bims-amyloi 2026-09-13 papers

bims-amyloi

Biomed News

on Amyloid

Issue of 2026–09–13
nine papers selected by
Alexander Röntgen, University of Cambridge

When Pathologies Collide: The Intersection of Tau and Alpha-Synuclein in Neurodegenerative Diseases.
Mitochondrial NMNAT3 reduces amyloid aggregates in Drosophila and alters the amyloid processing in the 3xTgAD mouse.
Mass Spectrometric Footprinting and DFT Calculations Explain the Effect of Curcumin on the Aggregation of Amyloid β 42 (Aβ42).
Differential aggregation and seeding of tau microtubule-binding region fragments in vitro.
Novel Amyloid-β Aggregation Inhibitors Based on Phenylalanine Structure.
Cross-disease protein aggregate interactions in neurodegeneration: from molecular mechanisms to therapeutic strategies.
Expression differences and diagnostic efficacy of core plasma biomarkers in Alzheimer's disease, cerebral small vessel disease and healthy adults.
Missense mutations in the SNCA gene: Molecular mechanisms and clinical implications.
Proteoform-Resolved Cross-Linking Reveals Environment-Dependent Structural Effects of α-Synuclein S129 Phosphorylation.

Mol Neurobiol. 2026 Sep 08. pii: 882. [Epub ahead of print]63(1):

When Pathologies Collide: The Intersection of Tau and Alpha-Synuclein in Neurodegenerative Diseases.

Jenna N Hunt, Sandhya Kortagere.

  Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are becoming increasingly prevalent in today's aging population and with significant cost to society. While these diseases were traditionally defined by distinct protein aggregates, namely, tau tangles and amyloid-β (Aβ) plaques in AD and α-synuclein (α-syn) inclusions in PD, substantial evidence reveals frequent mixed pathologies, with tau, α-syn, and Aβ aggregates coexisting in patients. This copathology complicates understanding disease mechanisms, classification, and progression, highlighting the need to examine mixed pathologies in neurodegenerative diseases to develop disease-modifying therapies. The presence of mixed proteinopathies suggests shared or converging pathological mechanisms, including synergistic aggregation, enhanced seeding capabilities, and shared protein-protein interactions. Understanding these molecular mechanisms is essential for identifying disease modifiers and refining experimental models. This review explores the pathogenic mechanisms of α-syn and tau individually, followed by exploration of their molecular interactions and potential mechanisms of coaggregation and exacerbation of pathology. By recognizing the intersection of these pathologies, further research can refine disease classifications for neurodegenerative diseases.

Keywords:  Mixed proteinopathies; Neurodegenerative diseases; Parkinson’s disease; Synuclein; Synucleinopathy; Tau

DOI:  https://doi.org/10.1007/s12035-026-06163-6
Mitochondrial Commun. 2026 ;4 1-9

Mitochondrial NMNAT3 reduces amyloid aggregates in Drosophila and alters the amyloid processing in the 3xTgAD mouse.

Zhu Yi, Naynika Juvvadi, Grace Zhai, Carlos T Moraes, Milena Pinto.

Alzheimer's disease is a progressive neurological disorder characterized by two main neuropathological hallmarks: neurofibrillary tangles and amyloid plaques. Both are protein aggregates, composed mainly of hyperphosphorylated Tau and the amyloid fragment Aβ, respectively. NMNAT (Nicotinamide mononucleotide adenylyltransferase) is an endogenous enzyme involved in the conversion of NMN to NAD. It is known for its neuroprotective functions, particularly against axonal degeneration. We have previously shown that different isoforms of NMNAT can protect cells from neurotoxic stress caused by protein aggregates by acting as chaperones. Accordingly, the mitochondrial-localized isoform NMNAT3 exhibits potent chaperone activity, which antagonizes the aggregation of a wide spectrum of pathological amyloid client proteins in culture, including Tau and amyloid beta. Although mostly cytosolic, Aβ has also been detected in mitochondria and mitochondrial membranes. To investigate whether NMNAT3 could serve as a neuroprotective factor in amyloid pathology in vivo, we overexpressed NMNAT3 in two different models: a Drosophila model overexpressing APP and PS1 in developing photoreceptors, and the 3xTg-AD mouse, in which NMNAT3 was expressed in forebrain neurons and which accumulates neurofibrillary tangles and plaques in the hippocampus and cortex. When expressed in the Drosophila eye, APP accumulated in a location- and time-dependent manner, and co-expression of NMNAT3 decreased the total number of aggregates. When expressed in the mouse brain, NMNAT3 did not affect amyloid plaque number or volume; nonetheless, it altered APP processing, leading to the accumulation of oligomers and soluble C-terminal fragments. We conclude that the effects of NMNAT3 on APP differ between models, likely due to differences in access to the sites of protein aggregation and the neuronal environments between flies and mice.

DOI: https://doi.org/10.1016/j.mitoco.2026.01.001
J Am Chem Soc. 2026 09 02. 148(34): 36365-36378

Mass Spectrometric Footprinting and DFT Calculations Explain the Effect of Curcumin on the Aggregation of Amyloid β 42 (Aβ42).

George Mathai, Saketh Chemuru, Austin B Moyle, Jong Hee Song, Don Rempel, Daryl Giblin, Michael L Gross.

Curcumin, a polyphenolic natural product, binds to Aβ42, a protein involved in Alzheimer's Disease, to inhibit self-aggregation in vitro. Molecular understanding of the binding is important in designing new molecules to inhibit Aβ42 aggregation. We performed OH radical footprinting of Aβ42 in the presence and absence of curcumin by using fast photochemical oxidation of proteins (FPOP), followed by mass spectral analysis, to monitor changes in Aβ42 protein dynamics in the presence of curcumin. The results reveal that curcumin binding reduces oxidative footprinting at the N-terminus and middle region, indicating binding at these sites. Kinetic modeling of the percentage modification shows a significant change in the aggregation of Aβ42 in the presence of curcumin, whereby one aggregate population nearly disappears. The [Aβ42:curcumin] binding complexes were also explored using density functional theory (DFT), optimizating the starting structures at the B3LYP/6-31G(d) level for both the N-terminal/middle and C-terminal/middle regions. The structure of the lowest-energy complex has curcumin binding at the N-terminal plus middle regions, and this was validated by reoptimization using 6-311G(d,p) and applying Grimme's dispersion function (GD3). This structure was further confirmed by reoptimization in aqueous media using the Conductor-like Polarizable Continuum Model (CPCM). The new structure not only accounts for the observed changes in •OH footprinting of the N-terminal, middle, and C-terminal regions but also forecasts how this approach can provide insight into protein aggregation. A molecular-level understanding of the binding site of curcumin with Aβ42 should be helpful in the design of new aggregation modulators.

DOI: https://doi.org/10.1021/jacs.5c22337
Biochem Biophys Res Commun. 2026 Sep 09. pii: S0006-291X(26)01339-2. [Epub ahead of print]836 154575

Differential aggregation and seeding of tau microtubule-binding region fragments in vitro.

Min-Seok Kim, Seong-Jun Hwang, Dong-Hou Kim, Seung-Yong Yoon.

  The microtubule-binding repeat region (MTBR) of tau is central to pathological aggregation and propagation in Alzheimer's disease (AD). Cryo-electron microscopy has defined residues 306-378, encompassing R3 and R4, as the ordered fibril core of AD tau; however, whether this structural core also represents the most potent seeding unit remains unclear. We generated recombinant tau fragments beginning at R1, R2, or R3 and compared their amyloid-forming and cellular seeding activities. Thioflavin T assays showed that R3-R4 and R3-378, corresponding to the AD fibril core, exhibited strong amyloid-forming activity. In contrast, FRET-based cellular assays showed maximal seeding with R2-starting fragments. Extension of R2-containing fragments into R1 markedly reduced seeding activity, indicating that R2 accessibility and sequence context, rather than the mere presence of R2, influence seed competence. These findings demonstrate a dissociation between sequence determinants of mature fibril formation and cellular tau seeding and identify exposure of R2 as a potential feature of propagation-competent tau.

Keywords:  Aggregation; Alzheimer's disease; Microtubule-binding repeat region; PHF6*; Tau; Tau seeding

DOI:  https://doi.org/10.1016/j.bbrc.2026.154575
Curr Alzheimer Res. 2026 Sep 07.

Novel Amyloid-β Aggregation Inhibitors Based on Phenylalanine Structure.

Mingming Xu, Hongmin Wang, Shihong Li, Junjie Ye, Yuanjun Sun, Yidan Xu, Haiyan Zhang, Weimin Zhao, Jingjing Zhang.

   INTRODUCTION/OBJECTIVE: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) aggregation, making its inhibition a promising therapeutic strategy. This study evaluated the effects of two phenylalanine derivatives on Aβ aggregation and associated neurotoxicity.
METHODS: Interactions between Aβ monomer and two compounds (12a and 5g) were explored by molecular docking. The inhibitory effects of the compounds on Aβ aggregation were evaluated using a thioflavin-T (ThT) assay, transmission electron microscopy (TEM), and dot blot. The neuroprotective ability of the two compounds was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay.
RESULTS: Docking analysis revealed that compounds 12a and 5g can bind to monomeric Aβ and identified the amino acids responsible for the interactions. The two compounds significantly reduced ThT fluorescence during the 48-hour incubation at all concentrations in ThT kinetics assays. The inhibitory effects were further confirmed in TEM. Both compounds suppressed Aβ oligomerization (reductions to 42.72% and 35.90% of the untreated control group, respectively). Furthermore, compound 5g, with a new structure, showed remarkable protection (cell viability increased to 97.86% of the control) against Aβ oligomer-treated human neuroblastoma SH-SY5Y cells, while having no intrinsic effect on cell viability.
DISCUSSION: Compounds 12a and 5g act as more specific Aβ oligomerization inhibitors than traditional polyphenols such as (-)-epigallocatechin-3-gallate (EGCG). The results may provide molecular insights for the rational design of potent Aβ aggregation inhibitors for AD therapy.
CONCLUSION: This study demonstrates that phenylalanine derivatives hold great promise as novel AD therapeutic leads.

Keywords:  Alzheimer’s disease; Amyloid-β; aggregation inhibitors; and neuroprotection.; molecular docking; oligomerization

DOI:  https://doi.org/10.2174/0115672050489243260827065622
Neurol Sci. 2026 Sep 08. pii: 764. [Epub ahead of print]47(10):

Cross-disease protein aggregate interactions in neurodegeneration: from molecular mechanisms to therapeutic strategies.

Wenqi Yang, Yan Lu.

   BACKGROUND: Neurodegenerative diseases have traditionally been classified by their predominant protein pathology. However, accumulating evidence reveals extensive molecular cross-talk between distinct pathological proteins, particularly in Alzheimer's disease (AD).
OBJECTIVE: This review examines cross-disease protein interactions and their implications for diagnosis and treatment.
METHODS: We systematically reviewed peer-reviewed literature published between 2020 and 2025, complemented by seminal earlier studies, examining molecular mechanisms of protein cross-seeding, clinical evidence of co-pathology, and emerging therapeutic strategies.
RESULTS: Cross-seeding between amyloid-β (Aβ), tau, α-synuclein, and TDP-43 has been demonstrated in vitro and in vivo. Harmonized autopsy studies reveal that 91% of individuals over 80 years harbor multiple neuropathologies. Co-pathology accelerates cognitive decline and complicates biomarker interpretation. Anti-amyloid immunotherapies lecanemab and donanemab demonstrate 27-35% slowing of cognitive decline, while anti-tau antibodies targeting N-terminal epitopes have uniformly failed, prompting investigation of combination approaches.
CONCLUSIONS: Recognition of cross-disease protein interactions necessitates a paradigm shift toward multi-target therapeutic strategies and precision medicine approaches accounting for individual co-pathology burden.

Keywords:  Alzheimer's disease; Amyloid-β; Cross-seeding; Immunotherapy; Neurodegeneration; TDP-43; Tau; α-Synuclein

DOI:  https://doi.org/10.1007/s10072-026-09364-y
Front Neurol. 2026 ;17 1934127

Expression differences and diagnostic efficacy of core plasma biomarkers in Alzheimer's disease, cerebral small vessel disease and healthy adults.

Wang Xiandong, Wu Junqi, Zhang Xuan, Ma Daichao, Zhao Xiaoyan, He Lihua, Zhang Hui.

   Objective: Alzheimer's disease (AD) and cerebral small vessel disease (CSVD) are the two leading causes of cognitive impairment in the elderly, with overlapping clinical manifestations. This study aimed to explore the expression differences of plasma Aβ1-42, Aβ1-40, Aβ1-42/Aβ1-40, p-Tau181, p-Tau217, NfL and GFAP among patients with AD, CSVD and healthy populations, and to evaluate the diagnostic value of these biomarkers for AD as well as the differential diagnostic efficacy between AD and CSVD.
Methods: A total of 120 participants were enrolled and divided into AD group, CSVD group and healthy control group, with 40 cases in each group. Plasma biomarkers were detected by chemiluminescence immunoassay, and cognitive function and neuroimaging examinations were completed simultaneously. The differences of biomarker levels among the three groups were compared. Spearman correlation analysis was used to analyze the correlation between each biomarker and MMSE score, and ROC curve was adopted to evaluate the diagnostic and differential diagnostic efficacy of single biomarker.
Results: Plasma Aβ1-42 and Aβ1-42/Aβ1-40 ratio were significantly decreased, while p-Tau181 and p-Tau217 were markedly elevated in the AD group. The GFAP level in the CSVD group was specifically and significantly higher than that in the AD group and healthy control group. NfL was significantly increased in both disease groups. p-Tau217 exhibited optimal efficacy in distinguishing AD from healthy controls (AUC = 0.894) and differentiating AD from CSVD (AUC = 0.877). GFAP showed excellent diagnostic value in distinguishing CSVD from healthy controls (AUC = 0.881). All biomarkers were significantly correlated with MMSE scores.
Conclusion: Among patients with isolated AD or isolated CSVD, plasma p-Tau217 is the optimal specific biomarker for the diagnosis of AD and differentiation between AD and cerebral small vessel disease. GFAP acts as a key indicator for identifying CSVD. These findings should be interpreted cautiously for patients with AD-CSVD co-pathology. Combined detection of multiple plasma biomarkers provides an important clinical basis for non-invasive early screening and etiological classification of cognitive impairment in patients with pathologically isolated cognitive disorders.

Keywords:  Alzheimer’s disease; cerebral small vessel disease; cognitive impairment; diagnostic efficacy; plasma biomarkers

DOI:  https://doi.org/10.3389/fneur.2026.1934127
Mol Cell Neurosci. 2026 Sep 07. pii: S1044-7431(26)00046-1. [Epub ahead of print]139 104116

Missense mutations in the SNCA gene: Molecular mechanisms and clinical implications.

Pranaya Gade, Nishant Patel, Jamir Pitton Rissardo, Jorge Patino, Ana Letícia Fornari-Caprara, Ian M Walker.

  The SNCA gene on chromosome 4 encodes the alpha-synuclein (αSyn) protein, which plays a central role in the pathogenesis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). While αSyn has established roles in synaptic vesicle dynamics and neuronal signaling, alterations in SNCA regulation and sequence contribute to protein misfolding, aggregation, and loss of function. Alterations in secondary and tertiary structure, as well as protein aggregation, affect biochemical interactions, ultimately leading to pathogenesis. This review outlines the molecular architecture of the SNCA gene, including regulatory regions, alternative splicing, and untranslated regions that influence αSyn expression and isoform diversity. Seven missense mutations of the SNCA gene are discussed in detail from the genomic level, extending to phenotypic presentations. These missense mutations have different effects on the aggregation kinetics and fibril formation. Specific genotype-phenotype correlations are evident, with mutations such as A30P and H50Q commonly resembling idiopathic PD, E46K strongly associated with DLB, and G51D, A53T, and A53E linked to atypical parkinsonism and MSA-like syndromes. Differences in age at onset, disease progression, cognitive involvement, and response to therapy further reflect mutation-specific effects and modifying influences of allelic dosage and epigenetic regulation. Collectively, these findings emphasize the importance of SNCA genetic variation in shaping disease phenotype and progression. Improving the understanding of SNCA genotype-phenotype relationships in future studies may facilitate earlier diagnosis, refine prognostic stratification, and support the development of targeted, disease-modifying therapies for synucleinopathies.

Keywords:  Molecular mechanisms; Neurodegeneration; Pathogenic variants; Protein aggregation; Structural modeling; Synucleinopathy

DOI:  https://doi.org/10.1016/j.mcn.2026.104116
J Am Chem Soc. 2026 09 02. 148(34): 37102-37109

Proteoform-Resolved Cross-Linking Reveals Environment-Dependent Structural Effects of α-Synuclein S129 Phosphorylation.

Ashlyn N Dollar, Daniel W Kelley, Ian K Webb.

Intrinsically disordered proteins (IDPs) drive many neurodegenerative disorders, but their structures remain difficult to define because they populate dynamic ensembles that change with the chemical environment. This problem is central for α-synuclein (aSyn), a Parkinson's disease-linked IDP in which S129 phosphorylation is highly enriched in disease-associated aggregates. Although S129 phosphorylation stabilizes a more compact aSyn ensemble in dilute solution, whether this structural effect persists across other biochemical environments has remained unknown. Here, we developed a quantitative cross-linking mass spectrometry framework to determine how WT and pS129 aSyn respond to chemically distinct environments. We compared dilute buffer with two perturbations relevant to aSyn biology: trimethylamine N-oxide (TMAO), a gut-microbiome-derived metabolite associated with Parkinson's disease that can also act as a compacting osmolyte at high concentration, and octyl glucoside (OG) micelles, which provide a membrane-mimetic surface. TMAO rewired the phosphorylation-dependent structural response in a concentration-dependent manner: 1.8 M TMAO shifted WT aSyn toward the dilute pS129 contact pattern by increasing long-range contacts between the N-terminal and C-terminal regions, whereas 3.4 M TMAO collapsed both proteoforms and reduced their structural differences. In OG micelles, the proteoforms diverged. WT favored an extended-helix-like contact pattern with stronger contacts between the C-terminal tail and micelle-bound N-terminal region, whereas pS129 favored contacts between the N-terminal and NAC regions and fewer contacts to the C-terminal tail, consistent with a broken-helix-like topology. By integrating regional contact counts, normalized cross-link intensities, and geometric compatibility analysis, this workflow distinguishes broad contact accessibility from the residue-level contacts that dominate each condition. These results establish a proteoform-by-environment model for IDP structure, in which phosphorylation effects are not fixed but are rewritten by the surrounding chemical environment.

DOI: https://doi.org/10.1021/jacs.6c10987