bims-amyloi 2026-08-30 papers

bims-amyloi

Biomed News

on Amyloid

Issue of 2026–08–30
sixteen papers selected by
Alexander Röntgen, University of Cambridge

Gangliosides GM3 and GD3 modulate insulin aggregation pathways and reduce cytotoxicity through structural remodeling.
Distinctive properties of the prion protein in the brain and retina in the amyloidosis associated with the PRNP F198S mutation.
Benzothiazole-driven molecular probes and therapeutics for neurodegenerative diseases: focus on amyloid-beta (Aβ), tau, and α-synuclein.
Fabrication of Mesoporous Manganese Nanoparticles Incorporated Aβ-Peptide Inhibits Aβ Aggregation and Alleviates Neuroinflammation Against Alzheimer's Disease.
Proteostasis breakdown and aggregate diversity in aging and neurodegenerative disease.
A Metabolomics-Based Strategy for Identifying Endogenous Inhibitors of IAPP Aggregation.
Low-frequency magnetic fields can improve behavioral abnormalities and suppress Aβ accumulation detected by thioflavin T in Caenorhabditis elegans models of Alzheimer's disease.
Apolipoprotein E lipidation, rather than isoform identity, determines amyloid-β binding and astrocyte clearance.
Distinct Filament Conformation for Receptor-Bound Amyloid-β from Alzheimer's Disease Brain.
Revealing the Mechanisms of Alzheimer's, Parkinson's and Huntington's Diseases Through Invertebrate Models.
Pathological Mutation E46K Acts as an Electrostatic Switch to Increase Distant Interdomain Interactions and Promote α‑Synuclein Phase Separation.
Quantifying the Acute Toxicity of Alpha-Synuclein Membrane-Accumulation in a Cell-Based Assay.
Structural Basis of Amyloid Fibril Assembly by Plant Seed Storage Proteins.
Current Targeted Nanoparticle Therapy for Alzheimer's Disease: Current Advances and Future Prospects.
Divergent tau pathology profiles induced by distinct alpha-synuclein aggregates in non-human primates.
Emerging diagnostic biomarkers and therapeutic targets in Alzheimer's disease.

Int J Biol Macromol. 2026 Aug 28. pii: S0141-8130(26)04193-0. [Epub ahead of print] 154247

Gangliosides GM3 and GD3 modulate insulin aggregation pathways and reduce cytotoxicity through structural remodeling.

Nazifa Tasnim Ahmad, Jhinuk Saha, Yimin Mao, Robert Silvers, Zaid Abulaban, Joshua Mysona, Ayyalusamy Ramamoorthy.

  Insulin amyloid aggregation is a key pathological and pharmaceutical concern, particularly in the context of Type-2 Diabetes (T2D), where amyloid deposition can impair therapeutic efficacy and contribute to local tissue damage. While gangliosides are known to modulate amyloid formation in neurodegenerative systems, their influence on insulin aggregation remains largely unexplored. In this study, we investigate the effects of gangliosides GM3 and GD3 on insulin amyloid aggregation using Thioflavin-T (ThT) based fluorescence kinetics, Fourier Transform Infrared (FTIR) spectroscopy, Circular Dichroism (CD) spectroscopy, Small Angle X-ray Scattering (SAXS), Nuclear Magnetic Resonance (NMR) spectroscopy, and Transmission Electron Microscopy (TEM)to examine the aggregation pathway, changes in the secondary structure and morphology of insulin aggregates. Our results show that both GM3 and GD3 lipids accelerated insulin aggregation in a concentration-dependent manner while steering the pathway away from classical fibril formation, producing short, beaded structures distinct from the extended fibrils observed under lipid-free conditions. Structural analyses revealed distinct non-fibrillar intermediates with β-sheet-rich globular clusters in presence of GD3 and α-helical intermediates in GM3-treated samples. Notably, these ganglioside-induced aggregates exhibit significantly reduced cytotoxicity when compared to insulin-only aggregates. Furthermore, ganglioside-bound insulin species retain seeding capacity, suggesting that they can nucleate further aggregation despite their non-fibrillar morphology. These findings underscore the role of gangliosides in modulating insulin amyloid polymorphism and toxicity, offering new insights into their potential impact on the pathology of T2D and treatment strategies.

Keywords:  Cytotoxicity; Gangliosides; Insulin amyloid aggregation; Non-fibrillar aggregates; Polymorphism; Type-2 diabetes (T2D)

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.154247
Acta Neuropathol. 2026 Aug 26. pii: 25. [Epub ahead of print]152(1):

Distinctive properties of the prion protein in the brain and retina in the amyloidosis associated with the PRNP F198S mutation.

Bernardino Ghetti, Bradley S Glazier, Michele Fiorini, Kathy L Newell, José M Bonnin, Jill R Murrell, Leah Rie Varner, Max Jacobsen, James F Striebel, Suzette A Priola, Gianluigi Zanusso.

  Prion protein (PrP) deposits in the form of diffuse and cored plaques occur in most gray matter areas of the brain of individuals affected by Gerstmann-Sträussler-Scheinker disease (GSS) associated with the F198S mutation in PRNP; however, the PrP deposits in the retina have not been characterized. Furthermore, a comparative analysis of PrP deposits occurring in the brain and in the retina in GSS has not been carried out. We hypothesize that the PrP aggregation and seeding properties in the brain and retina differ. The aim of this study was to analyze PrP from brains and retinas of individuals affected by GSS, all carriers of the PRNP F198S mutation from the same pedigree. Postmortem tissues from these patients were analyzed using neuropathologic and biochemical methods including Real-Time Quaking Induced Conversion assay. PrP deposits in the retina were found only in the outer plexiform layer, did not have tinctorial property of amyloid and were immunopositive using nine antibodies recognizing epitopes throughout the PrP sequence. Biochemical analysis showed that PrP_F198S in the retina is partially detergent-insoluble, is assembled in large-size aggregates, and has seeding property. In addition, the glycosylation of full-length PrP in the retina was more complex than that of control PrP. Furthermore, the homogenates of retina did not contain the 8 kDa PrP internal fragments (PrPIF) as brain homogenates do; however, a PrPIF was experimentally generated using proteinase K. In conclusion, we report for the first time the neuropathologic and biochemical properties of PrP in the retina of individuals carrying PRNP F198S and compare them with those in the brain of the same individuals. The fact that in GSS F198S, PrPIF is constitutive only in the brain points to the need of identifying whether there is a difference in proteolytic mechanisms between retina and brain.

Keywords:   PRNP F198S mutation; PRNP gene; Gerstmann–Sträussler–Scheinker disease; Prion; Retina

DOI:  https://doi.org/10.1007/s00401-026-03060-z
RSC Med Chem. 2026 Aug 13.

Benzothiazole-driven molecular probes and therapeutics for neurodegenerative diseases: focus on amyloid-beta (Aβ), tau, and α-synuclein.

Nitin Kumar, Izhar Khan, Jyoti Singh, Krishan Kumar, Virendra Kumar Kushwaha, Sunil Kumar, Smriti Ojha, Alok Kumar Dash, Gauri Shankar.

Neurodegenerative disorders, particularly Alzheimer's disease (AD) and Parkinson's disease (PD), represent a rapidly growing global health challenge characterized by progressive neuronal loss, irreversible cognitive decline, and the absence of effective disease-modifying therapies. A major obstacle in the clinical management of these disorders is the inability to accurately diagnose pathological changes at early stages, when therapeutic intervention is most likely to be effective. The pathological aggregation of amyloid-β (Aβ), hyperphosphorylated tau, and α-synuclein (α-syn) constitutes a central molecular hallmark of neurodegeneration and has therefore emerged as a critical target for both diagnostic imaging and therapeutic intervention. Among the numerous heterocyclic scaffolds investigated for central nervous system drug discovery, benzothiazole (BZT) has attracted exceptional attention owing to its favorable blood-brain barrier permeability, synthetic versatility, and intrinsic affinity toward β-sheet-rich protein aggregates. The clinical success of Pittsburgh compound-B (PiB) established BZT as a privileged molecular recognition motif for in vivo visualization of amyloid pathology and stimulated extensive medicinal chemistry efforts toward the development of next-generation imaging probes. More recently, advances in structure-guided design and multitarget-directed ligand (MTDL) strategies have transformed BZT from a purely diagnostic scaffold into a versatile theranostic platform capable of simultaneously recognizing and modulating neurodegenerative proteinopathies. Between 2020 and 2026, a wide range of structurally diverse BZT-based derivatives and hybrid molecules have been reported with improved affinity, selectivity, and sensitivity toward Aβ plaques, tau fibrils, and α-synuclein aggregates, while also exhibiting therapeutic activities such as inhibition of protein aggregation, fibril destabilization, cholinesterase inhibition, monoamine oxidase modulation, antioxidant activity, metal chelation, mitochondrial protection, and neuroinflammation suppression. This review provides a comprehensive overview of recent advances (2020-2026) in the design, synthesis, structure-activity relationships, molecular mechanisms, diagnostic applications, and therapeutic potential of BZT-based agents for neurodegenerative disorders. Particular emphasis is placed on the molecular basis of BZT recognition of amyloidogenic proteins, the evolution of diagnostic probes into multifunctional therapeutic hybrids, and emerging theranostic strategies targeting interconnected pathological pathways associated with AD, PD, and related proteinopathies. Furthermore, key trends in medicinal chemistry, translational challenges, and future opportunities for the development of next-generation BZT-derived diagnostics and therapeutics are critically discussed. Collectively, the evidence highlights BZT as one of the most promising privileged scaffolds for integrating early diagnosis, disease monitoring, and disease-modifying intervention within a unified molecular framework for neurodegenerative disorders.

DOI: https://doi.org/10.1039/d6md00462h
J Biomed Mater Res B Appl Biomater. 2026 Sep;114(9): e70131

Fabrication of Mesoporous Manganese Nanoparticles Incorporated Aβ-Peptide Inhibits Aβ Aggregation and Alleviates Neuroinflammation Against Alzheimer's Disease.

Haipeng Lu, Chuanchen Hu, Yaming Fu.

  Extracellular amyloid plaques from Aβ accumulation and intracellular neurofibrillary tangles (NFTs) from hyperphosphorylated Tau (p-Tau), both leading to neuronal dysfunction, synapse loss, and cognitive decline. Nonetheless, achieving an effective therapeutic outcome is challenging due to the limited drug bioavailability through the blood-brain barrier (BBB) and the complex microenvironment within the brain. This study proposes MM-TA for the synergistic treatment of AD, utilizing mesoporous manganese (MM) as a nanocarrier to deliver a LK7 (Aβ-inhibiting peptide) and a DAA (amino acid-peptide) that inhibits Tau-related fibrils formation. A biomimetic nanocarrier (MM-LD@4CM termed as MLDC) encapsulated with 4T1 cell membranes (4CM) was developed, inspired by 4T1 cells' ability to facilitate BBB penetration. Following traversal of the BBB, MLDC concurrently prevented Tau phosphorylation and suppressed Aβ aggregation. Furthermore, by leveraging MM's catalase-mimetic properties, MLDC mitigated oxidative stress and altered the microenvironment associated with AD progression. In contrast to the singular therapeutic agent, MLDC ameliorated nerve damage and enhanced cognitive function in AD mice by reducing Aβ oligomers, phosphorylated Tau, and inflammation, thereby providing a synergistic therapeutic approach with significant potential for effective AD treatment.

Keywords:  Alzheimer's disease; Aβ aggregation; mesoporous manganese; scavenging ROS; tau phosphorylation

DOI:  https://doi.org/10.1002/jbm.b.70131
Front Aging Neurosci. 2026 ;18 1910154

Proteostasis breakdown and aggregate diversity in aging and neurodegenerative disease.

Zohaib Nisar Khan.

  Protein aggregation and proteostasis decline are central features of aging and neurodegenerative disease, arising from progressive impairment of protein quality-control systems and transitions into aggregation-prone states. During aging, diverse proteins, including metabolic and proteostasis-related factors, gradually accumulate in aggregated forms as proteostasis capacity declines. Although these aggregates often remain compatible with cellular function, increasing aggregate burden progressively challenges proteostasis resilience. Neurodegenerative diseases are characterized by the emergence and amplification of highly toxic, structurally ordered protein assemblies, including amyloid-β (Aβ) and tau, which exist along a continuum with broader age-associated proteome instability rather than as entirely distinct phenomena. Oxidative and metabolic imbalances promote non-enzymatic post-translational modifications (PTMs), including cysteine oxidation, S-nitrosylation, and carbonylation, which alter protein structure, impair degradation pathways, and facilitate misfolding and aggregation. Here, we compare oxidative PTM-driven aggregates observed during aging with disease-associated protein assemblies, highlighting both shared biophysical mechanisms and distinct pathological outcomes. We propose a threshold model in which the cumulative burden of oxidative PTMs, protein misfolding, and impaired clearance progressively erodes proteostasis capacity, increasing susceptibility to the emergence of selective, self-amplifying aggregates. By integrating intracellular quality-control systems with extracellular clearance pathways, including glymphatic and meningeal lymphatic networks, this framework provides a mechanistic perspective on how aggregate diversity evolves toward disease-associated pathology and suggests therapeutic strategies that combine aggregate-specific targeting with restoration of global proteostasis and clearance capacity.

Keywords:  aging; amyloid-β and tau; glymphatic system; neurodegenerative disease; protein aggregation; proteostasis

DOI:  https://doi.org/10.3389/fnagi.2026.1910154
Metabolites. 2026 Aug 03. pii: 549. [Epub ahead of print]16(8):

A Metabolomics-Based Strategy for Identifying Endogenous Inhibitors of IAPP Aggregation.

Dandan Xia, Liubao Gu, Lei Yang, Jiaojiao Hu, Xiaowei Xu, Dechen Jiang, Qiuling Zheng, Bing Wan.

  Background/Objectives: Human islet amyloid polypeptide (IAPP) aggregation plays a critical role in the pathogenesis of type 2 diabetes mellitus (T2DM). Although metabolic alterations are a hallmark of T2DM, the functional roles of differential metabolites in regulating disease-associated molecular processes remain largely unexplored. This study aimed to establish a metabolomics-guided strategy for identifying endogenous metabolites with anti-amyloid activity and to investigate their underlying chemical interactions with IAPP. Methods: Untargeted metabolomic profiling of clinical samples from T2DM patients, obesity patients and healthy controls was performed to identify differential metabolites. Candidate metabolites were subsequently screened for their ability to modulate IAPP aggregation. Transmission electron microscopy (TEM), thioflavin T (ThT) fluorescence assays, and cell viability measurements were employed to evaluate their effects on fibril formation and cytotoxicity. Mass spectrometry was further used to characterize metabolite-IAPP interactions. Results: Metabolomic analysis identified 3-hydroxypyruvic acid (also known as β-hydroxypyruvic acid, hereafter referred to as HPA) as a significantly altered endogenous metabolite associated with T2DM and a candidate regulator of IAPP aggregation. Functional assays demonstrated that HPA effectively inhibited amyloid fibril formation, as evidenced by the absence of typical fibrillar structures and a prolonged lag phase during aggregation. HPA also significantly alleviated IAPP-induced cytotoxicity. Mass spectrometric analysis revealed the formation of HPA-IAPP oligomer complexes (n < 4), suggesting that HPA directly interacts with early oligomeric intermediates and interferes with their progression toward mature fibrils. Conclusions: This work demonstrates that untargeted metabolomics of clinical samples can serve as an effective strategy for discovering bioactive endogenous metabolites involved in disease-related molecular processes. The identification of HPA as a potential endogenous inhibitor of IAPP aggregation provides new chemical insight into the relationship between metabolic dysregulation and amyloidogenesis and highlights endogenous metabolites as a valuable source of potential therapeutic lead compounds.

Keywords:  IAPP aggregation; mass spectrometry; metabolomic analysis

DOI:  https://doi.org/10.3390/metabo16080549
Electromagn Biol Med. 2026 Aug 27. 1-8

Low-frequency magnetic fields can improve behavioral abnormalities and suppress Aβ accumulation detected by thioflavin T in Caenorhabditis elegans models of Alzheimer's disease.

Mirei Kiyota, Yangtai Jin, Naohiro Nemoto, Makiko Kakikawa.

  Amyloid β (Aβ) accumulation and Aβ-related senile plaques, the pathological hallmarks of Alzheimer's disease (AD), damage neurons and impair cognitive functions in patients. Previous studies have shown that low‑field magnetic stimulation attenuates Aβ and enhances cognitive performance. In this study, AD models of Caenorhabditis elegans expressing Aβ in the nerves were placed in a low-frequency magnetic field (LFMF) and then subjected to a chemotaxis assay to evaluate attractive behavior. In control C. elegans (CL2122), which do not express Aβ but carried only the vector, the chemotactic behavior was normal and unaffected by LFMF. In contrast, in the AD model expressing Aβ within the nervous system, abnormalities in chemotactic behavior were observed; however, these were improved in a manner dependent on LFMF strength. In addition, the AD model expressing Aβ in the muscle exhibited paralysis, which was significantly attenuated by LFMF. Thioflavin T staining revealed that, in the AD model expressing in muscles, Aβ accumulation declined in the LFMF-treated group compared to that of the non-LFMF group. These results suggest that LFMF can improve abnormal chemotactic behavior and attenuate Aβ-induced paralysis by suppressing the accumulation and aggregation of Aβ in a C. elegans model of AD.

Keywords:  Aβ aggregation; Chemotaxis; thioflavin T staining

DOI:  https://doi.org/10.1080/15368378.2026.2722639
J Biol Chem. 2026 Aug 27. pii: S0021-9258(26)02366-5. [Epub ahead of print] 113494

Apolipoprotein E lipidation, rather than isoform identity, determines amyloid-β binding and astrocyte clearance.

Kamila Nurmakova, Gregory-Neal W Gomes, Zachary A Levine.

  Inherited variations in the Apolipoprotein E (APOE) gene are the largest genetic determinant for late-onset Alzheimer's disease, with the APOEε4 allele conferring the highest risk. While APOE was shown to modulate amyloid beta (Aβ) pathology in a genotype-specific manner (APOEε4>APOEε3>APOEε2), it remains an open question whether these differences are due directly to isoform-specific interactions between ApoE and Aβ or indirect effects on Aβ clearance. To disentangle how single ApoE mutations confer vastly different effects on Aβ pathology, we investigated how both the ApoE isoform and lipidation modulate its binding to Aβ species, and its effect on Aβ uptake and cytotoxicity in human astrocytes. We found that ApoE lipidation, not isoform, has the biggest impact on its interaction with Aβ, on the uptake of Aβ by astrocytes, and on Aβ-induced cytotoxicity. Specifically, unlipidated ApoE preferentially interacts with Aβ oligomers and fibrils, which substantially inhibits their uptake by astrocytes. Conversely, lipidated ApoE showed no interaction with Aβ oligomers and had a reduced ability to inhibit Aβ uptake. Our observations suggest that previously reported ApoE isoform-specific differences in Aβ oligomer levels are not driven by intrinsic sequence-specific differences in the affinity between ApoE and Aβ, but potentially by isoform-specific differences in ApoE lipidation in the brain. We propose that the impaired lipidation of ApoE4 in the brain increases levels of unlipidated ApoE, which then bind toxic Aβ oligomers and reduce their clearance by astrocytes. Such a mechanism underscores the therapeutic potential of interventions aimed at increasing ApoE lipidation.

Keywords:  Alzheimer's disease (AD); ApoE lipidation; Apolipoprotein E (ApoE); Aβ oligomers; amyloid beta (Aβ); astrocytes; fluorescence correlation spectroscopy (FCS); protein‐protein interaction

DOI:  https://doi.org/10.1016/j.jbc.2026.113494
Nat Commun. 2026 Jul 22. pii: 8953. [Epub ahead of print]17(1):

Distinct Filament Conformation for Receptor-Bound Amyloid-β from Alzheimer's Disease Brain.

Mikhail A Kostylev, Carmen Butan, Graham P Roseman, Yangyi Liu, Tanina Arab, Ruibing Wu, Pallavi Gopal, Stephen M Strittmatter.

Alzheimer's disease is triggered by amyloid-β, with symptoms linked to synapse loss. Oligomeric amyloid-β, rather than monomeric or fibrillar amyloid-β, has been proposed to be the proximate mechanistic cause, but the relevant molecular characteristics have remained unclear. To define the biologically relevant species, we isolated a receptor-bound amyloid-β pool from Alzheimer's disease brain by release with a receptor antagonist and purification to homogeneity. This discrete receptor-bound amyloid-β pool is ten times more abundant than free unbound amyloid-β and is comprised of 65 nm long filaments. The tips of these short filaments bind to prion protein and drive synapse loss from human neurons. Cryo-electron microscopy shows that the receptor-bound amyloid-β consists of two symmetric S-shaped amyloid-β monomers per filament rung. The overall structure is similar to much longer plaque-associated amyloid-β filaments from the same brain and fails to reveal an unrelated "oligomeric" conformation. Nonetheless, the receptor-bound amyloid-β can be distinguished from plaque filaments by the tilt angle of repeating amyloid-β subunits within each filament rung, by amino terminal conformation, by length and by amyloid seeding properties. Characterizing receptor-bound amyloid-β provides insight into neuronal dysfunction separate from plaque aggregation.

DOI: https://doi.org/10.1038/s41467-026-75895-9
Biology (Basel). 2026 Aug 10. pii: 1351. [Epub ahead of print]15(16):

Revealing the Mechanisms of Alzheimer's, Parkinson's and Huntington's Diseases Through Invertebrate Models.

Xing Ding, Peijin Wang, Limin Zhou, Xingxia Li.

  The neural circuits of the human brain are highly complex (due to the number of neurons and the diversity of synaptic connections), hindering the analysis of the pathological mechanisms of neurodegenerative diseases. Invertebrates with simple yet well-differentiated nervous systems have a natural advantage over mammalian model organisms in the identification of pathogenic genes and functional studies of neurodegenerative diseases. They can provide unique and profound insights into the pathogenesis of complex human neurodegenerative diseases and the formulation of intervention strategies. This article reviews the conserved mechanisms of three neurodegenerative diseases across species, including protein homeostasis imbalance and aggregation toxicity, mitochondrial dysfunction and metabolic abnormalities, axonal transport defects, and loss of synaptic function. Based on research on three invertebrates in the field of neurodegeneration, namely Caenorhabditis elegans (C. elegans), Drosophila melanogaster (D. melanogaster), and Bombyx mori (B. mori), we cover three major types of neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). The aim is to find important inspirations for the future prevention and treatment of neurodegenerative diseases from the aspects of the material basis and existing treatment strategies.

Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; conservative mechanism; inspiration for the future; invertebrate models

DOI:  https://doi.org/10.3390/biology15161351
JACS Au. 2026 Aug 24. 6(8): 4537-4549

Pathological Mutation E46K Acts as an Electrostatic Switch to Increase Distant Interdomain Interactions and Promote α‑Synuclein Phase Separation.

Zhongyuan Yang, Yiming Tang, Jitao Wen, Cong Guo, Yun Zhou, Zihan Wang, Tong Pan, Yuan Tan, Sarah Perrett, Si Wu, Guanghong Wei.

  The Parkinson's disease-related protein α-synuclein can form solid amyloid fibrils through liquid-liquid phase separation (LLPS) and liquid-to-solid phase transition. The most deleterious familial mutation E46K has recently been shown to enhance α-synuclein LLPS and subsequent solidification; yet, the precise mechanisms remain largely unknown. Here, using molecular dynamics simulations at different spatiotemporal scales combined with biochemical experiments, we show that the E46K mutation acts as an electrostatic switch to remodel interactions between the oppositely charged N-terminal domain (NTD) and C-terminal domain (CTD) of α-synuclein. This remodeling shifts the interaction site of NTD with CTD from its N-terminus to the mutation region. Such reorganization increases the hydrophobic solvent exposure of key LLPS-promoting motifs, potentially facilitating intermolecular interactions that initiate phase separation. Phase coexistence simulations further support this hypothesis, showing that the E46K mutant exhibits enhanced LLPS and solidification propensities. This enhancement is primarily driven by intermolecular electrostatic interactions between the mutation region and the CTD, followed by the hydrophobic NAC-NAC interactions mediated by the LLPS-promoting motifs. Collectively, these results reveal that NTD-CTD electrostatic crosstalk acts as the key modulator of α-synuclein phase separation, while NAC-NAC interactions play an auxiliary role, both of which synergistically govern α-synuclein phase separation. This study offers a complete and detailed mechanistic framework for understanding α-synuclein phase separation and its enhancement induced by the E46K mutation.

Keywords:  Parkinson’s disease; familial mutation; molecular dynamics simulation; phase separation; α-synuclein

DOI:  https://doi.org/10.1021/jacsau.6c00631
J Mol Neurosci. 2026 Aug 22. pii: 136. [Epub ahead of print]76(3):

Quantifying the Acute Toxicity of Alpha-Synuclein Membrane-Accumulation in a Cell-Based Assay.

Baoyi Li, Amirah K Anderson, Heba Alnakhala, Oren A Levy, Nagendran Ramalingam, Ulf Dettmer.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects over 12 million people worldwide. A central pathological feature is the accumulation of aggregated alpha-synuclein (αS) in Lewy bodies and Lewy neurites. Engineered αS variants such as 3K (E35K+E46K+E61K) and KLK (KTKEGV→KLKEGV in 6 repeats) have been shown to enhance membrane binding and aggregation propensity, contributing to cellular toxicity. To further investigate the impact of 3K and KLK on αS biology, we developed a sensitive assay in a human neuroblastoma model to assess expression levels and cytotoxicity. Relative to wild-type αS, the 3K mutant exhibited reduced steady-state expression and increased toxicity, consistent with prior reports. In contrast, the KLK mutant showed no marked change in protein expression but induced significantly higher toxicity, more than the 3K variant. Furthermore, stearoyl-CoA desaturase (SCD) inhibition partially rescued the toxicity of 3K and KLK αS, with 3K showing greater restoration of cell growth than KLK, validating the sensitivity of our live-cell assay to detect pharmacological responses. These findings underscore the utility of our assay in dissecting disease-relevant mechanisms and highlight the potential of engineered αS variants to model pathogenic features of PD. This platform offers a versatile tool for evaluating therapeutic strategies targeting αS aggregation and toxicity in PD and related synucleinopathies.

Keywords:  Alpha-synuclein; Cellular assay; Parkinson’s disease; Synucleinopathy

DOI:  https://doi.org/10.1007/s12031-026-02578-x
Nat Commun. 2026 07 28. pii: 9134. [Epub ahead of print]17(1):

Structural Basis of Amyloid Fibril Assembly by Plant Seed Storage Proteins.

Yiling Zhang, Danni Li, Qinyue Zhao, Shiran Lv, Wencheng Xia, Yongyi Xu, Yingshan Li, Yunxia Li, Yaoyang Zhang, Dan Li, Bo Sun, Wenyan Kang, Cong Liu, Bin Dai.

Amyloid fibrils are highly ordered protein assemblies characterized by a cross-β architecture. A wide range of proteins can adopt amyloid states, contributing to both disease-related pathology and normal physiological function. While animal-derived amyloids have been extensively examined in atomic detail, amyloid fibrils formed by plant proteins remain relatively understudied. Here we systematically assess three major seed storage proteins-oat 12S globulin, soybean 7S globulin, and rice glutelin-under harsh cooking-like conditions (pH 2, 85 °C). Oat globulin and rice glutelin readily form fibrils in both purified preparations and whole-seed extracts, whereas soybean globulin forms fibrils only in purified preparations and remains largely amorphous in whole-seed extracts. Using cryo-electron microscopy, we determine the structure of oat globulin fibrils at 3.9 Å resolution. The fibril core adopts a compact triangular architecture with pseudo-threefold symmetry and is stabilized by extensive hydrophobic and aromatic packing. Our findings establish the molecular basis of amyloid formation in plant seeds and expand the structural landscape of amyloid fibrils beyond animal and microbial systems, providing a foundation for understanding amyloid formation in plant- and food-derived proteins.

DOI: https://doi.org/10.1038/s41467-026-76001-9
Curr Neurovasc Res. 2026 Aug 01.

Current Targeted Nanoparticle Therapy for Alzheimer's Disease: Current Advances and Future Prospects.

Ravindra Mishra, Nidhi Chauhan, Krishn Kumar Agrawal.

   BACKGROUND: The effects of Alzheimer's disease (AD) on society are profound. The blood-brain barrier selectively permits the penetration of specific forms of molecules through the blood circulation into the CNS, which can restrict the effectiveness of medications supplied systemically. The therapeutic targets are located in the CNS. However, local administration channels to the CNS are rather intrusive, which can lead to patient discomfort and limit the feasibility of repeated treatments.
METHODOLOGY: This article has evaluated treatment methodologies for AD that use nanoparticles to target the brain and the pathological features of the illness. The material that is currently available has been categorized based on the aspect of AD that is discussed: targeted medication and neurodegeneration.
RESULT: The use of nanoparticles in the targeted delivery of medications intended to alleviate the symptoms of AD or halt the disease's progression has yielded positive results. Because of their multivalence, nanoparticles can target the treatment site, pass through the blood-brain barrier, and be functionalized with various targeting groups. Intravenous administration, rather than more intrusive techniques, has enhanced drug bioavailability in the CNS. Furthermore, the development of vaccinations and medication formulations for intranasal delivery has utilized nanoparticles.
DISCUSSION: This study focused on the advancement of AD treatment. Nanoparticles are designed to enhance drug bioavailability through intravenous and intranasal routes for quicker brain access with fewer side effects. Nanoparticles also aid in targeting disease features like amyloid- beta plaques and tau tangles. While results in animal models are positive, transitioning to human clinical trials requires a more profound understanding of AD mechanisms and biomarker identification.
CONCLUSION: Research employing animal models suggests that targeted nanoparticles can enhance the effectiveness of AD treatments. A deeper understanding of AD mechanisms will lead to more successful targeted nanoparticle applications.

Keywords:  Alzheimer's disease (AD); Blood-brain barrier; CNS; nanoparticles; neurodegenerative; targeted medicine

DOI:  https://doi.org/10.2174/0115672026471444260724103751
Brain. 2026 Aug 22. pii: awag284. [Epub ahead of print]

Divergent tau pathology profiles induced by distinct alpha-synuclein aggregates in non-human primates.

Morgane Darricau, Camille Neu-Faber, Mathieu Bourdenx, Sandra Dovero, Gregory Porras, Marie-Laure Thiolat, Ines Trigo-Damas, Nuria Garcia-Carrillo, Maria Trinidad Herrero, Miquel Vila, Jose A Obeso, Vincent Planche, Erwan Bezard, Benjamin Dehay.

  Proteinopathies are frequently accompanied by co-pathologies, which complicate understanding the pathophysiological mechanisms of neurodegenerative diseases. In this study, we employed a well-characterised baboon cohort to investigate the occurrence of tau pathology following intrastriatal injections of two distinct α-synuclein extracts (small aggregates: SA and large aggregates: LA) derived from the brains of Parkinson's disease (PD) patients. Biochemical and histopathological analyses (6, 12, or 24 months after injections) revealed significantly higher phospho-tau expression and greater frequency of neuropil threads in both LA- (n=18) and SA-injected baboons (n=12) compared with control animals. We also observed distinct patterns of tau pathology depending on the assembly of α-synuclein aggregates. Baboons injected with SA exhibited tangle-like phosphorylated tau lesions and neuropil threads, with no significant differences across post-injection time points. Moreover, a uniform distribution of tau pathology was detected along the rostro-caudal axis of the medial temporal lobe, affecting neuronal, oligodendroglial, and astrocytic cell types. On the other hand, baboons injected with LA exhibited neuropil threads and few glial lesions but lacked phospho-tau intraneuronal aggregates. The occurrence of phospho-tau lesions was associated with phospho-synuclein pathology. These observations suggest a link between nigrostriatal synucleinopathy and limbic tau co-pathology, providing pathophysiological insights into PD dementia.

Keywords:  Parkinson’s disease; co-pathologies, neurodegeneration; non-human primates; tau; α-synuclein

DOI:  https://doi.org/10.1093/brain/awag284
Inflammopharmacology. 2026 Aug 22.

Emerging diagnostic biomarkers and therapeutic targets in Alzheimer's disease.

Thumbar Kishan Dineshbhai, Dhvani Rafaliya, Aditya Singh, Shubhrat Maheshwari, Manisha Lalan, Guno Sindhu Chakraborthy.

  Alzheimer's disease (AD) is a progressive neurodegenerative disease and is the most common cause of dementia in the world. Cognitive decline, memory problems, behavioral disturbances, and, finally, loss of functional independence characterize it. AD has risen and continues to increase globally, especially among aging people. A team of researchers at the University of Alberta says that we need faster, better diagnosis and treatment of AD. It elaborates on the progressive understanding of AD pathophysiology, biomarkers, emergent targets, and the latest delivery solution. The paper covers and discusses various disease-causing mechanisms like plaque formation, tau hyperphosphorylation, etc., which causes AD. Research is also being undertaken on the role of genetic and epigenetic factors in the pathogenesis and evolution of diseases, including but not limited to APOE polymorphisms, DNA methylation, modifications of histones, and non-coding RNAs. Researchers have discovered biomarkers relevant to AD, particularly those found in CSF and blood. The biomarkers include Aβ42, phosphorylated tau, neurofilament light chain, GFAP, and TREM2. Other biomarkers include salivary, urinary, neuroimaging, and digital. Next come the therapeutic strategies targeting amyloid aggregation, tau pathology, and other types of dysfunctions. Recent developments in monoclonal antibodies, kinase inhibitors, anti-inflammatory agents, neurotrophic agents, and antioxidant therapies are stressed. Moreover, nanotechnology-based and targeted delivery systems being developed for drugs include, but are not limited to, liposomes, polymeric nanoparticles, dendrimers, nanoemulsions, and intranasal formulations to enhance blood-brain barrier permeability. A combination of biomarker-guided diagnostics with mechanism-based therapies might enable precision medicine approaches and improve clinical outcomes in AD.

Keywords:  Alzheimer disease; Cognitive decline; DNA methylation; Hyperphosphorylation; Neurofilament light chain

DOI:  https://doi.org/10.1007/s10787-026-02341-z