bims-amyloi 2026-08-09 papers

bims-amyloi

Biomed News

on Amyloid

Issue of 2026–08–09
29 papers selected by
Alexander Röntgen, University of Cambridge

Inhibition of amyloid β aggregation by venetoclax: a computational and in vitro experimental approach.
No Significant Secondary Structural Change of α-Synuclein Monomer by Site-Specific DOPA or Phosphorylation Introduction in Its C-Terminal Region.
Modulating amyloid-β 42 aggregation and neurotoxicity by Kunitz domains and their derived peptides.
Mechanistic insights into the inhibition of α-synuclein aggregation by sugar-based nanoparticles.
Human chaperone DNAJB6b suppresses tau fibril formation through co-aggregation.
Comparison of amyloid and tau pathology in the small and large intestines of individuals with Alzheimer's disease, Parkinson's disease, and Dementia with Lewy bodies.
Aggregation kinetics define the temporal window of IAPP proteotoxicity.
Distinct factors drive the progression of tau pathology in Alzheimer's disease.
Recent Advances in Autophagy and Immunotherapy for the Clearance of Aggregated α-Synuclein in Parkinson's Disease.
Molecular Dynamics Simulations of Aβ42 Dimers with Solid-State NMR Restraints Capture the Key Structural Motifs in Aβ42 Fibrillation Pathways.
Epitranscriptomic imprints on glial cell polarization: METTL3/IGF2BP2 axis as a driver of neurodegeneration in Alzheimer's disease.
Prospect of Muscle-Building Supplement HMB in Alzheimer's Disease.
Targeting Ubiquitinated Protein Aggregates in Neurodegenerative Diseases: current Status and Future Directions.
Curcumin attenuates α-synuclein pathology in Parkinson's disease model mice through modulation of UBC9-associated SUMOylation signaling.
Conformational determinants of glucagon stability and aggregation kinetics in aqueous and commercial formulations.
Gallein-Loaded Albumin Nanoparticles Prevent Amyloid-β-Induced Amyloidogenic APP Processing, Synaptic Loss, and Dendritic Pathology.
Aggregation and propagation of TAF15 trigger neurodegeneration.
Bioinformatic Tools to Explore the Mechanisms and the Multitarget Recognition of Huperzine A in Alzheimer's and Parkinson's Diseases.
Modulation of the phospholipid dynamics and bilayer water accessibility with the membrane-associated nucleation of β-amyloid (Aβ) peptides.
Brain insulin resistance as a driver of proteinopathy in neurodegeneration: from cell-type-specific mechanisms to targeted therapeutics.
Proteomic comparison of hippocampal neurofibrillary tangles in PART, intermediate Alzheimer's disease and advanced Alzheimer's disease.
The Oral-Brain Axis: Mechanistic Insights Linking Periodontitis With Alzheimer's and Parkinson's Diseases.
Polymorphic structures of rapidly twisting 40-residue amyloid-β fibrils.
A single-domain antibody targets aggregation-prone region of α-synuclein to reduce synucleinopathy, rescue neurodegeneration and improve function.
GPR146 Deficiency Enhances Microglial Phagocytosis and Blood-Brain Barrier-Associated Markers in an Acute Amyloid-β Model.
α-Synuclein blocks endoplasmic reticulum co-translational protein translocation early in Parkinson's disease.
Phase separation leads to significant conformational change in the N-terminal region of the prion protein.
Kaempferol-Conjugated Manganese Oxide Nanocomposites Mitigate Aluminium Chloride-Induced Neurobehavioral Impairments in a Rat Model of Alzheimer's disease.
Plasma Concentrations of Amyloid-β Peptides, BACE-1, and Tau Proteins in Alzheimer's Disease.

RSC Adv. 2026 Aug 03.

Inhibition of amyloid β aggregation by venetoclax: a computational and in vitro experimental approach.

Bei-Bei Liu, He-Cheng Wang, Yi-le He, Liu-Jie Zhang, Dong-Li Meng, Yun Fu, Ming-Yong Wang, Wei Zhang.

The aggregation of amyloid β-protein (Aβ) plays a key role in the pathological progression of Alzheimer's disease (AD). Given the current absence of effective therapeutic strategies, the drug repurposing approach provides novel insights into the treatment of AD. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor, has demonstrated remarkable efficacy in the treatment of hematological malignancies, characterized by well-defined pharmacokinetic properties and a favorable safety profile. However, its effects and molecular mechanisms in the treatment of AD remain unexplored. Here, we investigated the potential of venetoclax in the inhibition of Aβ aggregation and elucidated its underlying mechanism. The inhibitory effect of venetoclax on Aβ aggregation was assessed using thioflavin T (ThT) fluorescence assays, transmission electron microscopy (TEM), and circular dichroism (CD) spectroscopy. Cellular assays were performed to evaluate the neuroprotective effects of venetoclax against Aβ42-induced neurotoxicity and oxidative stress. Molecular dynamics (MD) simulations were conducted to explore the molecular interactions between venetoclax and Aβ42 peptides. Venetoclax significantly inhibited Aβ aggregation, reduced fibril formation, and decreased β-sheet content at molar ratios of 2 : 1 and 1 : 1 (Aβ : venetoclax). Cellular assays showed that venetoclax attenuated Aβ42-induced neurotoxicity and oxidative stress. MD simulations revealed that venetoclax stabilized Aβ peptides via hydrogen-bonding networks, increasing solvent accessibility and reducing hydrophobic interactions. Venetoclax inhibited Aβ aggregation and mitigated Aβ-induced neurotoxicity by stabilizing Aβ peptide dynamics. These findings support the potential of venetoclax as a repurposed therapeutic candidate for AD.

DOI: https://doi.org/10.1039/d6ra03199d
J Pept Sci. 2026 Sep;32(9): e70118

No Significant Secondary Structural Change of α-Synuclein Monomer by Site-Specific DOPA or Phosphorylation Introduction in Its C-Terminal Region.

Tatsuhito Matsuo, Isao Suetake, Mariko Kimura, Satoshi Hashimoto, Koichi Matsuo, Sakiko Matsumoto, Shinji Hirotsune, Hironobu Hojo.

α-Synuclein (αSyn) is a major component of pathogenic Lewy bodies and Lewy neurites and is closely associated with Parkinson's disease. Among the various posttranslational modifications of αSyn, several have been implicated in the degeneration of dopaminergic neurons and are thought to promote Parkinson's disease through enhanced misfolding, aggregation, and accumulation of αSyn. Two such modifications, phosphorylation at Ser129 (S129Phos) and hydroxylation at Tyr136 (Y136DOPA), exert distinct effects on αSyn aggregation: S129Phos has been reported to either inhibit or promote aggregation, whereas Y136DOPA induces the formation of short oligomeric species. To gain insight into the molecular basis underlying the initiation of αSyn multimerization, we semisynthesized αSyn carrying either S129Phos or Y136DOPA and prepared recombinant unmodified full-length αSyn as a control. Vacuum-ultraviolet circular dichroism (VUVCD) spectroscopy revealed that these αSyn variants in their monomeric states possessed essentially identical secondary structures. These results suggest that the modifications themselves do not induce significant secondary structural changes in monomeric αSyn.

DOI: https://doi.org/10.1002/psc.70118
N Biotechnol. 2026 Aug 07. pii: S1871-6784(26)00097-X. [Epub ahead of print]

Modulating amyloid-β 42 aggregation and neurotoxicity by Kunitz domains and their derived peptides.

Maya Rabinovich, Shiran Lacham-Hartman, Niv Papo.

  Alzheimer's disease is associated with the aggregation of amyloid-β42 (Aβ42) into species of varying sizes, with intermediate oligomers being the most neurotoxic. We recently reported that amyloid precursor protein inhibitor (APPI), a Kunitz-type protein, and a cyclic peptide derived from its β-domain reduced Aβ42-mediated neurotoxicity, the former by reducing Aβ42 aggregation and formation of toxic Aβ42 oligomers, and the latter by promoting Aβ42 aggregation to form fibrils rather than the neurotoxic Aβ42 oligomers. To address the question of whether these two inhibition mechanisms are controlled by the structure or the amino acid sequence of the protein/peptide, we exploited three Kunitz-type proteins, bikunin, bovine pancreatic trypsin inhibitor (BPTI) and tissue factor pathway inhibitor (TFPI) - chosen for their similar β-strand-rich structures but different sequences to one another and to APPI - and also short peptides that mimic their β-domains, in either cyclic or linear conformation. In-vitro studies showed that the formation of Aβ42 aggregates was reduced by the three Kunitz-type proteins and by their derived cyclic peptides, but not by the linear counterparts of the cyclic peptides. In SH-SY5Y neuroblastoma cells, the Kunitz-type proteins and the cyclic (but not the linear) peptides reduced the intracellular and extracellular accumulation of Aβ42 aggregates, respectively. Both the Kunitz-type proteins and the cyclic peptides inhibited Aβ42-induced mitochondrial membrane depolarization and reduced Aβ42-mediated apoptosis and cell death. Overall, this study thus reveals the potential of the β-hairpin structure, whether as a segment within the Kunitz-type proteins or isolated as a cyclic peptide, to interact with Aβ42, thereby reducing Aβ42 aggregation and hence its neurotoxicity.

Keywords:  Alzheimer's disease; Aβ42 aggregation; BPTI; Kunitz-type proteins; TFPI; bikunin; neurotoxicity; β-hairpin

DOI:  https://doi.org/10.1016/j.nbt.2026.08.001
Biochim Biophys Acta Proteins Proteom. 2026 Aug 02. pii: S1570-9639(26)00045-2. [Epub ahead of print] 141168

Mechanistic insights into the inhibition of α-synuclein aggregation by sugar-based nanoparticles.

Danish Alam, Tanzeel Khan, Iqra Sadiq, Priyanka Mudad, Malik Aquib Javed, Tokeer Ahmad, Asimul Islam, Meryam Sardar.

  The pathological accumulation of α-synuclein (α-syn) into amyloid fibrils is a key hallmark of Parkinson's disease and related synucleinopathies. Inhibiting the early stages of α-syn aggregation remains a major therapeutic challenge. In this work, we report the fabrication and investigation of five sugar-based nanoparticles (NPs), including glucose, fructose, maltose, sucrose, and trehalose, and their ability to inhibit α-synuclein aggregation. Using a combination of biophysical strategies, comprising thioflavin-T fluorescence, dynamic light scattering, circular dichroism, and confocal microscopy, we illustrate that sugar NPs prevent β-sheet formation and the growth of α-syn fibrils in a concentration-dependent manner. Isothermal titration calorimetry revealed spontaneous, high-affinity interactions between α-syn and sugar NPs, suggesting direct binding to aggregation-prone regions. Importantly, cytotoxicity assays using SH-SY5Y neuroblastoma cells showed that NP-treated α-syn aggregates exhibited significantly reduced neurotoxicity. Collectively, these findings demonstrate that sugar-derived nanoparticles act as potent inhibitors of α-syn aggregation during the lag phase, thereby stabilizing non-toxic conformers. These results highlight the promise of sugar-based nanostructures as biocompatible and mechanistically active molecules for modulating synucleopathies associated with various neurodegenerative disorders.

Keywords:  Aggregation; Neurodegenerative disorders; Sugar nano-osmolytes; α-synuclein

DOI:  https://doi.org/10.1016/j.bbapap.2026.141168
Commun Chem. 2026 Aug 01. pii: 263. [Epub ahead of print]9(1):

Human chaperone DNAJB6b suppresses tau fibril formation through co-aggregation.

Andreas Carlsson, Emil Axell, Johan Wallerstein, Dev Thacker, Ulf Olsson, Sara Linse.

The aggregation of the tau protein into intraneuronal fibrillar tangles is closely associated with the pathology of Alzheimer's disease. The endogenous defense system against this process includes molecular chaperones, among which DNAJB6b has emerged as a key component. Using a tau model system comprising the tau fragment 304-380C322S, which spans the amyloidogenic core of ex vivo Alzheimer's disease fibrils, we investigated the impact of DNAJB6b on tau fibril formation. Here, we show that DNAJB6b potently delays tau aggregation by co-assembling with small tau aggregates and by binding to mature fibrils, thereby reducing their ability to catalyze further fibril growth. This interplay between tau and the chaperone results in greatly reduced fibril formation rate and a lower final fibril mass, which we interpret as increased tau solubility. Moreover, solution-state NMR spectroscopy confirms that DNAJB6b does not interact with tau monomers.

DOI: https://doi.org/10.1038/s42004-026-02108-1
MicroPubl Biol. 2026 ;2026

Comparison of amyloid and tau pathology in the small and large intestines of individuals with Alzheimer's disease, Parkinson's disease, and Dementia with Lewy bodies.

Angela M Floden, Gunjan D Manocha, Natalia I Frolov, Andrea E Lerick, Colin K Combs.

Alzheimer's disease (AD) brains are characterized by accumulations of neurofibrillary tangles and amyloid β (Aβ) plaques. Since enteric neurons express tau and the amyloid precursor protein (APP), we asked whether neurofibrillary tangles and Aβ aggregates were present in AD intestines compared to healthy controls and individuals with Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Neuron-like APP and Aβ immunoreactivities were observed in all groups with no observable plaques. No tangle-like structures were observed in any group although p-Ser 396/404 tau immunoreactivity was seen. The enteric nervous system appears to be protected from developing tangle and plaque pathology in AD.

DOI: https://doi.org/10.17912/micropub.biology.002056
Proc Natl Acad Sci U S A. 2026 Aug 11. 123(32): e2615786123

Aggregation kinetics define the temporal window of IAPP proteotoxicity.

Annette Plesner, Ping Cao, Daniel P Raleigh, Andisheh Abedini.

  Aggregation of islet amyloid polypeptide (IAPP) to form amyloid contributes to β-cell dysfunction in type 2 diabetes, yet the identity and temporal persistence of the toxic species is unresolved. Competing models attribute toxicity to mature fibrils, fibril growth, or transient prefibrillar intermediates formed during the lag phase or via secondary nucleation. Here, we directly test these models by combining time-resolved β-cell functional assays with concurrent biophysical measurements of IAPP aggregation across multiple perturbations and sequence variants. Across 22 independent experiments spanning more than a 450-fold range in lag times, we find that maximal toxicity occurs during the lag phase and declines as fibrils accumulate. The duration of β-cell dysfunction scales linearly with lag phase length, establishing aggregation kinetics as a quantitative predictor of the onset, peak, and termination of toxicity. Perturbations that alter aggregation kinetics, including concentration, temperature, and sequence, predictably shift the temporal window of toxicity. The diabetes-associated S20G variant produces higher peak toxicity over a compressed time window, whereas the slower-aggregating variants examined prolong toxicity without increasing its magnitude. These results resolve competing models by demonstrating that transient lag-phase intermediates, rather than growth phase processes or mature fibrils, dominate β-cell dysfunction, and establish aggregation kinetics as a predictor of the timing and duration of cellular exposure to toxic intermediates.

Keywords:  IAPP; amylin; amyloid; beta cell; diabetes

DOI:  https://doi.org/10.1073/pnas.2615786123
Fundam Res. 2026 Jul;6(4): 2289-2298

Distinct factors drive the progression of tau pathology in Alzheimer's disease.

Yifan Luo, Honglu Yu, Keqiang Ye.

  Alzheimer's disease (AD) is the most common cause of dementia worldwide. The primary histopathological markers for AD diagnosis are extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs), featured by aggregation of hyperphosphorylated and truncated tau proteins. Emerging evidence shows that tau pathology, rather than amyloid-β deposition, exhibits a stronger correlation with brain atrophy and cognitive decline in AD, emphasizing its pivotal role in disease progression. However, the molecular mechanisms of tau propagation in the brain are incompletely understood, and there is no effective therapy to halt tau pathology propagation in AD. In this review, we summarize current knowledge on the multifactorial triggers of tau pathology in AD in the aspects of (1) physiological or pathological driving factors, (2) different types of brain cells and (3) key regulatory proteins that steer tau aggregation and spread. Based on these findings, we also critically evaluate the current and potential therapeutic strategies against tau pathology in AD. Together, this review provides a comprehensive understanding of tau pathology regulation and highlights promising strategies for therapeutic intervention.

Keywords:  Alzheime’s disease; Cognitive impairment; Neurodegenerative diseases; Neurofibrillary tangles; Tau pathology

DOI:  https://doi.org/10.1016/j.fmre.2025.04.001
Aging Dis. 2025 Aug 06. 17(5): 2468-2489

Recent Advances in Autophagy and Immunotherapy for the Clearance of Aggregated α-Synuclein in Parkinson's Disease.

Khoshnur Jannat, Sang-Bong Lee, Hong-Ryeol Jung, Rengasamy Balakrishnan, Yon-Suk Kim, Mujeeb Ur Rahman, Dong-Kug Choi.

Parkinson's disease is a neurodegenerative condition characterized by the accumulation of misfolded and aggregated α-synuclein in Lewy bodies and neurites. These protein aggregates contribute to neurodegeneration and motor symptoms such as bradykinesia, rigidity, and tremor. While the ubiquitin-proteasome system degrades soluble α-synuclein, aggregated and oligomeric forms are primarily cleared via the autophagy-lysosomal pathway. Mutations of the SNCA gene exacerbate α-synuclein aggregation and significantly impair its clearance, highlighting the importance of targeting toxic α-synuclein species. Strategies such as promoting autophagosome formation via 5'-AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) or facilitating autophagosome maturation via RAB7-a member of the RAS oncogene family-and related effectors, have shown promise in enhancing autophagy and reducing α-synuclein pathology. Pharmacological agents such as rapamycin, trehalose, and nilotinib have demonstrated preclinical efficacy in enhancing α-synuclein clearance and alleviating disease features. Concurrently, immunotherapy approaches, including passive and active immunization, aim to enhance the immune system's ability to recognize and eliminate toxic α-synuclein species. Emerging strategies such as peptide-based therapies aim to inhibit aggregation or promote degradation of α-synuclein. At the same time, nanotechnology enables the targeted delivery of therapeutic agents across the blood-brain barrier with improved efficiency. Additionally, novel AUTOTAC (autophagy-targeting chimera) platforms offer a precision strategy to tag α-synuclein for autophagic degradation. This review explores many advances in autophagy-mediated aggregated α-synuclein clearance, emphasizing its potential as a therapeutic strategy to address the limitations of current symptomatic treatments and slow the progression of Parkinson's disease.

DOI: https://doi.org/10.14336/AD.2025.0642
ACS Omega. 2026 Jul 28. 11(29): 44425-44433

Molecular Dynamics Simulations of Aβ42 Dimers with Solid-State NMR Restraints Capture the Key Structural Motifs in Aβ42 Fibrillation Pathways.

Angelo L Chu, Betty S L Chu, Wei Qiang.

Formation of the β-amyloid (Aβ) plaques is a pathological hallmark of Alzheimer's disease (AD) and is believed to be a primary cause of dementia in elderly individuals. In the present work, we performed molecular dynamics (MD) simulations on the conformational evolution of Aβ42 dimers in solution and in a membrane-like environment to explore the folding of Aβ42 during fibrillation. Particularly, the MD simulation was steered by experimental internuclear distance restraints obtained using solid-state nuclear magnetic resonance (ssNMR) spectroscopy. Our results revealed that several hydrophobic and polar motifs within the Aβ42 sequence played key roles in the early-stage nucleation process of fibrillation, and these motifs are also the stabilizing agents in the mature fibrils, as judged by the energy contribution. Our results also indicated that the membrane-binding of small Aβ oligomers could modulate their structural evolution pathways toward fibrillation. These findings contributed to a better understanding of the molecular-level structural polymorphisms inherent to Aβ42 fibrils. Further, the current work demonstrated that the combination of MD simulations with ssNMR-based experimental restraints provided a reliable method for studying structural changes of Aβ.

DOI: https://doi.org/10.1021/acsomega.6c05189
Psychopharmacology (Berl). 2026 Aug 05.

Epitranscriptomic imprints on glial cell polarization: METTL3/IGF2BP2 axis as a driver of neurodegeneration in Alzheimer's disease.

Neha, Khadga Raj Aran.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving synapse dysfunction, neuronal death and disorientation of cognitive processes that are caused by the accumulation of amyloid-β (Aβ) along with aberrant phosphorylation of tau. Aberrant proteolytic processing of amyloid precursor protein (APP) promotes Aβ production, which is pro-oxidant, activates microglia, and promotes chronic neuroinflammation. In parallel, neurofibrillary tangle formation, microtubule destabilisation, and impaired axonal transport are the consequences of pathological tau phosphorylation, which together are associated with accelerated neuronal degeneration. Recent findings implicate epitranscriptomic Dysregulation as an important, but understudied, component of AD pathobiology. In particular, emerging evidence suggests that the expression and activity of METTL3 are dynamically regulated throughout the course of AD, with up- or down-regulation at different disease stages, in specific brain regions, and across cell types, indicating that METTL3 signalling is dysregulated rather than uniformly increased or decreased in AD pathogenesis. Therefore, the changes in m6A deposition mediated by METTL3 could be different in various pathological contexts and cell types, with different downstream consequences in terms of neuronal survival, glial activation and inflammatory signalling. Context-dependent dysregulation of this regulatory axis drives a pronounced elevation in important pro-inflammatory mediators and promotes pyroptosis, including NLRP3, IL-1β, and STAT3, thereby enhancing glial activation, inflammasome assembly and caspase-dependent neuronal death. Integrating the Ab-mediated pathology, tau-mediated cytoskeletal dysfunction and chronic neuroinflammation, the METTL3/IGF2BP2 pathway defines a convergence point that helps break down neuronal homeostasis and plasticity. This review compiles new mechanistic truths of how m6A-dependent RNA regulation contributes to the progression of AD and discusses therapeutic opportunities of METTL3/IGF2BP2 axis targeting for novel RNA-based therapies for neurodegenerative disease.

Keywords:  Alzheimer’s disease; Amyloid β; Glial cell; METTL3/IGF2BP2; m6A methylation

DOI:  https://doi.org/10.1007/s00213-026-07137-1
J Clin Exp Immunol. 2026 ;11(3):

Prospect of Muscle-Building Supplement HMB in Alzheimer's Disease.

Abhiram Uppalapati, Ahiri Vishnubhotla, Kalipada Pahan.

  Alzheimer's disease (AD) is the most common progressive and irreversible neurodegenerative disorder in humans that affects memory, thinking and behavior. Impairment in synaptic plasticity is one of the hallmarks in AD, with most of the impairment occurring in the hippocampal region, a key part of the brain for memory and learning. Therefore, the upregulation of hippocampal plasticity is critical to remediate the progression of AD and preserve memory formation and cognitive functions. Recent studies have described β-hydroxy-β-methylbutyrate (HMB), a body building supplement commonly used by athletes, as a candidate molecule for improving hippocampal plasticity. Clinically, AD is characterized by the abnormal accumulation of beta amyloid (Aβ) plaques, coupled with intracellular aggregates of hyperphosphorylated tau protein. In addition to enhancing hippocampal plasticity, HMB has been also demonstrated to lower amyloid plaques in a mouse model of AD. Although liver is rich in peroxisome proliferator-activated receptor alpha (PPARα), recent findings have established the presence of PPARα in hippocampus and other parts of the brain. Interestingly, HMB has been shown to utilize PPARα for lowering plaques and increasing hippocampal plasticity. Here, we discuss these newly described features of HMB with possible implications for the use of HMB supplement in patients with dementia and AD.

Keywords:  ADAM10; Alzheimer’s Disease; Amyloid Plaque; Autophagy; CREB; HMB; Hippocampal Plasticity; PPARα; TFEB

DOI:  https://doi.org/10.33140/jcei.11.03.01
Mol Cell Biol. 2026 Aug 04. 1-19

Targeting Ubiquitinated Protein Aggregates in Neurodegenerative Diseases: current Status and Future Directions.

Masahiko Takahashi, Takayuki Abe, Masahiro Fujii.

  Various cellular stressors inhibit translation initiation and promote ribosome disassembly, thereby transiently inducing stress granules (SGs), dynamic ribonucleoprotein condensates that contain mRNAs and RNA-binding proteins. Although SG assembly is usually reversible, dysregulated SG dynamics can trigger the formation of persistent ubiquitin-positive protein inclusions. There is increasing evidence that this conversion of SGs into insoluble aggregates represents a central pathogenic mechanism in neurodegenerative proteinopathies, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). TAR DNA-binding protein 43 (TDP-43) and Tau are causative factors in ALS and AD, respectively, and both localize to SGs under stress conditions. During disease progression, TDP-43 or Tau within SGs undergoes pathological changes that promote the formation of neurotoxic inclusions, which propagate neuronal dysfunction and death. This review summarizes recent advances in understanding the molecular factors that regulate SG assembly and disassembly, as well as the pathological processes that drive the conversion of SGs into aggregates associated with neurodegenerative diseases. Particular emphasis is placed on the role of the ubiquitin-specific protease 10 (USP10), which modulates SG dynamics and has been mechanistically implicated in both ALS and AD. Finally, we discuss the therapeutic potential of targeting these pathways to mitigate neurodegenerative disease progression.

Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; stress granule; ubiquitin-specific protease 10

DOI:  https://doi.org/10.1080/10985549.2026.2705871
Front Neurosci. 2026 ;20 1885786

Curcumin attenuates α-synuclein pathology in Parkinson's disease model mice through modulation of UBC9-associated SUMOylation signaling.

Yao Li, Zhuang Zhu, Kezhong Zhang.

   Background: Post-translational modifications, particularly SUMOylation, plays a crucial role in α-synuclein (α-syn) aggregation, a key pathological feature of Parkinson's disease (PD). Curcumin, a natural polyphenol, has shown neuroprotective potential, but its effects on SUMOylation-related signaling in PD remain unclear.
Objective: This study aimed to investigate whether curcumin modulates α-syn SUMOylation and to elucidate the underlying molecular mechanisms in PD model mice.
Methods: A PD model was established in male C57BL/6 mice via unilateral intrastriatal injection of α-syn preformed fibrils (PFFs). Six months after α-syn PFFs injection, mice were treated intravenously with curcumin (25 mg/kg/day) or vehicle for 1 month. Behavioral tests (open field, rotarod) assessed motor function. Neuropathology was evaluated by immunohistochemistry and western blotting for tyrosine hydroxylase (TH), phosphorylated α-syn (p-syn), SUMOylation pathway components (SUMO1, SAE2, UBC9, PIAS1/2), and ubiquitin. Striatal dopamine levels were measured by HPLC.
Results: Curcumin treatment ameliorated motor deficits and anxiety-like behaviors in PD mice. It partially preserved dopaminergic neurons and reduced p-syn aggregation in the substantia nigra, accompanied by increased striatal dopamine levels. Mechanistically, curcumin was associated with reduced SUMO1 and increased ubiquitin levels, suggesting modulation of SUMOylation-related signaling. Among SUMOylation enzymes, UBC9 expression was decreased, whereas E1 (SAE2) and E3 (PIAS1/2) components were not substantially affected.
Conclusion: Our findings demonstrated that curcumin exerted neuroprotective effects in a PD model by attenuating α-syn pathology. The protective mechanism involves the inhibition of α-syn SUMOylation, primarily through the downregulation of the UBC9 enzyme. This study identifies UBC9-mediated SUMOylation as a potential target for curcumin and highlight a promising strategy for modifying α-syn-associated pathology in PD.

Keywords:  SUMOylation; UBC9; curcumin; neuroprotection; α-synuclein

DOI:  https://doi.org/10.3389/fnins.2026.1885786
Protein Sci. 2026 Sep;35(9): e70750

Conformational determinants of glucagon stability and aggregation kinetics in aqueous and commercial formulations.

Angelo Santoro, Marco Macis, Michela Buonocore, Antonio Ricci, Anna Maria D'Ursi.

  Glucagon is a well-established therapeutic peptide, widely used to treat hypoglycemia. Like many peptide drugs, it offers advantages such as specificity, biocompatibility, and high affinity for receptor targets, but suffers from limited physical and chemical stability. In particular, improper conditions can promote the formation of amyloid fibrils, leading to loss of biological activity and, in some cases, cytotoxicity. Understanding the conditions that modulate the structural behavior of glucagon is therefore crucial. Currently, two injectable formulations are available on the market: a lyophilized vial of glucagon with lactose at acidic pH, and a more recent auto-injector ready-to-use (RTU) formulation containing glucagon in dimethyl sulfoxide (DMSO) with trehalose. In this study, we investigated the conformational properties of glucagon in these two marketed formulations and compared them with glucagon dissolved in aqueous solution at pH 3.5, a metastable condition prone to aggregation. Preliminary circular dichroism and fluorescence spectroscopy were used to confirm glucagon stability over time; subsequently, NMR analysis showed that structural destabilization consistently begins at the C-terminal region, while the 11Ser-Leu14 segment remains structured across all environments. These findings highlight two key determinants of glucagon stability and aggregation. Strategies that preserve the integrity of the C-terminal region while stabilizing the 11Ser-Leu14 motif may improve peptide solubility and extend shelf life, providing a rational basis for the design of next-generation glucagon formulations for emergency use.

Keywords:  conformational stability; glucagon; peptide aggregation; peptide formulation; structure–stability relationship

DOI:  https://doi.org/10.1002/pro.70750
Mol Neurobiol. 2026 Aug 06. pii: 816. [Epub ahead of print]63(1):

Gallein-Loaded Albumin Nanoparticles Prevent Amyloid-β-Induced Amyloidogenic APP Processing, Synaptic Loss, and Dendritic Pathology.

Romina Soledad Almirón, Cecilia Tettamanti, Sofía Martinez, Magdalena Antonino, Paula Marmo, Ángela Debiagge, Delfina Toselli, Lucia Moro, Daniel Allemandi, Alfredo Lorenzo, Daniela Alejandra Quinteros, Elena Anahi Bignante.

  Alzheimer's disease (AD) is a multifactorial and highly debilitating disorder with a long clinical course. The development of new therapeutic strategies capable of mitigating or delaying disease progression remains a major challenge. We previously identified the amyloid precursor protein (APP) as a receptor for aggregated amyloid-β (Aβ) species that signals through a Go/Gβγ-dependent pathway, thereby promoting amyloidogenesis and neurotoxicity. In this context, gallein (GAL), a selective inhibitor of Gβγ signaling, has demonstrated robust neuroprotective effects in preclinical AD models. However, GAL exhibits poor stability and limited aqueous solubility, which may restrict brain bioavailability. To overcome these limitations, a nanotechnology-based formulation strategy was implemented. Here, we report the design and generation of human serum albumin-based nanoparticles (HSA NPs) loaded with GAL (NP-GAL) using a green desolvation method followed by thermal stabilization. Using murine neuroblastoma cells, primary rat cortical neurons, and human iPSC-derived neurons, we demonstrate that NP-GAL effectively prevents Aβ-induced amyloidogenic APP processing, dendritic dystrophy, and presynaptic loss. In addition, both empty NPs and NP-GAL exhibit association with Aβ aggregates, suggesting an additional benefit, as these nanoparticles mitigate amyloid-associated toxicity. Notably, the nanoparticles themselves exert beneficial effects on dendritic morphology and provide protection against neurotoxic insults beyond amyloid pathology, including those induced by rotenone, a widely used experimental model of Parkinson's disease. Together, these in vitro findings suggest that HSA-based nanoparticles hold potential as a platform to stabilize GAL and exert intrinsic neuroprotective effects. These results provide a proof-of-concept for exploring nanoparticle-mediated Gβγ inhibition to counteract Aβ-induced neuronal dysfunction and synaptic pathology.

Keywords:  Alzheimer’s disease; Amyloid beta; Gallein; Human Serum Albumin; Nanoparticle; Neuroprotection

DOI:  https://doi.org/10.1007/s12035-026-06116-z
Neuron. 2026 Aug 06. pii: S0896-6273(26)00490-3. [Epub ahead of print]

Aggregation and propagation of TAF15 trigger neurodegeneration.

Lanxia Meng, Congcong Liu, Huangchuan Gong, Yan Gao, Meihui Li, Han Liu, Hanying Teng, Min Xiong, Hui Liu, Mingmin Yan, Dae Ki Hong, Seong Su Kang, Jing Xiong, Zhentao Zhang.

  Protein misfolding and propagation contribute to neurodegenerative diseases. Recently, cryogenic electron microscopy of insoluble amyloid fibrils derived from individuals with frontotemporal lobar degeneration (FTLD) revealed new species of amyloid fibrils, which are composed of aggregated TATA-binding protein-associated factor 15 (TAF15). However, it remains unknown whether TAF15 fibrils propagate in a prion-like manner and drive neurodegeneration. Here, we show that TAF15 forms amyloid fibrils that can self-propagate. Strikingly, a single injection of synthetic TAF15 pre-formed fibrils into the prefrontal cortex of wild-type mice led to the aggregation of endogenous TAF15 and cell-to-cell transmission of pathologic TAF15. TAF15 pathology was accompanied by progressive degeneration of cortical neurons, cognitive impairments, and anxiety- and depression-like behaviors. The detrimental effects of TAF15 fibrils were abolished by genetic deletion of endogenous TAF15. Together, these observations indicate that TAF15 aggregation drives neurodegeneration.

Keywords:  FTLD; TAF15; aggregation; cognitive impairments; neurodegeneration

DOI:  https://doi.org/10.1016/j.neuron.2026.06.022
Curr Drug Targets. 2026 Jul 28.

Bioinformatic Tools to Explore the Mechanisms and the Multitarget Recognition of Huperzine A in Alzheimer's and Parkinson's Diseases.

Luis Antonio Ramirez-Contreras, Gabriela Camargo-Hernández, Sergio Sanchez-Enriquez, Jorge Manuel Silva-Jara, Salvador Hernández Estrada, Luis Alfonso Hernández Villaseñor, Luis Miguel Anaya Esparza.

   INTRODUCTION: Considering the shared physiological mechanisms between Alzheimer's disease (AD) and Parkinson's disease (PD), it is plausible that certain compounds may exert therapeutic effects on both neurological disorders. This study aimed to employ in silico techniques to investigate the pharmacological mechanisms of huperzine A (HA) as an alternative treatment for PD and AD.
METHODS: Molecular targets of HA and genes associated with AD and PD were identified from public databases. Gene Ontology analysis, metabolic pathway analysis, and protein-protein interaction (PPI) network construction were performed to identify shared molecular targets. Molecular docking was performed to assess HA affinity for hub proteins and to compare it with that of drugs used to treat AD and PD.
RESULTS: The results suggested that HA interacts with 77 molecular targets common to both diseases. Enrichment analysis revealed that proteins from these targets were involved in biological functions, such as serotonin and amine binding. Hub proteins (SRC, TP53, AKT1, and CASP3) were identified from the PPI network. Furthermore, molecular docking simulations showed favorable binding of HA to the hub proteins and adequate binding to the targets of standard drugs (MAOB and ACHE). On the other hand, molecular dynamics analyses were performed to compare the binding characteristics of HA with those of the control targets.
DISCUSSION: HA may modulate SRC, CASP3, and AKT1, suggesting a pleiotropic mechanism underlying the association between AD and PD. These computational findings provide a rational basis for experimental validation by modulating signaling pathways implicated in inflammatory processes and inhibiting enzymes involved in neurotransmitter degradation.
CONCLUSION: This study contributes to the understanding of the neuroprotective activity of HA in AD and PD. However, further in vitro and in vivo investigations are required to confirm the dual therapeutic potential of HA in the treatment of AD and PD.

Keywords:  Biocompounds; molecular docking; network pharmacology; neuroprotection

DOI:  https://doi.org/10.2174/0113894501499352260714060149
Biophys Chem. 2026 Nov;pii: S0301-4622(26)00126-2. [Epub ahead of print]338 107693

Modulation of the phospholipid dynamics and bilayer water accessibility with the membrane-associated nucleation of β-amyloid (Aβ) peptides.

Brian Lum, Wei Qiang.

  Membrane disruption along the amyloidogenic aggregation of β-amyloid (Aβ) peptides is considered a molecular mechanism for the Aβ-induced cell toxicity and death. Yet, the underlying structural basis for the harmful Aβ-membrane interactions that lead to disruption remains poorly understood. We have been utilizing solid-state nuclear magnetic resonance (ssNMR) spectroscopy to explore the intermediate states of membrane-associated Aβ aggregation, as well as their roles in membrane disruption process. Aligning with this general objective, complementary quantitative ssNMR spectroscopy focusing on the modulation of phospholipid dynamics in membrane bilayers will provide useful insight about how these intermediate states influence the physicochemical properties and architecture of membranes. In the current work, we systematically investigate how specific molecular motions of phospholipids change in the presence of membrane-associated 40- and 42-residue Aβ isoforms, within the time frame of nucleation processes. Physicochemical parameters, including the lipid headgroup and lateral diffusive motion correlation time, the lipid alkyl chain to headgroup 1H1H cross relaxation rate, and the H2O-assisted 1H13C cross polarization rate to lipid alkyl 13Cs, were monitored by various ssNMR spectroscopic approaches. The outcomes suggest a general rigidification of bilayers upon instant Aβ-bilayer interactions across different bilayer phospholipid compositions and Aβ isoforms, accompanied by increase of water accessibility to bilayer interiors. These observations, together with the knowledge of molecular structural evolution of Aβ within the same time frame, help to establish a molecular-level, schematic explanation of the membrane-associated Aβ nucleation process.

Keywords:  Early-stage intermediates; Lipid dynamics; Membrane interactions; Solid-state NMR spectroscopy; β-Amyloid peptides

DOI:  https://doi.org/10.1016/j.bpc.2026.107693
Transl Neurodegener. 2026 Aug 03. pii: 36. [Epub ahead of print]15(1):

Brain insulin resistance as a driver of proteinopathy in neurodegeneration: from cell-type-specific mechanisms to targeted therapeutics.

Man Xiang, Si-Yu Cao, Xue-Heng Sun, Jing-Wen Hu, Ming-Zhe Lv, Jia-Yi Li, Wen Li.

  Neurodegenerative diseases are increasingly linked to systemic metabolic dysfunction, with brain insulin resistance (BIR) positioned as a central mediator. Yet translating this insight into effective therapies has proven remarkably difficult. This review argues that BIR-driven neurodegeneration should be interpreted at two distinct but interconnected levels: cell-type-specific disruption of brain homeostasis by BIR, and the direct, mechanistic role of BIR in driving the proteinopathies that define Alzheimer's and Parkinson's diseases. We first show how BIR produces distinct functional deficits across neurons, astrocytes, microglia, and oligodendrocytes, impairing synaptic plasticity, metabolic coupling, immunometabolic homeostasis, and myelination, resulting in a cellular milieu that favors proteinopathy. We then map molecular pathways through which BIR directly distrubs the metabolism of amyloid-β, tau, and α-synuclein. We further examine how islet amyloid polypeptide cross-seeds cerebral amyloid pathology, suggesting a direct molecular interaction between the peripheral drivers of BIR and protein aggregation. In this framework, BIR functions not as a passive risk factor, but as an active, upstream driver of proteostatic collapse. Cellular dysfunction combined with proteostatic failure, defines the therapeutic target space. We evaluate interventions accordingly, distinguishing those that primarily restore cellular function from those that enhance protein clearance, and those that achieve both. For each strategy, we assess the translational evidence, critically appraising the barriers that have limited their clinical success, including patient heterogeneity, narrow therapeutic windows, and inadequate central nervous system delivery. By integrating cell-type-specific biology with proteostatic mechanisms and a clinically oriented therapeutic framework, this review aims to provide a foundation for multi-target strategies that address the BIR-neurodegeneration axis at its mechanistic roots.

Keywords:  Alzheimer’s disease; Amyloid-β; Brain insulin resistance; Parkinson’s disease; Tau; α-Synuclein

DOI:  https://doi.org/10.1186/s40035-026-00573-1
Acta Neuropathol. 2026 Aug 01. pii: 13. [Epub ahead of print]152(1):

Proteomic comparison of hippocampal neurofibrillary tangles in PART, intermediate Alzheimer's disease and advanced Alzheimer's disease.

Manon Thierry, Dominique Leitner, Kaleah Balcomb, Tomas Kavanagh, Lauren Tang, Evgeny Kanshin, Christopher William, Derek Oakley, Bradley Hyman, Beatrix Ueberheide, Eleanor Drummond, Thomas Wisniewski.

  Alzheimer's disease (AD) is characterised by the intraneuronal aggregation of phosphorylated Tau (pTau) into neurofibrillary tangles and by the extracellular deposition of β-amyloid (Aβ). Tau pathology restricted to the hippocampal formation is frequently observed in the elderly brain in the absence of any Aβ deposition and considered as "primary age-related tauopathy" (PART). Here, we applied an unbiased proteomic approach to determine how concomitant Aβ pathology modifies the neurofibrillary tangle proteome. Neurofibrillary tangles were isolated by dissecting Tau pSer202/pThr205 "AT8" immunopositive neuronal profiles, combining chromogenic immunohistochemistry with laser capture microdissection, from hippocampal sections of 17 post-mortem brains spanning three groups: PART (n = 5; A0, B1-2, C0 scores), intermediate AD (n = 6; A1-2, B2-3, C1-2 scores) and advanced AD (n = 6; A3, B3, C3 scores). A label-free quantitative liquid chromatography-mass spectrometry based proteomic analysis, using data independent acquisition (DIA) on a Bruker timsTOF, was performed. A conserved core of 63 proteins was identified as enriched in tangles across all groups, mostly associated with "RNA binding" and "regulation of mRNA metabolic process", based on the Gene Ontology database. Group-specific signatures were also observed: 33 proteins were significantly enriched only in tangles collected from PART cases and were predominantly linked to "structural molecule activity", whereas Aβ-positive cases showed specific enrichment of "RNA binding" and "cytoplasmic translation" pathways-with intermediate AD cases displaying a transitional profile. Our findings are consistent with PART having distinct tangle proteomic features; however, the majority of its proteomic signature is in common with tangles within the AD continuum. By addressing how Aβ accumulation alters the tangle proteome, this study provides mechanistic insights into the expansion of Tau pathology, paving the way towards the identification of biomarkers and therapeutic strategies that would allow for stabilisation of Tau pathology in the elderly.

Keywords:  Alzheimer; Aβ; Neurofibrillary tangles; PART; Proteomics; Tau

DOI:  https://doi.org/10.1007/s00401-026-03064-9
Cureus. 2026 Jun;18(6): e111856

The Oral-Brain Axis: Mechanistic Insights Linking Periodontitis With Alzheimer's and Parkinson's Diseases.

Roopse Singh, Shilpi Asthana, Anveksha Arya, Mayur Kaushik, Mehvish Khan.

  Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are major causes of disability and mortality worldwide. Emerging evidence suggests that chronic peripheral inflammation and microbial dysbiosis may contribute to neurodegenerative processes. The oral-brain axis has recently gained attention as a biological framework linking oral microbial communities, systemic inflammatory responses, immune regulation, and central nervous system function. Within this context, periodontitis, a prevalent chronic inflammatory disease driven by oral dysbiosis, has been proposed as a potential modifiable risk factor for neurodegeneration. This narrative review examines current evidence supporting the oral-brain axis and its role in the relationship between periodontitis and neurodegenerative disorders. Key mechanisms include systemic dissemination of periodontal pathogens and their virulence factors, persistent inflammatory signaling, blood-brain barrier dysfunction, neuroimmune activation, oxidative stress, and protein aggregation. Particular attention is given to the contribution of Porphyromonas gingivalis and associated virulence factors to neuroinflammation, amyloidogenesis, and neuronal injury. Epidemiological, clinical, and experimental studies linking periodontal disease with cognitive decline, Alzheimer's disease, and Parkinson's disease are also discussed. Current evidence supports a biologically plausible association between periodontal disease and neurodegeneration through interconnected microbial, inflammatory, and vascular pathways. Although causality remains to be established, the oral-brain axis provides valuable insight into potential mechanisms underlying this relationship. Improved understanding of these interactions may facilitate the development of preventive and therapeutic strategies that integrate oral healthcare with approaches aimed at preserving neurological health and reducing the burden of neurodegenerative diseases.

Keywords:  alzheimer’s disease; blood-brain barrier; neurodegenerative diseases; neuroinflammation; oral microbiome; oral-brain axis; parkinson’s disease; periodontal disease (pd); periodontitis

DOI:  https://doi.org/10.7759/cureus.111856
Biophys J. 2026 Aug 07. pii: S0006-3495(26)00545-X. [Epub ahead of print]

Polymorphic structures of rapidly twisting 40-residue amyloid-β fibrils.

Motahareh G Larimi, Kent R Thurber, Robert Tycko.

Fibrils formed by 40- and 42-residue amyloid-β peptides (Aβ40 and Aβ42) are polymorphic, containing molecular structures that vary with growth conditions in ways that are not fully understood. Here we use cryogenic electron microscopy to characterize the structure of rapidly twisting Aβ40 fibrils, for which the distance between apparent width minima in electron microscope images ("cross-over distances") is approximately 25 nm. From samples grown under a single set of growth conditions, we obtain high-resolution structures for three different rapidly twisting polymorphs. Although their cross-over distances are similar, the three rapidly twisting polymorphs differ in twist handedness, symmetry, molecular conformations, and intermolecular contacts. Two of the rapidly twisting polymorphs resemble Aβ40 polymorphs with longer cross-over distances that have been described previously, including polymorphs extracted from brain tissue of Alzheimer's disease patients or created by seeded growth from amyloid in brain tissue, but have shorter conformationally ordered segments and other specific conformational differences. These results contribute to our understanding of amyloid polymorphism, connections between morphology and molecular structure, and relationships between brain-derived and in vitro-grown fibrils.

DOI: https://doi.org/10.1016/j.bpj.2026.08.003
bioRxiv. 2026 Jul 10. pii: 2026.07.07.735601. [Epub ahead of print]

A single-domain antibody targets aggregation-prone region of α-synuclein to reduce synucleinopathy, rescue neurodegeneration and improve function.

Pragati, Erin E Congdon, Yixiang Jiang, Hediye Erdjument-Bromage, Huai-Wei Huang, Ruimin Pan, Isabella S Marchal, Xiang-Peng Kong, Thomas A Neubert, Hyung Don Ryoo, Einar M Sigurdsson.

Synucleinopathies are a group of neurodegenerative disorders characterized by the accumulation of aggregated α-synuclein (α-syn), including Parkinson's disease, Dementia with Lewy Bodies, and Multiple System Atrophy. These diseases are marked by locomotor and non-motor impairments, as well as mitochondrial dysfunction and the loss of dopaminergic (DA) neurons. We have developed several anti-α-syn single-domain antibodies (sdAbs) and demonstrated the diagnostic imaging potential of two of them and the acute therapeutic benefit of one in clearing α-syn in a mouse model. However, whether these sdAbs can suppress α-syn-mediated neuronal loss and locomotor impairment in vivo remains unclear. We evaluated the therapeutic potential of five anti-α-syn sdAbs to clear pathological α-syn in mouse neuronal culture and then demonstrated their in vivo efficacy in a Drosophila model of synucleinopathy. The sdAbs differed in their efficacy to lower levels of phospho-serine 129 α-syn, prevent loss of DA neurons, alleviate mitochondrial dysfunction, improve motor function, and prolong survival in synucleinopathy flies. The most effective sdAb, 2H1, has not been reported before. It binds strongly to the aggregation prone region of α-syn and robustly improves all these disease parameters. Additionally, that sdAb is associated with α-syn in the fly neurons, as shown through proximity dependent turboID biotinylation assays. The sdAb-turboID also biotinylated α-syn-associated proteins involved in synapse/vesicle trafficking pathways, pinpointing the location of their intracellular interaction. Our findings provide an insight into the therapeutic mechanism of action of these sdAbs and strongly support their clinical development.

DOI: https://doi.org/10.64898/2026.07.07.735601
Mol Neurobiol. 2026 Aug 05. pii: 810. [Epub ahead of print]63(1):

GPR146 Deficiency Enhances Microglial Phagocytosis and Blood-Brain Barrier-Associated Markers in an Acute Amyloid-β Model.

Shaobin Yang, Yanhong Li, Yanling Guo, Yumeng Li, Meiqi Li, Hongxia Li, Yimeng Zhang.

  Dysregulation of brain cholesterol homeostasis is increasingly recognized as a critical driver of Alzheimer's disease (AD) pathogenesis. G protein-coupled receptor 146 (GPR146) has emerged as a pivotal regulator of systemic cholesterol metabolism; however, its role in the central nervous system and AD remains elusive. Here, we report that GPR146 deficiency in mice modulates ERK/PKA signaling without affecting baseline physiology or general behavior. Following intracerebroventricular (i.c.v.) injection of amyloid-β (Aβ)42 oligomers, GPR146 was associated with altered Aβ42-evoked ERK/PKA/Akt signaling both in vivo and in vitro. Mechanistically, Gpr146 ablation potentiated microglial Aβ phagocytosis, which correlated with the transcriptional upregulation of phagocytic receptors, including TREM2, GPR34, P2Y6, and CR3, alongside increased expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Moreover, GPR146 deficiency was linked to elevated levels of blood-brain barrier (BBB)-associated markers Cldn-5 and Glut-1 protein levels, while attenuating Aβ‑induced inflammatory responses in brain endothelial cells. At the metabolic level, GPR146 knockout modulated the expression of key enzymes governing glucose (GLUT1, GLUT3, G6PD, PFK, HK) and lipid (HMGCS1, ACACA, FASN, SCD1) metabolism and markedly reduced Aβ‑elicited lipid droplet accumulation in the cortex and hippocampus. Collectively, our findings establish GPR146 as a novel neurometabolic regulator whose deficiency correlates with enhanced Aβ phagocytosis, maintenance of BBB-associated proteins, and altered cerebral metabolism, thereby presenting a potential therapeutic axis for early AD intervention.

Keywords:  Alzheimer’s disease; Amyloid-beta; Blood–brain barrier; G protein–coupled receptor 146; Metabolism

DOI:  https://doi.org/10.1007/s12035-026-06100-7
Nat Commun. 2026 Aug 06. pii: 7768. [Epub ahead of print]17(1):

α-Synuclein blocks endoplasmic reticulum co-translational protein translocation early in Parkinson's disease.

Chor Lai Lam, Nicholas J F Gatford, Ana Aragón-González, Benedict Tanudjojo, Anis Sahoo, Andrew R Castle, Devika Agarwal, Ashwin Jainarayanan, Svenja S Hester, Navoneel Sen, Justin L P Benesch, Roman Fischer, David Sims, George K Tofaris.

The primary mechanism and subcellular localisation of α-synuclein toxicity in Parkinson's disease pathogenesis remain unknown. We spatially and temporally resolved proteomic and transcriptomic changes in human iPSC-derived dopaminergic neurons with increasing burden of pathological α-synuclein. We found that misfolded α-synuclein proteoforms, signified by the formation of nanoscale intraneuronal puncta, are associated with impaired translocon function at the endoplasmic reticulum (ER). We show that α-synuclein interacts with Sec61A in iPSC-derived dopaminergic neurons and in post-mortem brain tissue from patients with Parkinson's disease. This interaction interferes with the co-translational translocation of ER-processed proteins including the vacuolar-type ATPase V0a1 subunit, glucocerebrosidase, and Cathepsin B, causing defective organelle function such as reduced lysosomal acidification, leading to increased extracellular vesicle release of α-synuclein. Defective ER-translocation was associated with increased ribosomal UFMylation and proteasomal recruitment but not activation of the unfolded protein response. Reduction of pathological α-synuclein by either CRISPRi to decrease α-synuclein expression or pharmacological activation of proteasomal degradation with repurposed drugs mitigates the ER defect. Our study offers a unifying mechanistic link between α-synuclein pathology and dysregulation of diverse organelle-associated proteins that are both Sec61A translocon substrates and genetic modifiers of Parkinson's disease risk. Our data also provide a therapeutic rationale for proteasomal activation in early Parkinson's disease.

DOI: https://doi.org/10.1038/s41467-026-76173-4
Protein Sci. 2026 Sep;35(9): e70742

Phase separation leads to significant conformational change in the N-terminal region of the prion protein.

Suman Pal, Jayant B Udgaonkar.

  Understanding the link between phase separation (PS) of disease-linked proteins to form liquid-like condensates, and their aggregation, requires insights into the conformational changes that the proteins undergo inside the condensates as they age and become solid-like. In this study, the structural changes undergone by the mouse prion protein (moPrP) inside condensate induced by PS have been characterized. Hydrogen-deuterium exchange in conjunction with mass spectrometry reveals that the N-terminal region (NTR), which is unstructured in monomeric native moPrP, gains significant stable structure as the condensate ages. The structured C-terminal domain remains native-like, albeit with higher stability, but subtle changes are seen. Conformational change initiates in the native monomer inside the condensate, with different regions undergoing rapid, slow, or no conformational change as it ages. The β1-α1 loop undergoes rapid conformational change to lose stability, while the NTR gains structure slowly concomitantly with conformational change at the C-terminal end of α3. Infrared (IR) spectroscopy shows that β-structure forms, IR and circular dichroism spectroscopy indicate that secondary structure becomes heterogeneous, and dynamic light scattering measurements reveal that the protein forms oligomeric nanoscale assemblies as the condensate ages. The formation of the nanoscale assemblies inside the condensate is responsible for the fraction of protein present as mobile monomer decreasing with time of aging, when fluorescence recovery after photobleaching is quantified. Such assembly and the resultant conformational change in the protein appear to be responsible for a change in its material properties of the condensate, which manifests itself as a liquid-like to solid-like transition.

Keywords:  condensates; hydrogen‐deuterium exchange mass‐spectrometry; phase separation; prion protein

DOI:  https://doi.org/10.1002/pro.70742
J Mol Neurosci. 2026 Aug 04. pii: 122. [Epub ahead of print]76(3):

Kaempferol-Conjugated Manganese Oxide Nanocomposites Mitigate Aluminium Chloride-Induced Neurobehavioral Impairments in a Rat Model of Alzheimer's disease.

Heng Yu, Xiufeng Liu, Juan Liu, Dong Tang.

  The neurodegenerative illness Alzheimer's disease (AD) causes cognitive decline. The production of oxidative stress in neurons is thought to play a role in the emergence of AD. The antioxidants, including kaempferol, reduce the course of AD; however, their use is limited by poor bioavailability. Kaempferol-conjugated manganese oxide nanocomposites (KMF@PEG-MnO2 NCs) exhibit enhanced protective effects against AD compared to free kaempferol. In this study, the potential of KMF@PEG-MnO2 NCs as an anti-Alzheimer's disease (AD) agent was explored through in silico and experimental approaches. The effective preparation of KMF@PEG-MnO2 NCs was validated by FT-IR, XRD, DLS, and SEM-EDX characterization techniques. The influence of KMF@PEG-MnO2 NCs on antioxidant capacity using the DPPH assay, reactive oxygen species (ROS) quantification with the SH-SY5Y cell line, and determining the amyloid β disaggregation was determined. Additionally, blood-brain barrier permeability was assessed with brain endothelial cells, and an anticholinesterase study was performed to explore its potential for treating Alzheimer's disease. Surface characterization revealed a spherical shape of the nanoparticle. DPPH and FR assay showed a substantial rise in antioxidant defence for KMF@PEG-MnO2 NCs compared to KMF. Anti-aggregation studies demonstrated the nanoparticle's ability to inhibit Aβ fibrils. Additionally, the BBB permeability assay indicated that the nanoparticle can permeate the BBB. Furthermore, in vivo studies demonstrated that KMF@PEG-MnO2 NCs protected against cognitive and synaptic deficits in AlCl3-induced AD rats (AlCl₃-AD). KMF@PEG-MnO2 NCs significantly reduced AChE activity. Furthermore, it markedly reduced the brain's levels of nitric oxide (NO) while increasing the function of superoxide dismutase (SOD) and catalase (CAT) activities. Overall, the findings suggest that KMF@PEG-MnO2 NCs may serve as a promising therapeutic candidate for AD management.

Keywords:  Aluminium chloride; Alzheimer’s disease; Manganese oxide; Neurotoxicity; Oxidative stress

DOI:  https://doi.org/10.1007/s12031-026-02571-4
Turk J Pharm Sci. 2026 Aug 05.

Plasma Concentrations of Amyloid-β Peptides, BACE-1, and Tau Proteins in Alzheimer's Disease.

Nejla Yıldırım, Naile Merve Güven Aksu, Başak Özlem Perk, Benay Can Eke.

   Objectives: The aim of this study was to compare, using ELISA, plasma levels of amyloid beta (Aβ)40, Aβ42, beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), total tau (t-tau), and phosphorylated tau (p-tau), as well as the Aβ42/Aβ40 ratio, between patients with Alzheimer's disease (AD) and healthy controls, and to evaluate their diagnostic performance in relation to demographic and lifestyle factors.
Materials and Methods: This study is a single-center, cross-sectional, case-control study. Twenty-four individuals diagnosed with AD and 37 healthy volunteers included in the study. Alongside the analysis of plasma samples obtained from the participants, demographic data were analyzed to assess the potential influence of lifestyle and environmental factors on disease development.
Results: Analysis of the case data showed that increasing age was a risk factor for AD, higher education level was associated with an increased risk of AD, and tea consumption was inversely associated with AD. While age is a well-known risk factor, both the increased risk of AD associated with higher education and the relatively protective effect of tea consumption against AD are supported by the literature. Evaluation of the levels of Aβ40, Aβ42, BACE-1, t-tau, and p-tau and of the Aβ42/Aβ40 ratio revealed no significant differences between the patient and control groups. Additionally, Aβ40, Aβ42, BACE-1 showed correlations in both the control and Alzheimer's groups, whereas t-tau did not.
Conclusion: None of the investigated plasma biomarkers (Aβ40, Aβ42, BACE-1, t-tau, p-tau, and the Aβ42/Aβ40 ratio) discriminated Alzheimer's patients from healthy controls, with all receiver operating characteristic area under the curve values below 0.62. These findings indicate that in this cohort, plasma levels of these individual markers did not provide diagnostic value; larger longitudinal studies including cerebrospinal fluid comparisons and multi-marker panels are needed.

Keywords:  Alzheimer’s disease; BACE-1; ELISA; amyloid beta; tau

DOI:  https://doi.org/10.4274/tjps.galenos.2026.68256