and are unlikely to act as a single, uniformly toxic species in PD pathology.

DOI: https://doi.org/10.1038/s41467-026-77728-1
J Am Chem Soc. 2026 Oct 14. 148(40): 42969-42980

Binding without Docking: Small-Molecule Binding Paths on Disordered Proteins.

Adelie Louet, Gerhard Hummer, Michele Vendruscolo.

Disordered proteins are challenging targets for drug design because they lack well-defined binding pockets. Small molecules can bind them, but when the bound state remains conformationally heterogeneous, these interactions are not readily characterized in terms of conventional binding pockets. Here, we use the concept of binding paths to describe how small molecules interact with disordered proteins. A binding path is a stochastic sequence of transient residue clusters that a ligand engages as it diffuses across a disordered protein, with each cluster forming and breaking up on time scales comparable to the overall residence time. We formalize this approach using a Markov state model (MSM), in which each state corresponds to a set of residues simultaneously contacting the ligand and the transition probabilities capture how the ligand moves between these sets. We apply this framework to the interactions of 10074-G5 with Aβ42 and of fasudil with α-synuclein, two disordered proteins associated with Alzheimer's disease and Parkinson's disease, respectively. The MSM enables both a dynamic mapping of transient binding sites and a calculation of dissociation constants consistent with experimental measurements. By generalizing the concept of static binding pockets to dynamic binding paths, this approach provides a quantitative framework for characterizing small-molecule binding by disordered proteins and for identifying druggable regions on these challenging targets.

DOI: https://doi.org/10.1021/jacs.6c05891
Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2618695123

Heterogeneous amyloid β dimerization revealed by single-molecule FRET and MD simulation.

Fanjie Meng, George A Pantelopulos, Jae-Yeol Kim, Robert B Best, Hoi Sung Chung.

  The correlation between specific amyloid fibril polymorphs and diseases suggests that characterization of heterogeneity in the aggregation process is key to understanding disease mechanisms. In this work, we use single-molecule Förster resonance energy transfer (FRET) spectroscopy and molecular dynamics (MD) simulation to quantitatively characterize dimerization of amyloid β (Aβ), the first step of the aggregation process. We find that dimerization is extremely rare, with a high dissociation constant of >16 mM, yet there are multiple dimer states with distinct FRET efficiencies and stabilities, many of which survive for milliseconds to seconds. The dimer population increases with the increasing ionic strength and decreasing pH, indicating the importance of nonspecific electrostatic interactions in dimer formation. MD simulations with enhanced sampling demonstrate the formation of diverse bound states having a range of FRET efficiencies and flexible N termini, compatible with the experimental observations. There are conformational clusters represented by the formation of three mixed parallel/antiparallel β strands forming Greek key-like motifs and the formation of antiparallel β strands, which may be representative of dimers with longer and shorter lifetimes, respectively, observed in the FRET experiment. This structural and kinetic heterogeneity, resulting from transient interactions, reflects the rugged energy landscape of amyloid formation and may be related to the great diversity of fibrils ultimately formed in the aggregation process.

Keywords:  aggregation; amyloid fibril; polymorphism

DOI:  https://doi.org/10.1073/pnas.2618695123
Biochemistry. 2026 Oct 06. 65(19): 3003-3016

Residue-Resolved Mapping of Heterogeneous Structural Organization during Native-to-Amyloid Transition of an Amyloidogenic Protein.

Sonal R More, Prajna Mishra, Santosh Kumar Jha.

Protein misfolding and aggregation in neuronal cells are key molecular events underlying several fatal neurodegenerative disorders. Effective therapeutic intervention requires residue-resolved structural information on the early aggregation intermediates that precede amyloid formation. However, these transient and heterogeneous species remain poorly characterized because of their dynamic nature and the limitations of conventional structural approaches. Here, we employ a multisite fluorescence approach to obtain residue-specific insights into the misfolding and aggregation pathway of the nucleic acid-binding domain of TDP-43. Using a library of single-tryptophan-single-cysteine mutants combined with site-selective labeling, we systematically probe intramolecular distances, local solvation, conformational rigidity, and structural fluctuations across native, molten globule, oligomeric, and amyloid states. The results reveal that the early amyloidogenic molten globule retains native-like secondary structure but undergoes heterogeneous structural reorganization, including simultaneous local expansion and compaction, as revealed by multisite Förster resonance energy transfer. Residue-specific analyses also identify early unfolding sites and regions that progressively become incorporated into the amyloid core. These findings provide a residue-resolved view of the structural transitions that link native conformations to aggregation-prone states and establish a framework for understanding early events in TDP-43 misfolding.

DOI: https://doi.org/10.1021/acs.biochem.6c00438
Acta Neuropathol Commun. 2026 Jul 24. pii: 218. [Epub ahead of print]14(1):

De novo formation of familial Alzheimer's disease-relevant Aβ strains occurs exclusively in the human brain.

Alison Mao, Alejandro Ruiz-Riquelme, Marim M Barghash, Nicholas R G Silver, Heather H C Lau, Erica Stuart, Silvia Zampar, Dag Sehlin, Stina Syvänen, Michael S Pollanen, K Peter R Nilsson, Caroline Graff, Martin Ingelsson, Joel C Watts.

  In familial Alzheimer's disease (FAD), mutations in the amyloid precursor protein gene (APP) accelerate the aggregation of Aβ peptide, leading to deposition of amyloid plaques within the brain. Conformational variants of Aβ aggregates ("Aβ strains") possess distinct pathological properties and may contribute to disease heterogeneity. While the Swedish APP mutation produces wild-type (WT) Aβ, the Arctic APP mutation generates E22G-mutant Aβ. To clarify whether different FAD mutations are sufficient to specify the formation of distinct Aβ strains, we performed Aβ seeding studies in AppNL-F knock-in mice. Aβ aggregates purified from Swedish and Arctic FAD human brains induced distinct neuropathological signatures, characterized by differences in the morphology and localization of the seeded Aβ deposits, which were preserved upon serial passage. Neither synthetic E22G-mutant Aβ aggregates nor Aβ aggregates isolated from the brains of transgenic mice producing E22G-mutant Aβ recapitulated the phenotype induced by Arctic FAD brain-derived Aβ aggregates upon injection into AppNL-F mice. Similarly, neither synthetic WT Aβ aggregates nor Aβ aggregates from Swedish APP-mutant transgenic mice reproduced the seeding behavior of Swedish FAD brain-derived Aβ aggregates. This suggests that it is the structure of Aβ aggregates rather than the Aβ sequence that dictates seeding activity. We conclude that de novo formation of FAD-relevant Aβ strains occurs exclusively in the human brain, implying the existence of human brain-specific cofactors that modulate Aβ aggregate structure and seeding activity.

Keywords:  Alzheimer’s disease; Amyloid; Knock-in mice; Protein aggregation; Seeding; Strain

DOI:  https://doi.org/10.1186/s40478-026-02390-z
J Phys Chem B. 2026 Oct 22. 130(42): 11122-11131

Influence of Temperature and Osmolytes on Conformational Dynamics of Alpha Synuclein.

Jared Hampton, Cameron Lynch, Robert L Rider, Carter Lantz, Zhenyu Xi, David H Russell.

Alpha-synuclein (α-syn) is an intrinsically disordered protein (IDP) associated with amyloid formation in neurodegenerative diseases, including Parkinson's, dementia with Lewy bodies, and multiple system atrophy. Disease progression is linked to the transition of α-syn from native to misfolded conformations, although the mechanisms underlying this process remain unclear. An effective method for investigating protein dynamics is native mass spectrometry, specifically when coupled with ion mobility-mass spectrometry (IM-MS) to examine differences in the shape and size of various analytes. In this study, variable-temperature electrospray ionization ion mobility-mass spectrometry (vT-ESI-IM-MS) was used to investigate the conformational dynamics of wild-type and A30P α-syn in the presence and absence of five osmolytes trimethylamine-N-oxide (TMAO), urea, guanidine, 1-dodecylguanidine (dodine), and arginine. For both α-syn variants, the abundance of extended conformers increased with temperature in the absence of osmolytes, consistent with temperature-dependent conformational shifts. This study shows osmolytes significantly alter conformational distributions and temperature-dependent responses, with dodine promoting extended conformations and guanidine producing the lowest abundance of extended states. These results demonstrate the utility of vT-ESI-IM-MS for probing IDP dynamics and highlight the influence of osmolytes on IDP conformational behavior.

DOI: https://doi.org/10.1021/acs.jpcb.6c04859
Neurobiol Dis. 2026 Oct 17. pii: S0969-9961(26)00405-5. [Epub ahead of print] 107659

Cryo-EM advances in TDP-43 amyloid fibrils structure determination.

Zhengdong Xu, Xi Chen, Wenjuan Yi.

  TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein whose pathological aggregation characterizes a spectrum of neurodegenerative disorders known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and chronic traumatic encephalopathy (CTE). Recent breakthroughs in cryo-electron microscopy (cryo-EM) have revolutionized our understanding of these diseases by resolving the atomic structures of TDP-43 amyloid fibrils. These structural insights have been pivotal in elucidating the transition from functional liquid-liquid phase separation (LLPS) to irreversible solid-state aggregation. This review synthesizes key cryo-EM findings from 2019 to 2026, encompassing fibrils formed by the full-length low-complexity domain, disease-relevant core fragments, and filaments extracted directly from patient tissues, as well as the pathological implications of distinct structural polymorphs. These findings not only deepen our understanding of the brain science aspects of the pathogenesis of TDP-43 proteinopathies, but also provide an important structural basis for the development of specific conformational diagnostic methods and targeted therapeutic drugs.

Keywords:  Amyloid; Brain science; Cryo-EM; TDP-43; TDP-43 proteinopathies

DOI:  https://doi.org/10.1016/j.nbd.2026.107659
Food Res Int. 2026 Dec 01. pii: S0963-9969(26)02429-4. [Epub ahead of print]245(Pt 2): 120742

Formation mechanism of mung bean protein amyloid fibril hydrogels via acidic heating.

Shanshan Wu, Vijaya Raghavan, Quancai Sun, Yue Wang, Jin Wang.

  Food amyloid fibrils are innovative nano-biomaterials with high aspect ratios, stable β-sheet structures, and multifunctionality. Mung bean protein is a promising plant protein source for amyloid fibril production owing to its availability and environmental sustainability. Despite recent advances, the effects of protein concentration on the fibrillation process, fibril structural evolution, and gelation behavior of mung bean protein under acidic heating conditions have not been systematically investigated. This work revealed that soft hydrogels could be fabricated through a one-step acidic heating process of mung bean protein solution (2-6%, w/v), and higher protein concentrations accelerated in-situ hydrogel formation and improved their rheological properties. Atomic force microscopy (AFM) analysis showed that high protein concentrations (3-6%) promoted the formation of short, worm-like fibrils, whereas a low concentration (2%) predominantly yielded long, straight fibrils with greater height, contour length, and persistence length. The sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), thioflavin T (ThT) fluorescence analysis, and circular dichroism (CD) spectroscopy demonstrated that the protein concentration affected fibril growth via modulating hydrolysis, self-assembly, and secondary structure. In addition, the enhanced gel matrix was associated with fibril morphology and higher amyloid structure content at elevated protein concentrations. This work offered valuable insights into the formation mechanism of the multi-scale structure of mung bean protein amyloid fibrils and the assembled hydrogels, highlighting their potential as advanced soft biomaterials for applications in the food industry.

Keywords:  Amyloid fibril; Hydrogel; Multi-scale structure; Mung bean protein; Protein concentration; Rheological properties

DOI:  https://doi.org/10.1016/j.foodres.2026.120742
ACS Chem Neurosci. 2026 Sep 16. 17(18): 3306-3317

Impact of Lipid Composition and Synergistic Effect on Aβ42 Oligomer-Induced Changes in Membrane Conductance and Microviscosity.

Evelina Jankaitytė, Artu̅ras Polita, Andrius Sakalauskas, Rimgailė Tamulytė, Vytautas Smirnovas, Rima Budvytyte.

  The accumulation of the Aβ42 peptide is one of the key factors in the progression of Alzheimer's disease, as it disrupts synaptic signaling and impairs neuronal function. Although the peptide is known to compromise plasma membrane integrity, the detailed mechanisms underlying bilayer alterations and lipid-Aβ42 interactions remain unclear. In the present study, electrochemical impedance spectroscopy and fluorescence lifetime imaging microscopy were employed to investigate the impact of oligomeric Aβ42 on model membranes that mimic the lipid composition of the outer leaflet of the neuronal plasma membrane. Our results demonstrate that the presence of SM or GM1 within a DOPC/Chol backbone is enough to facilitate Aβ42 interaction with the membrane, as evidenced by increased membrane microviscosity; however, this interaction alone is insufficient to induce permeability-enhancing defects in the membrane. Extensive disruption of bilayer integrity required the complete lipid ensemble present in the outer leaflet of the neuronal membrane-mimicking composition, indicating that not only specific lipids but also their cooperative interplay and organization within the lipid bilayer are essential for Aβ42-induced membrane permeabilization.

Keywords:  Aβ42; aggregation; lipid membranes; membrane damage; microviscosity; permeability; β-amyloid

DOI:  https://doi.org/10.1021/acschemneuro.6c00244
Biophys Chem. 2026 Oct 13. pii: S0301-4622(26)00155-9. [Epub ahead of print]340 107722

NMR characterization of Tacrine in aqueous solution and insights into its interaction with amyloid-β1-40 aggregates revealed by STD.

Matheus Yoshimitsu Tatsuta Nakamae, Paula S Rivero-Jerez, Anna Paola Butera, Fernando Macedo.

  The deposition of β-amyloid peptide (Aβ) aggregates in the brain is widely accepted as one of the major factors driving the development of Alzheimer's disease (AD). Tacrine (9-amino-1,2,3,4-tetrahydroacridine) is one of the most potent acetylcholinesterase inhibitors approved for the symptomatic treatment of AD, but its clinical use was discontinued due to hepatotoxicity. Recent studies have reported that tacrine can interact with Aβ and inhibit its aggregation, although the underlying mechanism is not yet fully elucidated, highlighting the need for detailed spectroscopic characterization under physiologically relevant conditions. Here, we report, to the best of our knowledge, the first complete and unambiguous assignment of the 1H and 13C NMR resonances of tacrine in aqueous solution at near-physiological pH using a combination of ROESY, HSQC, and HMBC experiments. pH-dependent 1HNMR studies revealed that aromatic proton resonances are highly sensitive to protonation state, displaying pronounced but fully reversible chemical-shift variations. The resulting spectral map provides a reliable basis for ligand-observed NMR investigations of tacrine and related compounds in aqueous media. Moreover, saturation transfer difference (STD)-NMR experiments were optimized to investigate the interaction of tacrine with soluble Aβ1-40 aggregates. Under the optimized conditions, clear STD effects were observed exclusively in the presence of Aβ1-40, confirming direct ligand-aggregate interaction. Differential saturation transfer among aromatic protons, particularly for H-7, suggests distinct proximity relationships within the tacrine- Aβ1-40 complex. Together, these results establish a robust spectroscopic and methodological framework for future NMR studies of tacrine-based ligands and their interactions with amyloid assemblies.

Keywords:  (1)H; (13)C; Alzheimer's disease; Aβ(1–40) peptide (1–40); NMR; STD-NMR; Tacrine

DOI:  https://doi.org/10.1016/j.bpc.2026.107722
J Med Chem. 2026 Oct 22. 69(20): 24682-24705

Discovery of a BBB-Penetrant Lanosterol Derivative as an Aβ Aggregation Inhibitor for Alzheimer's Disease.

Baichen Xiong, Tengfei Zhen, Xinhai Wang, Weiting Zhang, Zhiqiang Wang, Mingkang Ma, Xiaoxue Bai, Jiawei Zhu, Na Zheng, Yuqing Wei, Mengxiao Chen, Pengkun Sun, Bingbing Lv, Chenyu Zhang, Ziyu Cao, Yuanyuan Wang, Xianshu Bai, Wenyuan Liu, Chaojun Wang, Yue Wu, Yao Chen, Haopeng Sun.

  The abnormal aggregation of amyloid-beta (Aβ) peptides is a core driver of Alzheimer's disease (AD). Developing central nervous system (CNS)-penetrant small-molecule Aβ inhibitors offers a complementary strategy to overcome the high costs and severe side effects of antibodies. Lanosterol has demonstrated excellent potential in inhibiting abnormal protein aggregation. However, poor physicochemical and pharmacokinetic profiles strictly hinder its direct therapeutic application. Herein, rational modifications on lanosterol were conducted to modulate the hydrophilic-lipophilic balance around the 3-hydroxyl group and aliphatic side chain. This systematic screening led to compound 10, a highly active candidate with significantly improved metabolic stability and physicochemical properties. Furthermore, oral administration of 10 rescued cognitive memory deficits and reduced the Aβ burden in the AD mouse model. This work provides a promising, CNS-active candidate for AD intervention, demonstrating that rational structural optimization of bioactive substances is a valuable strategy in the discovery of novel therapeutics for CNS diseases.

Keywords:  Alzheimer’s disease; CNS drug-like properties; lanosterol derivative; Aβ aggregation inhibitor

DOI:  https://doi.org/10.1021/acs.jmedchem.6c02238