bims-amyloi Biomed News
on Amyloid
Issue of 2026–11–01
fourteen papers selected by
Alexander Röntgen, University of Cambridge
  1. Real-Time Single Molecule Imaging Reveals Pathway-Selective Action of Aducanumab on Amyloid-β Aggregation.
  2. α-Halogenated Curcumins Enhance the Binding Affinity and Induced Structural Alterations to Amyloid-β Protein in Alzheimer's Disease.
  3. Electrostatic Regulation of Alpha-Synuclein Membrane Binding Couples Conformational Release to Aggregation Kinetics.
  4. Glycosaminoglycans Recruit IAPP Oligomers on Lipid Bilayers.
  5. Polymorphism of amyloid fibrils of a SARS-CoV-2 peptide associated with hemagglutination.
  6. Differential Effects of α-Synuclein Monomers and Seeds on the Material Properties of Tau Condensates.
  7. Leveraging the Gut Microbiota for Mechanistically Informed Therapeutics against Body-First Parkinson's Disease.
  8. Phenylalanine Fibrils Seed Native Lysozyme to Form Membrane-Active Pathological Complexes at Physiological Conditions.
  9. The pathological roles of intrinsically disordered proteins in lysosomal acidification dysfunction in neurodegenerative diseases.
  10. Large-Scale Mutagenesis Identifies Sequence Changes That Bias Tau Toward CTE-like Aggregation.
  11. Protein glycosylation and glycation in Alzheimer's disease: mechanisms, crosstalk, and therapeutic perspectives.
  12. Deep Eutectic Solvents Improve Protective Effects of Quercetin against Cytotoxic Amyloid Fibrillation of α-Synuclein.
  13. Gut-Derived α-Synuclein Condensates in Parkinson's Disease: Linking Liquid-Liquid Phase Separation, Blood Dissemination, and Chemical Biology.
  14. Tandem Tau and α-Synuclein Seed Amplification Assays Reveal α-Synuclein Copathology Potentiates Tau Seeding in Alzheimer's Disease.
  1. Nano Lett. 2026 Oct 28. 26(42): 14560-14568
    Real-Time Single Molecule Imaging Reveals Pathway-Selective Action of Aducanumab on Amyloid-β Aggregation.
    Takahiro Watanabe-Nakayama, Moeko Noguchi-Shinohara, Kenichi Umeda, Daiki Muramatsu, Hiroki Konno, Noriyuki Kodera, Toshio Ando, Kenjiro Ono.
      Aducanumab is an anti-amyloid-β (Aβ) antibody that binds aggregated Aβ species and has been reported to inhibit secondary nucleation on fibril surfaces. However, how antibody binding influences aggregate dynamics at the molecular level remains incompletely understood. Here, we used high-speed atomic force microscopy (HS-AFM) to directly visualize the interactions between aducanumab and Aβ42 aggregates in real time at single-molecule resolution. Aducanumab extensively decorated oligomers, protofibrils, and fibrils, with fibril binding depending on local surface structure. Consistent with its reported inhibition of secondary nucleation, bulk thioflavin T assays showed slowed aggregation. Nevertheless, in the continued presence of the antibody, protofibril formation proceeded─a pathway distinct from secondary nucleation. These observations reveal a pathway-selective mode of action: extensive surface binding and the suppression of secondary nucleation do not extend to protofibril formation, which proceeds in the continued presence of the antibody.
    Keywords:  Aducanumab; Alzheimer’s disease; amyloid; high-speed atomic force microscopy; humanized monoclonal antibodies; single molecule imaging
    DOI:  https://doi.org/10.1021/acs.nanolett.6c02842
  2. Int J Mol Sci. 2026 Oct 21. pii: 9355. [Epub ahead of print]27(20):
    α-Halogenated Curcumins Enhance the Binding Affinity and Induced Structural Alterations to Amyloid-β Protein in Alzheimer's Disease.
    Mateen A Khan, Raja Chinnappan, Sowmya Andole, Mohd Akif, Tanveer Ahmad Mir, Ahmed Yaqinuddin, Phuong-T T Pham, Mamoun M Bader.
      Amyloid-β (Aβ) aggregation and associated structural changes are central features of Alzheimer's disease (AD) pathology. In this study, we investigated the binding of α-halogenated curcumins, α-bromocurcumin and α-chlorocurcumin, to Aβ1-42 and examined their effects on the peptide secondary structure using fluorescence spectroscopy and circular dichroism (CD). Both α-halogenated curcumins interacted with Aβ1-42, but their binding properties differed from those of the parent curcumin. α-Chlorocurcumin exhibited a higher binding affinity for Aβ1-42 than curcumin, whereas α-bromocurcumin showed comparatively weaker binding. Temperature-dependent binding studies revealed that the association of α-halogenated curcumins with Aβ1-42 was influenced by temperature, with reduced binding affinity at higher temperatures. Thermodynamic analysis demonstrated favorable free-energy changes for the interactions and revealed that α-halogenation altered the relative enthalpic and entropic contributions to Aβ1-42 binding. CD analysis further showed that binding of the curcumin altered the secondary structure of Aβ1-42. These structural changes were more pronounced in the presence of the α-halogenated derivatives, indicating that halogen substitution influences the interaction and conformational response of Aβ1-42. Molecular docking analysis provided additional insight into the possible binding modes and predicted intermolecular contacts between the α-halogenated curcumin and Aβ1-42. Overall, the findings demonstrate that α-halogenation modulates the binding and structural effects of curcumin derivatives on Aβ1-42, with α-chlorocurcumin exhibiting particularly favorable binding characteristics. These findings provide a basis for further investigation of α-halogenated curcumins as potential modulators of Aβ-related molecular processes associated with AD.
    Keywords:  Alzheimer’s disease; amyloid-β; circular dichroism; fluorescence spectroscopy; molecular docking; α-halogenated curcumin
    DOI:  https://doi.org/10.3390/ijms27209355
  3. J Am Chem Soc. 2026 Sep 23. 148(37): 39591-39608
    Electrostatic Regulation of Alpha-Synuclein Membrane Binding Couples Conformational Release to Aggregation Kinetics.
    Mahdi Lavasani, Ping Lu, Shehani Siripala, Justin Medeiros, Carla Coackley, Scott D Ryan, Vlad Ladizhansky.
      Misfolding and aggregation of α-synuclein (α-syn) are central to Parkinson's disease (PD) pathology and are increasingly believed to be modulated by lipid-rich cellular environments. Electrostatic interactions between α-syn and anionic lipids play a key role in membrane binding and can significantly influence aggregation, yet the mechanisms by which physiologically relevant changes in membrane charge regulate the structure and dynamics of membrane-associated α-syn remain incompletely understood. Here, we investigate how membrane electrostatics reshape the conformational ensemble of membrane-bound α-syn using residue-resolved magic-angle spinning (MAS) NMR, Thioflavin T (ThT) aggregation assays, and transmission electron microscopy (TEM). Proteoliposomes made of 1,2-dioleoyl-sn-glycero-3-phosphate (DOPA) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) containing 40%, 35%, or 25% anionic lipid were used to systematically vary bilayer surface charge. MAS NMR measurements show a progressive, charge-dependent redistribution of the α-syn structural ensemble. At a high 40% membrane negative charge, α-syn adopts a primarily α-helical membrane-associated conformation, where the N-terminal region and the aggregation-prone non-amyloid-β component (NAC) domain stay bound to the bilayer, while the C-terminus remains flexible. As bilayer negative charge decreases to 35% and 25% anionic lipid, electrostatic interactions weaken, and the NAC-proximal segments increasingly detach from the membrane, leading to helix-to-coil transitions and greater solvent exposure of residues that have been shown to form the core of α-syn fibrils. ThT aggregation assays, coupled with TEM analysis, reveal that these charge-dependent conformational redistributions correlate with faster primary nucleation, differences in fibril morphology, and higher-order organization. Finally, super-resolution imaging in primary neurons shows that aggregated α-syn accumulates on phosphatidic acid (PA)-enriched mitochondria-derived vesicles, providing a cellular context for the electrostatic regime examined in the model membrane system. Together, our results identify a membrane charge density of 25-35% anionic lipid range as an electrostatic transition region in which the aggregation-prone NAC domain becomes solvent-exposed while the N-terminal anchor remains membrane-associated. These findings provide a residue-level framework for how membrane electrostatics shape the conformational landscape of membrane-bound α-syn and define aggregation-competent states in lipid environments.
    DOI:  https://doi.org/10.1021/jacs.6c08246
  4. J Phys Chem B. 2026 Oct 29. 130(43): 11452-11462
    Glycosaminoglycans Recruit IAPP Oligomers on Lipid Bilayers.
    Suhas Gotla, Meenal Jain, Silvina Matysiak.
      Glycosaminoglycans (GAGs) are anionic polysaccharides that coexist with cell membranes in the extracellular matrix and have been shown to cooperatively enhance the aggregation of islet amyloid polypeptide (IAPP) at zwitterionic lipid surfaces─a process implicated in β-cell death in type 2 diabetes. However, the molecular mechanisms by which GAGs and lipids concertedly promote IAPP aggregation remain poorly understood. Here, we develop a coarse-grained model for the GAG chondroitin-4-sulfate (CS) and employ molecular dynamics simulations to investigate the aggregation of the IAPP11-29 fragment in environments containing CS, a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer, or both. By comparing simultaneous and sequential assembly pathways, we show that the order of molecular encounters reshapes the aggregation landscape. CS drives rapid peptide consolidation at the bilayer surface through GAG-chain flexion and peptide crawling on the GAG chain, yielding ternary aggregates in which hydrophobic residues anchor into the bilayer, a globular peptide body extends above the membrane plane, while the CS chain forms a corona. CS further stabilizes helical intermediates through dipole-charge interactions, with helix half-lives four- to five-fold greater than in the bilayer-only system. When introduced to dispersed, bilayer-bound oligomers, CS recruits them into larger, more orientationally ordered aggregates that may serve as superior seeds for downstream fibrillation. Together, these results provide a molecular basis for the experimentally observed cooperative enhancement of IAPP aggregation by GAGs and zwitterionic lipids.
    DOI:  https://doi.org/10.1021/acs.jpcb.6c03348
  5. Nanoscale Adv. 2026 Oct 26.
    Polymorphism of amyloid fibrils of a SARS-CoV-2 peptide associated with hemagglutination.
    Manami Yamaguchi, Hidekazu Hiroaki, Emi Hibino.
      Long COVID, which develops following infection with SARS-CoV-2, includes numerous symptoms, and neurological disorders are particularly disruptive to daily life activities. Amyloid fibrils are often implicated in the pathogenesis of neurological disorders, and some fragment peptides derived from SARS-CoV-2, such as spike protein 192-211 (S192), have been reported to form amyloid fibrils. Organic solvents, such as 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and dimethyl sulfoxide (DMSO), are widely used to dissolve amyloidogenic peptides; however, they can influence the kinetics of aggregation of the peptide through their initial secondary structure. Therefore, determining how these different solvent environments affect S192 aggregation is important for understanding its structural characteristics. Here, we found that S192 peptide amyloid fibrils exhibit polymorphism under specific solvent conditions. The S192 peptide was dissolved in HFIP, diluted to a final concentration of 2% HFIP, and incubated to form amyloid fibrils with various morphologies. To clarify why the results differed between HFIP and DMSO, we analyzed the FTIR spectra of the S192 peptide dissolved in HFIP or DMSO, which indicated that the secondary structures were constituted differently. In addition, the lag-time for S192 dissolved in HFIP to form amyloids was significantly shorter than that in DMSO. These results are consistent with the hypothesis that rapid amyloid fibril formation may correlate with heterogeneous fibril morphology. Moreover, we examined hemagglutination to determine the functional significance of the polymorphism in the S192 amyloid fibrils. The results showed that amyloid fibrils formed from the S192 peptide dissolved in HFIP exhibited polymorphism and demonstrated higher hemagglutination activity than those in DMSO, which exhibited a single morphology.
    DOI:  https://doi.org/10.1039/d6na00438e
  6. J Am Chem Soc. 2026 Oct 07. 148(39): 41717-41723
    Differential Effects of α-Synuclein Monomers and Seeds on the Material Properties of Tau Condensates.
    Bineet Sharma, Jinying Wang, Priscilla Chinchilla Retana, Jean Baum, Zheng Shi.
      Tau and α-Synuclein (αSyn) frequently coaggregate in various neurodegenerative disorders. Recently, Tau has been shown to form dynamic, liquid-like condensates that can recruit αSyn, and potentially serve as a precursor to pathological crosstalk and aggregation. However, the quantitative impact of αSyn on the material properties of these condensates remains elusive. Here, we measure the viscosity and interfacial tension of Tau condensates and determine how these properties are modulated by αSyn monomers and fibril seeds. We find that while both forms of αSyn partition efficiently into Tau condensates, they exert vastly different effects on the condensate's material state. The viscosity of Tau condensates remains unchanged in the presence of αSyn monomers at concentrations up to 200 μM, accompanied by a moderate reduction in the condensates' interfacial tension. In contrast, adding just 5 μM αSyn fibril seeds triggers rapid maturation of Tau condensates, manifested by a nearly 100-fold increase in their steady-state viscosity within 1 h. These findings provide quantitative insights into condensate mechanics, highlighting the unique capacity of αSyn seeds to modulate Tau condensate viscosity, which may underlie the formation of pathological aggregates.
    DOI:  https://doi.org/10.1021/jacs.6c07726
  7. ACS Bio Med Chem Au. 2026 Oct 21. 6(5): 508-521
    Leveraging the Gut Microbiota for Mechanistically Informed Therapeutics against Body-First Parkinson's Disease.
    Julia M Balsamo, Elizabeth N Bess.
      Although some symptoms of Parkinson's disease can be pharmacologically alleviated, stopping disease progression is not currently possible. Motor impairment in Parkinson's disease is associated with accumulation of aggregates of the protein α-synuclein (α-syn) in dopaminergic neurons in the brain. In some Parkinson's disease cases, these pathogenic aggregates accumulate in the intestinal lining years before motor symptoms manifest. This long prodromal period provides a window of opportunity to detect Parkinson's disease and halt its progression. Specifically, elucidating the factors involved in disease onset in the gut would enable prevention of α-syn aggregation before it spreads to the brain. In this perspective, we highlight discoveries of gut bacteria that induce aggregation of intestinal α-syn as well as efforts to decipher the molecular-level mechanisms by which this process occurs. We also showcase the rationale and potential breadth of applications focused on manipulating the gut microbiome, including biotics, fecal microbiome transplants, and microbial editing. By understanding molecular mechanisms of intestinal α-syn aggregation, the microbiome may be harnessed to control the factors responsible for their pathogenic formation and spread. Such insights will ultimately enable the development of more effective therapeutics for prevention and treatment of Parkinson's disease.
    Keywords:  Parkinson’s disease; gut microbiome; microbial dysbiosis; microbiome-based therapeutics; α-synuclein
    DOI:  https://doi.org/10.1021/acsbiomedchemau.6c00110
  8. J Phys Chem B. 2026 Oct 29. 130(43): 11361-11368
    Phenylalanine Fibrils Seed Native Lysozyme to Form Membrane-Active Pathological Complexes at Physiological Conditions.
    Sourav Nandi, Shrabasti Mukherjee, Dipu Mondal, Ananya Barui, Rajib Kumar Mitra.
      Accumulation of metabolites at pathological concentrations can trigger nonclassical protein aggregation pathways that remain poorly understood. Here, we explore the molecular mechanism by which the metabolite phenylalanine (Phe), known to form amyloid-like fibrils in Phenylketonuria disease, induces a globular protein to form complex structures. We demonstrate that Phe fibrils act as molecular scaffolds to promote aggregation of a stable globular protein lysozyme (Lyz) under physiological conditions (pH 7.4, 37 °C), resulting in the formation of a heteronuclear Lyz-Phe complex. Spectroscopic and biophysical analyses reveal that π-π interactions between Trp residues of Lyz and the aromatic surface of Phe fibrils drive the initial association; additional hydrophobic interactions stabilize the complex. Unlike classical amyloidogenesis dominated by β-sheet enrichment in proteins, this heteronuclear complexation induces a substantial increment of random coil content in the protein's secondary structure with only a modest increase in the β-sheet content. The resulting complex strongly interacts with phospholipid bilayer membranes, compromises the membrane integrity, and exhibits significant cytotoxicity toward cultured mammalian fibroblast cells (L929). This study offers a hitherto unexplored alternative aggregation mechanism in which a metabolite imbalance, rather than intrinsic protein instability, converts a native globular protein into membrane-active, cytotoxic assemblies.
    DOI:  https://doi.org/10.1021/acs.jpcb.6c03957
  9. Transl Neurodegener. 2026 Oct 28. pii: 58. [Epub ahead of print]15(1):
    The pathological roles of intrinsically disordered proteins in lysosomal acidification dysfunction in neurodegenerative diseases.
    Kholoud Abd-ElRaouf, Dylan T Murphy, Lenny Yi Tong Cheong, Jialiu Zeng, Chih Hung Lo.
      Neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia (FTD), and Parkinson's disease (PD) are characterized by the accumulation of intrinsically disordered proteins (IDPs), including amyloid-β (Aβ), tau, and α-synuclein (αSyn). These proteins disrupt neuronal homeostasis through toxic aggregation, impaired proteostasis, and progressive neurodegeneration, in part via dysfunction of the autophagy-lysosomal pathway (ALP). A central feature of this impairment is defective vacuolar-type (H+)-ATPase (V-ATPase) function, leading to lysosomal deacidification and reduced degradative capacity. Pathological IDP species converge on V-ATPase through direct interactions with its subunits or by perturbing its assembly, while also exerting protein-specific effects, including lysosomal membrane destabilization, impaired hydrolase activity, and disrupted endolysosomal trafficking. These combined mechanisms create a reciprocal relationship between lysosomal dysfunction and IDP accumulation, in which impaired lysosomal degradation further promotes the persistence and aggregation of pathological IDP species. This review synthesizes current insights into the molecular interplay between IDPs and lysosomal acidification across AD, FTD, and PD, and highlights how these processes contribute to disease progression. We further discuss emerging therapeutic strategies aimed at restoring lysosomal function. These findings underscore lysosomal dysfunction as a common feature of IDP-driven neurodegeneration and a potential therapeutic target across these disorders.
    Keywords:  Autophagy; Intrinsically disordered proteins; Lysosomal acidification; Neuroinflammation and neurodegeneration; Protein degradation; Therapeutic strategies
    DOI:  https://doi.org/10.1186/s40035-026-00591-z
  10. bioRxiv. 2026 Oct 09. pii: 2026.10.08.757173. [Epub ahead of print]
    Large-Scale Mutagenesis Identifies Sequence Changes That Bias Tau Toward CTE-like Aggregation.
    Chad M Dashnaw, Simran Rastogi, Nabil Morgan, Isaam Memon, Klaudia Jaczynska, Binh An Nguyen, Lorena Saelices, Charles L White, Sarah Shahmoradian, Lukasz A Joachimiak.
      Tau amyloid fibrils adopt disease-specific structures across tauopathies, yet the sequence determinants that favor one pathological fold over another remain poorly defined. Here we combine computational saturation mutagenesis and energetic profiling, in vitro aggregation, cryo-EM and cellular seeding assays to identify sequence changes that alter tau fold compatibility. Across six tauopathy fibril structures, approximately 12,000 substitutions revealed that mutational sensitivity is concentrated within interaction networks formed by amyloidogenic motifs rather than uniformly distributed across the fibril core. Comparison of Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE) folds identified residues within the 335-363 region that differentially influence fold compatibility. The S341L/S352I double mutant accelerated aggregation and remodeled packing within the PAM4-containing amyloidogenic region, producing an alternative amyloid architecture in a minimal tau fragment. S341L/S352I biosensors preferentially responded to CTE-derived over Alzheimer's disease-derived seeds, while aggregates generated from recombinant S341L/S352I tau exhibited CTE-like cellular templating behavior. Although these assemblies are not established to reproduce the atomic CTE fold, the results demonstrate that targeted sequence changes can bias tau aggregation and propagation toward a CTE-compatible state. This framework provides a strategy for defining sequence-structure relationships in polymorphic amyloids and developing conformation-selective models and biosensors.
    DOI:  https://doi.org/10.64898/2026.10.08.757173
  11. Front Neurosci. 2026 ;20 1925934
    Protein glycosylation and glycation in Alzheimer's disease: mechanisms, crosstalk, and therapeutic perspectives.
    Yuqi Luo, Jingjing Gu.
      Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, pathologically characterized by extracellular senile plaques composed of amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau. Despite decades of research, the molecular mechanisms underlying AD pathogenesis remain incompletely understood, and effective disease-modifying therapies are still lacking. Protein glycosylation and glycation, two distinct post-translational modifications, have emerged as critical contributors to AD pathophysiology. Glycosylation, an enzymatically regulated process including N-linked glycosylation, O-GlcNAcylation, and O-GalNAc glycosylation, modulates the processing of amyloid precursor protein (APP), the aggregation propensity and hyperphosphorylation of tau, the function of apolipoprotein E (ApoE), and neuroinflammatory signaling. Aberrant glycosylation patterns have been consistently detected in the brain, cerebrospinal fluid (CSF), and plasma of AD patients, highlighting their potential as diagnostic biomarkers. In contrast, glycation is a non-enzymatic reaction between reducing sugars and proteins that generates advanced glycation end products (AGEs), which promote oxidative stress, neuroinflammation, blood-brain barrier (BBB) dysfunction, and Aβ and tau aggregation through interaction with the receptor for AGEs (RAGE). This review systematically summarizes recent advances in understanding the roles of glycosylation and glycation in AD pathogenesis, their crosstalk with classical hallmarks, and their translational value as biomarkers and therapeutic targets, providing novel perspectives for early diagnosis and multi-target intervention strategies for AD.
    Keywords:  Alzheimer's disease; advanced glycation end products (AGEs); amyloid-β; biomarkers; protein glycosylation; tau hyperphosphorylation
    DOI:  https://doi.org/10.3389/fnins.2026.1925934
  12. J Phys Chem B. 2026 Oct 29. 130(43): 11515-11528
    Deep Eutectic Solvents Improve Protective Effects of Quercetin against Cytotoxic Amyloid Fibrillation of α-Synuclein.
    Mahya Mohammad-Zaheri, Zahra Mousavi-Jarrahi, Somayeh Ahmadi, Foad Rezaeifar, Atiyeh Ghasemi, Mina Ghahremani, Fatemeh Mamashli, Ali Akbar Meratan, Ali Akbar Saboury.
      Natural polyphenols are among the most frequently investigated small molecules showing promising therapeutic effects against neurodegenerative diseases. However, drawbacks such as poor aqueous solubility and bioavailability have significantly restricted the biological applications of polyphenols, leading to research to overcome these limitations. Deep eutectic solvents (DESs) are a new class of green and biocompatible solvents with multiple applications, including their use to increase the aqueous solubility and bioavailability of natural polyphenols. This finding motivated us to investigate the effect of ethaline, a DES composed of choline chloride and ethylene glycol, on the capacity of quercetin in modulating the cytotoxic amyloid fibrillation of α-synuclein (α-syn). The results showed that dissolving quercetin in ethaline considerably increased the potential of quercetin to inhibit cytotoxic fibril formation of α-syn. We suggest that increasing the aqueous solubility of quercetin is likely the main mechanism contributing to the beneficial effects of ethaline. Thanks to its enhanced aqueous solubility, quercetin would interact more effectively with surrounding molecules, including α-syn monomers and reactive oxygen species. This increases not only the anti-amyloidogenic effects of quercetin, but can also improve its antioxidant activity, leading to more effective inhibition of α-syn fibrillation process as well as protecting cells against damage induced by α-syn aggregates. These findings may suggest that DESs could serve as new candidates to increase the therapeutic effects of polyphenols in relation to neurodegenerative diseases, including Parkinson's disease.
    DOI:  https://doi.org/10.1021/acs.jpcb.6c04016
  13. ChemMedChem. 2026 Oct 28. pii: e70545. [Epub ahead of print]21(20):
    Gut-Derived α-Synuclein Condensates in Parkinson's Disease: Linking Liquid-Liquid Phase Separation, Blood Dissemination, and Chemical Biology.
    Janci Arichandran, Shu-Huei Hsiao, Cheng-I Lee.
      Two advances have reshaped our understanding of α-synuclein (αSyn) in Parkinson's disease (PD). First, αSyn can assemble through liquid-liquid phase separation (LLPS) and related condensation pathways, forming condensates that mature into Lewy-body-like assemblies. Although conventional crowding-driven LLPS requires supraphysiological protein concentrations, membrane-templated surface condensation has been reported in vitro at ~10 nM, making this pathway plausible in the lipid-rich, electrically active enteric nervous system (ENS). Second, seeding-competent αSyn is detectable in blood before motor onset using seed-amplification assays. This review asks whether condensate-derived αSyn generated in the gut constitutes a blood-borne seed population that is systematically underrepresented by fibril-biased assays. We evaluate each step of the proposed pathway, including gut-specific LLPS triggers, release into and survival within the circulation, blood-brain barrier (BBB) traversal, and clinical detection, while distinguishing established evidence from indirect inference and testable hypotheses. Many of these questions are now experimentally accessible. Molecular rotors detect condensates through microviscosity rather than cross-β structure, condensate-stage modulators have emerged, and receptor-interception strategies such as bemcentinib provide opportunities for mechanistic interrogation. Together, these advances position chemical biology to determine whether condensate-derived seeds contribute to PD pathogenesis.
    Keywords:  blood–brain barrier; extracellular vesicles; gut–brain axis; hematogenous propagation; liquid–liquid phase separation; molecular rotors; α‐synuclein
    DOI:  https://doi.org/10.1002/cmdc.70545
  14. Res Sq. 2026 Sep 04. pii: rs.3.rs-10845149. [Epub ahead of print]
    Tandem Tau and α-Synuclein Seed Amplification Assays Reveal α-Synuclein Copathology Potentiates Tau Seeding in Alzheimer's Disease.
    Damian Gorski, Haley Evans, Michelle Pinho, Zaina Rehan, Matthew Perkins, Emile Pinarbasi, Jon Reader, Sami Barmada, Henry Paulson, Sandra Pritzkow, Claudio Soto.
      Accumulating evidence highlights the frequent co-occurrence of tau and α-synuclein (αSyn) pathology across neurodegenerative diseases, including Alzheimer's disease (AD) and synucleinopathies. Whether the co-deposition of these proteinopathic aggregates influences their respective seeding capacities remains unknown. Seed amplification assays (SAAs) enable sensitive and specific detection of pathological seeding activity in brain tissue and cerebrospinal fluid (CSF) and have been widely used to assess tau or αSyn seeding independently; however, their tandem application in the same individuals has not been thoroughly investigated. Here we apply Tau- and αSyn-SAA in parallel on a well-characterized postmortem cohort of matched brain tissue and CSF spanning AD, synucleinopathies, other neurological diseases, and neuropathologically defined controls. We demonstrate that tau seeding activity in both brain and CSF closely reflects underlying neuropathological burden, increasing stepwise with the grade of AD neuropathological change (ADNC) and neurofibrillary tangle (NFT) stage, with strong within-donor concordance between matrices (r = 0.79, p < 0.001). Tau-SAA measured in postmortem CSF robustly discriminated AD-related neuropathology from other groups, supporting its potential as a neuropathologically informed biomarker. αSyn-SAA identified all synucleinopathy donors as positive and revealed that 44% of AD donors harbor concomitant αSyn seeding activity. Leveraging this tandem dataset, we find that αSyn-SAA positive AD donors exhibit significantly enhanced tau seeding activity in both brain and CSF, independent of NFT stage, age, and sex (p = 0.014). In synucleinopathy donors, tau seeding did not alter αSyn seeding capacity (p = 0.606). Together, these results suggest a potentially unidirectional relationship between tau and αSyn seeding in human disease, wherein αSyn copathology acts as a catalyst of tau seeding in AD. Our findings carry implications for understanding how mixed proteinopathies shape disease burden and trajectory and may represent the beginning of a new direction in the field moving towards precision medicine to identify all types of pathology concomitantly affecting the brain, which will have a profound impact on patient prognosis and treatment.
    DOI:  https://doi.org/10.21203/rs.3.rs-10845149/v1
This page is being maintained by Thomas Krichel. It was last updated on 2026‒11‒05 at 11:25.