bims-proned 2025-12-28 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–12–28
thirty-one papers selected by
Verena Kohler, Umeå University

Basic Science and Pathogenesis.
Drug Development.
Alpha-Synuclein Neurobiology in Parkinson's Disease: A Comprehensive Review of Its Role, Mechanisms, and Therapeutic Perspectives.
Basic Science and Pathogenesis.
UV induces common cutaneous amyloid-like melanosomal protein aggregates.
Neuronal mitochondrial disaggregase CLPB ameliorates Huntington's disease pathology in mice.
The low complexity linker of DNAJB6b is key to its anti-amyloid function.
Drug Development.
Integrative Genomic and Functional Analyses Reveal NINL as a Modulator of Tau Aggregation.
Basic Science and Pathogenesis.
Developing Topics.
mGluR4-NPDC1 complex mediates α-synuclein fibril-induced neurodegeneration.
Basic Science and Pathogenesis.
Microfluidic platform for understanding Parkinson's disease and α-synuclein conformation.
The extent of alpha-synuclein aggregate accumulation in neurons varies depending on the type of neurotransmitter they release.
Developing Topics.
Acteoside exerts neuroprotective effects by preventing α-synuclein aggregation and oxidative stress in models of Parkinson's disease.
Targeting the activation heat shock proteins for the potential treatment of neurodegenerative disease.
Basic Science and Pathogenesis.
Drug Development.
Protein Misfolding in the Pathogenesis and Diagnosis of Neurodegenerative Diseases (Review).
Drug Development.
Intracellular aggregation of the transthyretin protein is limited by Hsp70 chaperones.
Drug Development.
Screening π-Extended Ruthenium(II) Complexes for the Photoinduced Oxidative Modulation of Amyloid-β Peptide Aggregation.
Basic Science and Pathogenesis.
Drug Development.
Helicobacter pylori infection and α-synuclein pathology drive parallel neurodegenerative pathways in the substantia nigra.
Drug Development.
Drug Development.
Basic Science and Pathogenesis.

Alzheimers Dement. 2025 Dec;21 Suppl 1 e100815

Basic Science and Pathogenesis.

Sungsu Lim, Yun Kyung Kim, Ae Nim Pae.

BACKGROUND: TDP43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), are characterized by the pathological aggregation and mislocalization of TDP43 protein. These aberrant aggregates disrupt cellular functions and contribute to neurodegeneration. However, the molecular mechanisms driving TDP43 aggregation remain unclear. Histone deacetylases (HDACs) regulate protein acetylation, a process implicated in protein aggregation and neurodegenerative diseases. This study aims to elucidate the role of HDAC inhibition and acetylation in TDP43 aggregation, particularly focusing on its mislocalization and oligomerization dynamics.
METHOD: We established a TDP43-BiFC (Bimolecular Fluorescence Complementation) cell model to visualize TDP43 oligomerization in living cells. Using this system, we examined the effects of cellular stress activators and HDAC inhibitors on TDP43 aggregation. The localization and aggregation patterns of TDP43 were analyzed via fluorescence microscopy, and biochemical characterization of aggregates was performed using SDS-PAGE, Western blotting, and immunocytochemistry.
RESULT: Cellular stress activators induced distinct nuclear and cytoplasmic TDP43 aggregation patterns, indicating the involvement of multiple stress-dependent pathways in TDP43 pathology. Broad HDAC inhibition triggered a time-dependent mislocalization of TDP43 from the nucleus to the cytoplasm, suggesting that HDAC-regulated acetylation is crucial for nuclear TDP43 retention. Furthermore, HDAC inhibition led to increased cellular acetylation, which promoted the formation of stable, SDS-resistant TDP43 oligomers via disulfide-linked aggregation. While phosphorylation was detected within these aggregates, our findings suggest that disulfide bonding plays a primary role in driving aggregation, rather than phosphorylation.
CONCLUSION: Our findings highlight the critical role of acetylation-mediated disulfide-linked aggregation in TDP43 pathology and suggest that HDAC inhibition contributes to TDP43 mislocalization and stable oligomer formation. Targeting this pathway may provide a novel therapeutic strategy for TDP43 proteinopathies, including ALS and FTLD.

DOI: https://doi.org/10.1002/alz70855_100815
Alzheimers Dement. 2025 Dec;21 Suppl 5 e107287

Drug Development.

Giulio Maria Pasinetti, Kenjiro Ono, Tom Lloyd, Nicole Less.

BACKGROUND: There is growing evidence that in many neurodegenerative disorders, cell-to-cell transmission of a pathological, misfolded protein, such as misfolding of α-synuclein (α-syn) in Parkinson's disease (PD), may be a vehicle for the spreading of pathology throughout the brain. This misfolded protein, or seed, further induces misfolding of native proteins within the cell. Pathological misfolded proteins may exist in diverse conformations with distinct cellular and biochemical properties. We investigate whether microbiota-derived metabolites may help attenuate the misfolding of α-syn and thereby promote resilience against PD phenotypes. We identified six biologically available gut microbiota-derived compounds (GMP10, GMP11, GMP26, GMP28, GMP39, and GMP44) for investigation.
METHOD: Using independent in vitro protein aggregation assays (e.g., photo-induced cross-linking of unmodified proteins assay, thioflavin-T, fluorescence assay, and electron microscopy), we demonstrated that three of the compounds (GMP26, GMP44, GMP28), potently inhibit aggregations of monomeric α-syn (or monomeric β-amyloid peptides) into neurotoxic protein aggregates, in vitro.
RESULT: Based on evidence linking the c9orf72 gene with expansions of GGGGCC hexanucleotide repeats and PD, as well as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), we continue to test the neuroprotective ability of our compounds in vivo using a Drosophila model with overexpression of GGGGCC hexanucleotide repeats. Overexpression of 30 GGGGCC repeats in the Drosophila eye causes age-dependent photoreceptor neurodegeneration. We treated Drosophila by mixing individual test compounds into the food. We found all six compounds significantly suppressed eye degeneration at 10 µM, with compounds GMP26 and GMP11 almost completely suppressing the eye phenotype. The comparative efficacy of the six compounds are GMP26 = GMP11 > GMP39 > GMP10 > GMP44 > GMP28.
CONCLUSION: Outcomes from our studies link gut microbiota with mechanisms underlying PD and suggest the feasibility of developing GMP26 as a means to simultaneously target both α-syn misfolding and C9orf72 expansion to increase the likelihood of therapeutic efficacy in PD, ALS, FTD patients with C9orf72 expansion.

DOI: https://doi.org/10.1002/alz70859_107287
Brain Sci. 2025 Nov 25. pii: 1260. [Epub ahead of print]15(12):

Alpha-Synuclein Neurobiology in Parkinson's Disease: A Comprehensive Review of Its Role, Mechanisms, and Therapeutic Perspectives.

Jamir Pitton Rissardo, Andrew McGarry, Yiwen Shi, Ana Leticia Fornari Caprara, George T Kannarkat.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and the presence of intracellular α-synuclein (αSyn) aggregates known as Lewy bodies (LB). αSyn, a presynaptic protein, is believed to play a crucial role in synaptic function, neurotransmitter release, and neuronal plasticity. However, its misfolding and aggregation are thought to be central to PD pathogenesis. This review provides a comprehensive analysis of αSyn's role in PD, exploring its normal physiological functions, pathological mechanisms, and therapeutic potential. The pathological transformation of αSyn involves structural alterations that promote oligomerization and fibrillization, leading to toxic gain-of-function effects. These aggregates disrupt cellular homeostasis through mechanisms including mitochondrial dysfunction, oxidative stress, lysosomal impairment, and endoplasmic reticulum stress. Furthermore, pathogenic αSyn is thought to exacerbate neurodegeneration via prion-like spread along interconnected neuronal circuits. Emerging evidence highlights the frequent co-occurrence of other proteinopathies, such as tau and amyloid-β, which may synergistically accelerate disease progression. Targeting αSyn has emerged as a potential therapeutic strategy. Approaches such as immunotherapy, small-molecule inhibitors, gene silencing, and modulation of protein degradation pathways (e.g., autophagy and proteasomal systems) are actively being explored. Additionally, lifestyle-based interventions, particularly exercise, have shown neuroprotective effects, potentially mediated by irisin-a myokine implicated in protein clearance and synaptic resilience-underscoring the importance of multimodal strategies in PD management.

Keywords:  biomarkers; co-pathology; immunotherapy; neurodegeneration; prion-like spread; synucleinopathy

DOI:  https://doi.org/10.3390/brainsci15121260
Alzheimers Dement. 2025 Dec;21 Suppl 1 e104344

Basic Science and Pathogenesis.

Matthew Reid, Anna Brown, William A McEwan.

BACKGROUND: Tauopathies, including Alzheimer's disease (AD), are defined by the pathological aggregation of tau proteins, a process linked to neurodegeneration. Misfolded tau spreads in a prion-like manner, recruiting native tau and propagating across brain regions. Existing models often rely on mutant tau or recombinant seeds, which fail to fully mimic tau conformations seen in AD, limiting therapeutic discovery.
METHODS: We developed a screening pipeline using HEK cells expressing wildtype 3R/4R tau seeded with AD post-mortem tissue-derived aggregates, ensuring disease relevance. As a complementary approach, primary mouse neurons expressing mutant tau were seeded with recombinant aggregates, offering a comparative model for validating hits. Additionally, an iPSC-derived neuronal model of seeded wildtype tau aggregation is under development to further enhance physiological relevance.
RESULTS: The pipeline successfully identified inhibitors of tau aggregation. In HEK cells, these inhibitors blocked AD-derived tau seeding, while in the primary neuron model, they prevented recombinant tau-induced aggregation. This dual approach demonstrates the inhibitors' efficacy across wildtype and mutant tau systems, bridging model relevance and translational potential.
CONCLUSION: This study establishes a robust pipeline for tau aggregation inhibitor discovery, integrating wildtype tau relevance with mutant tau models. The addition of an iPSC-neuronal model will further enhance the physiological fidelity of the pipeline. The mechanisms of the successful compounds are currently being determined to understand their mode of action, and will progress toward lead optimisation and preclinical evaluation, advancing therapeutic development for AD and related tauopathies.

DOI: https://doi.org/10.1002/alz70855_104344
bioRxiv. 2025 Dec 18. pii: 2025.12.17.689083. [Epub ahead of print]

UV induces common cutaneous amyloid-like melanosomal protein aggregates.

Nicholas Theodosakis, Porter B Howland, Miroslav Hejna, Stephen M Ostrowski, Talya A Cohen-Neamie, Remi A Joseph, Helen Ji, Allison E Greuel, Judith R Boozer, Mariam Y Demian, Alin Asim, Khanh Nguyen, Andrew Mu, Philip Seifert, Konrad Kaminiow, Yifan Zhang, Aline Fassini, Sharon Germana, Kristin C Shaw, William M Lin, Mai P Hoang, Xunwei Wu, Sreeganga S Chandra, Nir Hacohen, Andrea Ballabio, Rachit Bakshi, Namrata D Udeshi, Anand K Ganesan, Thomas Horn, George F Murphy, Steven A Carr, Bradley T Hyman, Jun S Song, David E Fisher.

Misfolding of aggregation-prone proteins underpins diseases known as proteinopathies. One of these proteins, alpha-synuclein, is a component of aggregates in neurodegenerative conditions such as Parkinson's disease. The melanosomal protein PMEL, which forms physiologic amyloid scaffold structures on which melanin is organized in melanosomes, similarly ectopically accumulates in the dermis in many forms of cutaneous hyperpigmentation. Here, we demonstrate in a wide range of common clinical pigmentary disorders, as well as in primary melanocyte and mouse models examined by molecular, proteomic, and electron microscopic tools, that melanocytic alpha-synuclein is a prominent component of intracellular protein aggregates bound to similar proteins as in Parkinson's disease, as well as melanized extracellular protein deposits. Using the Real Time Quaking-Induced Conversion Assay (RT-QuIC), we demonstrate that UV induces misfolded melanosomal proteins to self-propagate, augmenting this pathology in prion-like fashion. CUT&RUN chromatin profiling and single-cell RNA-seq demonstrate that melanocytes utilize microphthalmia-associated transcription factor (MITF)-regulated autophagy to counteract protein aggregation, identifying aggregate removal as a core function of tanning. In contrast to extracellular aggregation, impaired intracellular aggregate removal contributes to melanocyte senescence, which conversely exacerbates chronic hypopigmentation and photoaging-related discoloration. These findings identify melanosomal proteinopathy as a common contributor to melanocyte dysfunction and suggest aggregate-focused management approaches.

DOI: https://doi.org/10.64898/2025.12.17.689083
Theranostics. 2026 ;16(5): 2388-2404

Neuronal mitochondrial disaggregase CLPB ameliorates Huntington's disease pathology in mice.

Hyeonho Kim, Gaeun Hyun, Seunghye Kim, Changmo Yu, Young-Gi Hong, Jihyeon Yu, Sangsu Bae, Hyun-Woo Rhee, Jaewon Ko, Ji Won Um.

  Background: Huntington's disease (HD) is a devastating neurodegenerative disorder caused by CAG repeat expansion in the HTT gene, resulting in a polyglutamine-expanded huntingtin (HTT) protein that forms toxic aggregates. Although heat-shock proteins are known to facilitate the refolding or clearance of misfolded proteins, their precise role in modulating protein aggregation in HD remains unclear. Here, we explore the function of caseinolytic peptidase B (ClpB), a mitochondrial AAA+ ATPase and heat-shock protein, in maintaining proteostasis and synaptic integrity in HD. Methods: We examined how CLPB loss or overexpression in human embryonic kidney 293T (HEK293T) cells impacted the aggregation of wild-type HTT (HTT-Q23) and mutant HTT (HTT-Q79). In parallel, AAV-mediated ClpB knockdown or overexpression was applied to the striatum of HD model mice. and HTT aggregation and inhibitory synaptic alterations were assessed. Aggregate burden was quantified via immunostaining, and inhibitory synapse density was evaluated using VGAT immunohistochemistry and electrophysiological recordings. Results: In HEK293T cells, CLPB knockout led to abnormal aggregation of HTT-Q23 while CLPB overexpression reduced the size of HTT-Q79 aggregates. In the mouse striatum, ClpB knockdown increased HTT-Q23 aggregate numbers and altered HTT-Q79 aggregation morphology, whereas CLPB overexpression restored the density and size of VGAT-positive inhibitory synapses and improved inhibitory synaptic transmission in HD model mice. These effects of CLPB overexpression were associated with a reduced mitochondrial aggregation burden, suggesting that ClpB contributes to mitochondrial protein quality control. Conclusions: These results demonstrate that ClpB regulates both physiological and pathological HTT aggregation and contributes to maintaining inhibitory synaptic integrity. By modulating mitochondrial proteostasis, ClpB acts as a protective factor in HD pathology, highlighting its potential as a therapeutic target for neurodegenerative disorders characterized by protein misfolding.

Keywords:  ClpB; Huntington's disease; disaggregase; inhibitory synapse; mitochondria; striatum

DOI:  https://doi.org/10.7150/thno.122651
QRB Discov. 2025 ;6 e25

The low complexity linker of DNAJB6b is key to its anti-amyloid function.

Timas Merkelis, Ulf Olsson, Sara Linse.

  Neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, are associated with the formation of amyloid fibrils. The DNAJB6b (JB6) chaperone greatly inhibits the disease-related self-assembly of amyloid peptides in an ATP-independent manner. The molecular basis of this process is, however, not understood. Here, we studied the low complexity linker between the N- and C-terminal domains of JB6 as an isolated 110 amino acid residue construct, to get a better understanding of the role of the composition of the intact protein. We investigate the structure and aggregation behaviour of the linker and its anti-amyloid activity in comparison with the full-length chaperone. We find that the linker contains ca. 45% α-helix and 20% β-sheet and is in itself an amyloid-like peptide that self-assembles into different structures, which are bigger than those formed by the intact chaperone, including fibrils. The isolated linker protects against fibril formation of Aβ42 as well as α-synuclein, but is less potent than the intact chaperone. Based on our results, we propose a possible mechanism behind JB6 and linker amyloid suppression relating to their self-assembly behaviour. In the intact protein, the domains serve to solubilize the linker such that the solution concentration of exposed linker is high enough to sustain its high potency against amyloid formation.

Keywords:  amyloid inhibition; chaperone activity; low-complexity region; protein aggregation; protein folding

DOI:  https://doi.org/10.1017/qrd.2025.10016
Alzheimers Dement. 2025 Dec;21 Suppl 5 e099984

Drug Development.

Marc Shenouda, Janice Robertson.

BACKGROUND: Nuclear depletion and neuronal cytoplasmic aggregation of the transactive response DNA-binding protein 43 (TDP-43) is observed in up to 95% amyotrophic lateral sclerosis (ALS) cases, 70% of Alzheimer's Disease (AD) cases, and 50% of frontotemporal dementia (FTD) cases. The cytoplasmic aggregation of TDP-43 has been correlated with inducing neuronal loss. As such, preventing TDP-43 aggregation could have therapeutic potential for ALS/FTD and associated diseases. It has been shown that aggregation of TDP-43 can be attenuated by chaperone proteins. Herein, we have identificatied and validated a new small molecule 'JRMS' as potent binder of {IP-protein} which upregulates its non-canonical chaperone function to prevent/reverse TDP-43 aggregation.
METHOD: We developed high throughput models of TDP-43 aggregation by expressing the highly aggregation prone C-terminal fragment TDP-25 in cells through transient expression, mouse primary cortical neurons through lentiviral expression, and organotypic slices and mouse model through AAV9 expression.
RESULT: Acute and chronic treatment of JRMS reduced TDP-25 aggregation in a dose-dependent manner by ∼75% in cells. This reduction of TDP-25 aggregates was validated to be dependent on {IP-protein}, and that JRMS elevates activity of the target {IP-protein}. Similarly, in mouse primary cortical neurons transduced with TDP-25 lentivirus, JRMS reduced TDP-25 aggregates by ∼50% reduction. We screened JRMS on organotypic slices from 10 day-old mice inoculated with AAV9-TDP-25. Over 7-days, DMSO treated slices showed ∼60% increase, while JRMS treatment showed a ∼20% reduction in number of TDP-25 aggregates observed prior to treatment. Finally, two weeks treatments of AAV9-TDP-25 expressing mice at 6 weeks of age with JRMS exhibited ∼30% reduction in number of aggregates compared to DMSO control.
CONCLUSION: We have validated JRMS as a preclinical therapeutic candidate for the treatment of TDP-43 proteinopathy, with additional preliminary evidence for Tauopathies as well. We are currently working on building a Target Product Profile (TPP) with the goal of providing a drug(s) for clinical testing.

DOI: https://doi.org/10.1002/alz70859_099984
bioRxiv. 2025 Dec 16. pii: 2025.12.12.694063. [Epub ahead of print]

Integrative Genomic and Functional Analyses Reveal NINL as a Modulator of Tau Aggregation.

Samantha K Swift, Guangming Huang, J Nicholas Cochran, Miguel A Minaya, Patricia A Castruita, Katherine J Miller, Emma Starr, Grant Galasso, Jacob A Marsh, Aimee W Kao, Jennifer S Yokoyama, Celeste M Karch.

Introduction: Proteostasis dysfunction is a hallmark of frontotemporal dementia (FTD) and Alzheimer's disease (AD), yet the genetic and molecular pathways that disrupt protein homeostasis remain poorly understood.
Methods: We integrated human genetics, transcriptomics, and functional studies to identify proteostasis network components involved in tauopathy.
Results: We identified 18 proteostasis network genes harboring 75 rare, damaging variants enriched in FTD and/or AD. These genes, spanning multiple proteostasis pathways, were differentially expressed in MAPT mutant neurons and dysregulated in FTD and AD brains. NINL, which encodes Nlp, emerged as the only gene consistently upregulated across all datasets. NINL overexpression reduced tau seeding and enhanced lysosomal proteolytic activity, whereas two FTD-enriched NINL frameshift variants impaired Nlp expression and abolished these protective effects.
Discussion: Our findings identify a set of proteostasis genes with genetic and transcriptional links to neurodegeneration and reveal NINL as a novel regulator of tau aggregation, potentially upregulated as an adaptive response to proteotoxic stress.

DOI: https://doi.org/10.64898/2025.12.12.694063
Alzheimers Dement. 2025 Dec;21 Suppl 1 e106344

Basic Science and Pathogenesis.

Tomas Kavanagh, Kaleah Balcomb, Aysha Strobbe, He-Shyan Balnave, Diba Ahmadi Rastegar, Evgeny Kanshin, Beatrix Ueberheide, Glenda M Halliday, Eleanor Drummond.

BACKGROUND: Tau aggregation is a hallmark of tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), Pick's disease (PiD). While tau aggregation is common amongst these diseases, biochemical differences-such as aggregate composition (3R, 4R, or 3R+4R tau) and post-translational modifications-may influence toxicity. Current models typically rely on tau overexpression or use synthetic fibrils which lack the biochemical complexity of disease-derived tau. To address this limitation, we developed a tau seeding model without overexpression, enabling broader studies of tau interactions, toxicity, and therapeutic interventions in any cell-type.
METHOD: Tau aggregates were purified from AD, PiD, PSP, and cognitively normal controls (n = 3) brains using biochemical fractionation and precipitation and characterized by mass spectrometry. Normalized quantities of tau seeds were seeded onto SH-SY5Y, M03.13, U-87 and U-118 cells to induce tau aggregation. Aggregates were quantified using wide-field and confocal imaging. Cytotoxicity assays and pathway markers were used to assess tau toxicity and its impact on autophagy, lysosomes and mitochondria.
RESULT: Disease-derived tau seeds retained disease specific properties and were successfully used to induce tau aggregation across multiple cell lines in a titratable manner. Mass-spectrometry confirmed expected isoform biases, including elevated 4R tau in AD and PSP and identified APP enrichment in AD preparations. Mass spectrometry detected some contaminating proteins, but they were also present in similar abundance in control tau preparations. While seeding efficiency varied by cell type, PiD-derived tau seeds showed the highest seeding capacity, averaging 1.4 tau aggregates per cell compared to 0.6 for AD in SH-SY5Y cells. Optimized tau concentrations resulted in minimal short-term cytotoxicity. However, tau seeds induced distinct pathway-specific disruptions, with PiD-derived seeds doubling p62 puncta formation compared to control-derived tau.
CONCLUSION: This approach provides a robust model for studying tau pathology in a disease-specific context. By eliminating tau overexpression, it provides a more physiologically relevant platform to investigate tau interactions and assess potential therapeutic strategies targeting aggregation and toxicity.

DOI: https://doi.org/10.1002/alz70855_106344
Alzheimers Dement. 2025 Dec;21 Suppl 7 e108195

Developing Topics.

Soljee Yoon, Wonbin Seo, InWook Park, Suhyun Ye, Illhwan Cho, Hye Yun Kim, YoungSoo Kim.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder marked by the pathological accumulation of two key proteins in the brain: amyloid-β (Aβ) and tau. The Aβ-tau interaction is known to affect AD through mechanisms that are not fully understood. Consequently, the present study investigated the impact of tau repeats on Aβ aggregation dynamics. Given the inherent structural complexity of tau, we developed a simplified model system that focused on tau repeats.
METHOD: Direct interaction between Aβ and tau was observed via microscale thermophoresis (MST) and peptide mapping. To further investigate the role of tau in modulating Aβ aggregation, we utilized Thioflavin T (ThT) assays, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis (SDS-PAGE) / Photo-Induced Cross-Linking of Unmodified Protein (PICUP), and Transmission electron microscopy (TEM).
RESULT: Tau repeats demonstrate binding affinity for Aβ, particularly interacting with hydrophobic domains within Aβ. When further probed, all tau repeats significantly inhibited the fibrillization of Aβ. Notably, tau repeats have been observed to not only dissociate Aβ fibrils but also stabilize oligomer species. Tau repeats with amyloid motifs demonstrated most pronounced effect throughout the experiments.
CONCLUSION: Collectively, we have demonstrated that tau repeats modulate Aβ aggregation kinetics. These findings advanced the understanding of tau-Aβ interactions in neurodegeneration and established the foundation for future research tools.

DOI: https://doi.org/10.1002/alz70861_108195
Nat Commun. 2025 Dec 25.

mGluR4-NPDC1 complex mediates α-synuclein fibril-induced neurodegeneration.

Azucena Perez-Canamas, Mingming Chen, Leire Almandoz-Gil, Nabab Khan, Si Jie Tang, Allyson Ho, Erik C Gunther, Stephen M Strittmatter.

α-Synuclein (α-syn) fibrils accumulate in Parkinson's disease, spreading between cells to template misfolding and drive neurodegeneration. α-Syn fibril entry into healthy neurons is a key step. Here, we comprehensively assessed the membrane proteome for α-syn fibril binding. We identified mGluR4 and NPDC1 as nigral surface proteins binding and internalizing α-syn fibrils. While striatal α-syn fibril injection led to nigral dopamine neuron loss in wild type mice, deletion of either Grm4 or Npdc1 provided protection of dopamine neurons. We observed mGluR4 and Npdc1 to form a complex regulating mGluR4 function. Cultured neurons lacking both Grm4 and Npdc1 fail to bind α-syn fibrils, to accumulate phosphorylated α-syn and to lose synapses. Transheterozygous Grm4, Npdc1 mice showed protection of nigral neurons from α-syn fibrils, demonstrating genetic interaction. For transgenic α-syn A53T mice, double Grm4, Npdc1 heterozygosity increased mouse survival, motor function and spinal motoneuron number. Thus, a cell surface mGluR4-NPDC1 complex participates in α-syn neurodegeneration.

DOI: https://doi.org/10.1038/s41467-025-67731-3
Alzheimers Dement. 2025 Dec;21 Suppl 1 e105939

Basic Science and Pathogenesis.

Nicha Puangmalai, Urmi Sengupta, Nemil Bhatt, Abbigael Aday, Fadhl Al-Shaebi, Cynthia Jerez, Nikita Shchankin, Jai Yi Liew, Mauro Montalbano, Rakez Kayed.

BACKGROUND: Connexins, gap junction components, have been implicated in intercellular connectivity under physiological and pathophysiological conditions, including neurodegeneration. Synucleinopathies comprise a diverse group of neurodegenerative disorders pathologically characterized by α-synuclein (α-Syn) aggregates. However, little is known about connexin-associated α-Syn pathological spread in synucleinopathies METHOD: Here, we present evidence of connexin-50 (Cx50) directly interacting with α-Syn aggregates in human brains affected by synucleinopathies, including Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease (PD). We also observed this interaction in pre-clinical α-Syn mouse models that exhibit Parkinson's disease-related phenotypes. To achieve this, we utilized immunohistochemistry, pharmacological, and genetic manipulation techniques in connexin cell models and primary co-cultures.
RESULT: Utilizing well-characterized α-Syn oligomers (BDSOs) isolated from brains affected by Alzheimer's disease (AD), Lewy body dementia (DLB), and Parkinson's disease (PD), we demonstrate that BDSOs preferentially enter cells expressing connexin 50 (Cx50), a protein found in gap junctions, as confirmed by pharmacological inhibition. In live-cell imaging experiments, we observed a significant reduction in BDSO uptake in primary neurons-astrocytes co-cultured from human wild-type α-Syn transgenic mice expressing genetically modified Cx50. This reduction was accompanied by a decrease in α-Syn aggregates. Moreover, the downregulation of Cx50 was associated with a reduction in the activity of astrocytes, as evidenced by a decrease in pro-inflammatory and an increase in anti-inflammatory cytokines. These findings suggest that Cx50 plays a crucial role in the interplay between neurons and astrocytes.
CONCLUSION: This study presents compelling evidence of the connection between disease-relevant α-Syn aggregates and Cx50 in neurons that regulate astrocyte activity. This insight sheds light on the intricate process of pathogenic α-Syn spread in Synucleiopathies.

DOI: https://doi.org/10.1002/alz70855_105939
Transl Neurodegener. 2025 Dec 24. 14(1): 71

Microfluidic platform for understanding Parkinson's disease and α-synuclein conformation.

Tregub Pavel, Zembatov Georgy, Namiot Eugenia, Kolotyeva Natalia, Yurchenko Stanislav, Illarioshkin Sergey, Salmina Alla.

  Microfluidic systems are an innovative engineering solution that is increasingly being used in a wide range of scientific fields. These systems use fluids in microchannels (1 to 300 microns) to analyze extremely small volumes of sample and reagent, allowing precise delivery and mixing while maintaining accurate results. Parkinson's disease (PD) poses significant diagnostic challenges, with early detection being critical to improved treatment outcomes. A key pathological feature of PD is the presence of Lewy bodies composed of α-synuclein (αSyn) fibrils. Recent research has shown that αSyn oligomers can be toxic and contribute to neuronal loss. Therefore, microfluidics offers a promising approach for the diagnosis of different stages of αSyn pathology. This review comprehensively analyzes the application of microfluidics in single-cell analysis and protein aggregation studies. We discuss the concept of lab-on-a-chip analysis and examine different substrates for αSyn detection, citing relevant studies and expected protein concentrations and their correlations with disease progression and severity.

Keywords:  Aberrant protein; Lab-on-a-chip; Microfluidic; Organ-on-a-chip; Parkinson’s disease; α-Synuclein

DOI:  https://doi.org/10.1186/s40035-025-00526-0
Sci Rep. 2025 Dec 24. 15(1): 44530

The extent of alpha-synuclein aggregate accumulation in neurons varies depending on the type of neurotransmitter they release.

Hiroshi Kameda, Shinichiro Okamoto, Kakeru Ogasawara, Ayami Okuzumi, Nobutaka Hattori, Hiroyuki Hioki, Masato Koike.

  Alpha-synuclein (aSyn) is a highly conserved 140-amino acid presynaptic protein involved in neuronal plasticity and recognized as the pathogenic protein in Parkinson's disease. Aggregated aSyn propagates transsynaptically between neurons in vivo, impairing the cellular function of affected cells. However, it remains unclear whether aggregated aSyn propagates similarly across all neuronal cell types. In this study, we injected sonicated aSyn preformed fibrils into the striatum of mice and used immunohistochemistry to observe the intracellular localization of aSyn aggregates at designated survival times. Four weeks post-injection, numerous filamentous aggregates were detected in the striatum, neocortex, and substantia nigra. Multiple immunostaining techniques with neuronal markers, combined with electron microscopy, revealed that some filamentous aggregates accumulated in the perinuclear cytoplasm of neurons in these regions. However, quantitative analyses revealed that the number of cell bodies containing aSyn aggregates in the striatum was significantly lower than that in the neocortex or substantia nigra. Additionally, we examined aSyn aggregates in the glial cells of the striatum and found that filamentous aggregates were rarely detected, even 16 weeks post-injection. These findings suggest a cell-type preference depending on neurotransmitter identity for aSyn aggregation and propagation in vivo.

Keywords:  Alpha-synuclein; Mouse models; Neurodegeneration; Neuronal cell types; Parkinson’s disease; Protein aggregation

DOI:  https://doi.org/10.1038/s41598-025-28153-9
Alzheimers Dement. 2025 Dec;21 Suppl 7 e108969

Developing Topics.

Adam Ping Liu.

BACKGROUND: Clinical differences in Parkinson's Disease (PD) are highly impacted by distinct patterns of tau aggregation in various neuropathologies. Previous studies have shown pathological tau aggregation to be a defining feature of tauopathies, but their accumulation and the inherent vulnerability of select brain regions present challenges to understanding PD progression. These aggregation patterns, known as tau strains, possess a myriad of conformations that may affect tau transmission and neurodegeneration, though these effects are not clearly understood.
METHOD: To investigate this, we developed advanced mouse models to identify tau strains and analyze their varying degrees of pathology. We will use bioimaging analysis software to illustrate different areas of the brain and annotate their local pathologies following the injection of pathological tau into diverse mice brain regions. By qualitatively observing these images and quantitatively classifying their neuropathological characteristics, we will be able to examine certain tau aggregates that will help us in predicting the progression of strain-specific tauopathies.
RESULT: Morphology of tau strains varied greatly depending on strain, dictating disease phenotype. However, pathological tau was consistently characterized by aggregation in neurofibrillary tangles and hyperphosphorylation. PD-tau was primarily composed of the 3R and 4R isoforms.
CONCLUSION: Different tau strains induced various distributions of aggregation, demonstrating the profound diversity of tauopathies. Understanding the mechanisms of this pathology could be essential to treating PD and other tauopathies in the future.

DOI: https://doi.org/10.1002/alz70861_108969
Neurotherapeutics. 2025 Dec 22. pii: S1878-7479(25)00303-4. [Epub ahead of print] e00825

Acteoside exerts neuroprotective effects by preventing α-synuclein aggregation and oxidative stress in models of Parkinson's disease.

Alessia Lambiase, Giorgia Spandri, Hind Moukham, Elisa Toini, Annalisa D'Urzo, Giovanni Zecca, Mauro Commisso, Flavia Guzzo, Valentina Santoro, Anna Lisa Piccinelli, Enrica Calleri, Sofia Salerno, Francesca Rinaldi, Stefano Negri, Carlo Santambrogio, Maura Brioschi, Cristina Solana-Manrique, Massimo Labra, Fabrizio Grassi, Nuria Paricio, Farida Tripodi, Paola Coccetti.

  α-Synuclein is a small presynaptic protein whose aggregation is one of the hallmarks of Parkinson's disease (PD). In our quest to identify novel preventive or therapeutic treatments for PD, we collected 60 Italian plant species, representative of part of the Mediterranean flora, which were screened by a phylogenetic analysis in conjunction with a high-throughput screening in a yeast model of PD expressing human α-synuclein. The integration of these approaches led to the identification of four plants, Allium lusitanicum, Salvia pratensis, Verbascum thapsus and Glaucium flavum, whose extracts, characterized by a metabolomic analysis, exhibit robust inhibitory activity against the amyloid aggregation of α-synuclein in vitro, as well as in neuroblastoma cells overexpressing the protein. By employing a size exclusion chromatography affinity approach coupled to mass spectrometry, we identified the phenylpropanoid glycoside acteoside from the extract of the edible plant V. thapsus as the metabolite that directly binds α-synuclein and effectively inhibits its fibril formation. In addition, acteoside reduces oxidative stress in neuroblastoma cells exposed to α-synuclein fibrils and activates the NRF2 pathway. Notably, acteoside improves motor performance in a Drosophila model of PD and exhibits a significant reduction of protein carbonyl groups, suggesting that this compound may mitigate oxidative stress-induced protein damage. Our findings could pave the way for the development of new strategies aimed at discovering novel neuroprotective agents targeting PD-related diseases.

Keywords:  Drosophila melanogaster; Lifaspan; Saccharomyces cerevisiae; Verbascoside; Verbascum thapsus

DOI:  https://doi.org/10.1016/j.neurot.2025.e00825
Expert Opin Ther Targets. 2025 Dec 25. 1-3

Targeting the activation heat shock proteins for the potential treatment of neurodegenerative disease.

Anita K Ho, Han-Jou Chen.



Keywords:  HSF1; Heat shock response; heat shock protein; neurodegenerative diseases; protein aggregates

DOI:  https://doi.org/10.1080/14728222.2025.2608856
Alzheimers Dement. 2025 Dec;21 Suppl 1 e099419

Basic Science and Pathogenesis.

Sarah Kaufman, Jannis Bücking, Rudra Bose, Sarah Hoyle, Abi Wee, Man Wang, Gregory Merz, Daniel Southworth, William W Seeley, Martin Kampmann.

BACKGROUND: Tauopathies including Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) are characterized by the accumulation of aggregated tau protein in selectively vulnerable cell types that are lost in these diseases. The mechanisms that underlie tau aggregation and its associated toxicity are not known. While several human induced pluripotent stem cell (iPSC)-derived neuron tauopathy models have been developed, these models do not readily accumulate higher-order tau aggregates, which has hindered their use when studying mechanisms of tau aggregation and toxicity.
METHODS: I created a novel iNeuron tauopathy model system using an established human iPSC line (WTC11) that stably expresses 2N4R(P301S)-tau fused to mClover3/mApple ("FL-tau"). At baseline, FL-tau in control iPSCs and iNeurons remains soluble. However, transduction of tau aggregates originally derived from PSP subject brain lysate induces aggregation of FL-tau that is stably propagated in iPSCs and maintained through differentiation into iNeurons.
RESULTS: Bulk proteomics of PSP seeded FL-tau iNeurons versus control FL-tau iNeurons demonstrated enrichment of several splicing related RNA binding proteins (RBPs), including the nuclear speckle related protein pinin (PNN). While typically localized to the nucleus in non-dividing iNeurons, nuclear PNN staining was reduced in aggregate-containing iNeurons and co-localized with cytoplasmic FL-tau inclusions. Human neuropathologic analysis further showed that PNN mis-localizes to neuronal tau aggregates in AD and PSP, and nuclear PNN staining was reduced in these diseases compared to control subjects. CRISPRi mediated knockdown of PNN was toxic in human iPSCs, which further suggests changes in nuclear PNN may contribute to the neuronal loss observed in tauopathies. To identify additional modifiers of tau aggregation, I performed a large-scale CRISPRi screen of over 5,000 genes in PSP-seeded iNeurons. This screen identified several novel regulators of tau aggregation, including RBPs related to stress granule formation, RNA maintenance and degradation, and splicing related proteins.
CONCLUSIONS: This work identified several novel regulators of tau aggregation and toxicity, including PNN and stress granule related proteins. Future work will examine the mechanism(s) by which these RBPs modulate tau aggregation and toxicity.

DOI: https://doi.org/10.1002/alz70855_099419
Alzheimers Dement. 2025 Dec;21 Suppl 5 e103970

Drug Development.

Rijwan Uddin Ahammad, Brian Spencer, Robert A Rissman.

BACKGROUND: Dementia with Lewy bodies (DLB) is characterized by the accumulation of α-synuclein (α-syn) as well as Alzheimer's disease (AD) pathology, which includes the accumulation of amyloid beta (Aß) in plaques and phosphorylated tau in tangles, leading to neurodegeneration, cognitive loss and dementia. In DLB and other synucleinopathies, α-syn oligomers and proto-fibrils are thought to be mechanistically linked to the pathogenic neurodegenerative process. AD and related disorders (ADRD) are leading causes of dementia in the aging population and although new approaches are being tested, to date no disease-modifying therapies are available.
METHODS: We utilized 2'-OMe modified ASO-syn or ASO-scrambled, conjugated with ApoB11, which can cross the blood-brain barrier. ApoB11:2'-OMe ASO peptides were systematically delivered to DLB tg/non-tg mice to evaluated pharmacokinetics, pharmacodynamics and toxicology profile and determine its effects on α-syn and neurodegeneration using qPCR, immunohistochemistry and Western blot.
RESULTS: We found that ApoB11:2'-OMe ASO targeted to α-syn was well tolerated and safe in DLB tg mice without evidence of toxicity and it was successfully delivered to the mice brain. In addition, treatment with ApoB11:2'-OMe ASO targeted to α-syn significantly reduced α-syn aggregates in brains of DLB tg mice. Behavioral tests revealed improved spatial memory at 3 months, coinciding with early α-syn accumulation, and enhanced motor performance at both 3 and 9 months. These improvements were supported by increased neuronal survival and reduced neurodegeneration in treated mice.
CONCLUSION: Collectively, our findings suggest that the reduction of α-syn through the use of systemically-delivered ApoB11:ASO α-syn is a safe disease-modifying treatment for DLB and may hold promise as a future therapeutic for other synucleinopathies.

DOI: https://doi.org/10.1002/alz70859_103970
Sovrem Tekhnologii Med. 2025 ;17(4): 60-77

Protein Misfolding in the Pathogenesis and Diagnosis of Neurodegenerative Diseases (Review).

P P Tregub, N A Kolotyeva, P A Chekulayev, A A Groshkov, S N Illarioshkin, A B Salmina, M A Piradov.

  This review systematizes existing data on protein misfolding in the pathogenesis of neurodegenerative diseases (with a focus on α-synuclein, β-amyloid, and tau protein). Modern laboratory and neuroimaging methods used for clinical diagnosis and scientific research of proteinopathies are discussed. The paper describes promising protein amplification techniques that enable the detection of ultra-low concentrations of aberrant protein forms in biological fluids. The challenges and prospects of early diagnosis of neurodegenerative diseases through protein misfolding detection are also shown.

Keywords:  Alzheimer’s disease; Parkinson’s disease; biomarkers; misfolding; neurodegenerative diseases; protein amplification

DOI:  https://doi.org/10.17691/stm2025.17.4.06
Alzheimers Dement. 2025 Dec;21 Suppl 5 e099838

Drug Development.

Lawren VandeVrede.

The protein tau is central to the pathophysiology of many neurodegenerative diseases, including Alzheimer's disease (AD). Tau is ubiquitously expressed throughout the brain, and misfolded, insoluble tau protein deposits have been found at autopsy in neurons and glia in numerous neurodegenerative diseases, called tauopathies. In AD, a secondary tauopathy, aggregation of tau temporally follows amyloid plaque development. In AD, as in other tauopathies, the localization of tau corresponds with the resulting clinical features, and the amount of tau tangles seen on autopsy or positron emission tomography (PET) correlates with symptom severity throughout different stages of disease. As with amyloid, several lines of genetic evidence support tau's role in neurodegeneration, particularly pathogenic variants in the MAPT gene that codes for tau, which result in a diverse spectrum of clinical presentations, collectively called primary tauopathies. The normal physiologic role of tau is likely manifold, but it is a soluble cytoplasmic protein that interacts with and potentially stabilizes microtubules through a conserved microtubule binding region. However, the proposed role of tau in neurodegenerative disease is thought to be a toxic gain of function, supported by genetic evidence from genome wide association studies (GWAS) that have only identified gain-of-function variants. Additional evidence is found in nonclinical animal models, including tau knockout mice that have little to no apparent phenotype. Pathogenic species of tau are likely driven and defined by specific post-translational modifications, e.g., amyloid-induced hyperphosphorylation in the case of AD. The specific mechanism of propagation after toxic species of tau are produced is through cell-to-cell spread after an initial "seeding" event. In several neurodegenerative diseases, electronic microscopy has revealed distinct tau conformations specific to different tauopathies, each of which may be a unique seed. Targeting this tau toxic gain-of-function is possible through numerous pharmacological approaches, and early evidence from clinical trials where tau is pharmacologically reduced has shown reduction to be generally safe and well-tolerated.

DOI: https://doi.org/10.1002/alz70859_099838
bioRxiv. 2025 Dec 16. pii: 2025.12.14.694244. [Epub ahead of print]

Intracellular aggregation of the transthyretin protein is limited by Hsp70 chaperones.

Claire M Radtke, Adam S Knier, Sean A Martin, Jane E Dorweiler, Matt E Hudson, Anita L Manogaran.

Extracellular amyloid deposits are a hallmark feature of systemic protein aggregation diseases such as transthyretin amyloidosis (ATTR). However, emerging evidence suggests that extracellular transthyretin (TTR) aggregates are internalized and result in an intracellular stress response, including elevated Hsp70 levels. While ATTR research has predominantly focused on extracellular TTR amyloid, our understanding of TTR aggregation inside the cell is poorly explored. To better understand how intracellular chaperones impact intracellular TTR, we used a yeast model that expresses TTR fused eGFP (TTR-eGFP) within the cytoplasm. Since the Hsp70 chaperone family, and co-chaperones the J-domain proteins (JDPs) and Hsp110, act as a disaggregase in vitro, we asked how these molecular chaperones impact TTR aggregation intracellularly in vivo . TTR-eGFP forms detergent-soluble high molecular weight (HMW) aggregates in yeast that have biochemistry profiles similar to human patient TTR. While knockdown of the JDP, Sis1, and deletion of the Hsp110, Sse1, appear to slightly increase TTR-eGFP aggregation, the loss of two major yeast Hsp70s, Ssa1 and Ssa2, lead to a significant increase in the size of HMW species. Taken together, our data suggest that Hsp70s limit the formation of HMW TTR aggregates in the intracellular environment. Based on our results, it is possible that the age-related decline of protein homeostasis, including Hsp70s, may promote the intracellular aggregation of TTR.

DOI: https://doi.org/10.64898/2025.12.14.694244
Alzheimers Dement. 2025 Dec;21 Suppl 5 e106289

Drug Development.

Ajish Ariyath, Prashant Bharadwaj, Warnakulasuriya Mary Ann Dipika Binosha Fernando, Ralph N Martins.

BACKGROUND: In Alzheimer's disease (AD) brains, autophagy is over activated, however emerging research suggests that the ubiquitin-proteasome system might clear aggregation proteins and be a therapeutic target for AD and protein misfolding diseases. This study developed and validated novel small compounds targeting USP14 to improve protein homeostasis, reduce Aβ toxicity, and promote proteostasis in AD cell and worm models.
METHOD: Using the MC65 AD cell model, we screened 71 small molecule proteostasis modulators, identifying two promising USP14 ligands, AA10 and AA51. Their effects on autophagy, proteasome activity, Aβ toxicity, neurodegeneration, and behavior were assessed via fluorescence microscopy, toxicity analysis, western blotting, behavioral, and lifespan analysis in C. elegans.
RESULT: The AI-driven drug discovery platform AtomNet enabled the design and screening of 72 novel USP14-binding ligands. Two promising USP14 ligands AA10 and AA51 were tested in C. elegans AD model, neurodegeneration was reduced by 77% (IU1), 83% (AA10), and 84% (AA51) compared to control 33%. Furthermore, treated worms exhibited reduced lysosomal dysfunction through autophagic pathway modulation, enhanced behavioral activity (IU1-83%, AA10-88%, AA51-83%) compared to control 47%, and extended lifespan (IU1-4days, AA10-5days, AA51-5days), reinforcing their therapeutic potential. Notably, the use of autophagy inhibitors such as Bafilomycin A (BafA) and Chloroquine provided protection against Aβ toxicity, improved lifespan and behavior in AD worm model.
CONCLUSION: This is the first report of IU1's use in AD models as a USP14 inhibitor. AA10 and AA51 showed superior efficacy, making them promising candidates for future preclinical validations. The next phase involves testing therapeutic efficacy and brain bioavailability in AD mouse models to advance their potential as future treatments.

DOI: https://doi.org/10.1002/alz70859_106289
Inorg Chem. 2025 Dec 25.

Screening π-Extended Ruthenium(II) Complexes for the Photoinduced Oxidative Modulation of Amyloid-β Peptide Aggregation.

Grace Leech, Isabella Bayly, Alisher Talgatov, Patrick C Barrett, Colin G Cameron, Sherri A McFarland, Tim Storr.

Controlling the aggregation of amyloid-β (Aβ) peptides offers a promising strategy to mitigate Alzheimer's disease (AD). Herein, we introduce a series of photoactivatable Ru(II) complexes (Ru1-8) designed to efficiently generate singlet oxygen (1O2) and subsequently oxidatively modify the Aβ peptide. Upon light activation, these complexes rapidly direct Aβ1-42 aggregation toward high molecular weight amorphous species, with Ru1 demonstrating the most pronounced effect. Transmission electron microscopy (TEM) revealed that the amorphous aggregates formed immediately and persist over time. Complementary assays, including bicinchoninic acid (BCA) quantification and Western blotting, demonstrated rapid photoinduced aggregation and a decrease of soluble peptide upon photoactivation, while proteinase-K digestion showed that the resulting amorphous species are more susceptible to proteolysis in comparison to canonical fibrils. Control experiments under anaerobic conditions and in the presence of an 1O2 scavenger suggest that these effects are oxygen-dependent. Notably, photoactivation of Ru1 in the presence of preformed fibrils results in a morphology change to degradable amorphous aggregates, providing both preventive and disruptive activity. Together, these findings establish photoactivatable Ru1 as a light-controlled chemical tool capable of redirecting Aβ aggregation, enhancing aggregate protease degradation, and offering a versatile platform for therapeutic exploration.

DOI: https://doi.org/10.1021/acs.inorgchem.5c04609
Alzheimers Dement. 2025 Dec;21 Suppl 1 e103110

Basic Science and Pathogenesis.

Noelle Callizot, Laura Rouvière, Catherine Botto, Alexandre Wojcinski, Delphine Hardy, Alexandre Henriques.

BACKGROUND: The co-occurrence of multiple protein aggregates, or even hybrid aggregates, is very often observed in many neurodegenerative diseases, corroborating their molecular cross-links. Despite the emergence of studies indicating crossovers between Amyloid β (Aβ), hyperphosphorylated Tau protein (pTau) and alpha-synuclein (αSyn), a thorough understanding of their mechanistic coupling and subsequent pathogenicity is still lacking. It is well known that there are molecular interactions between these different proteins, and in particular between αSyn and pTau and Aβ. However, there is little evidence of a direct link between the formation of one and the appearance of the other. The close links between these proteins on their appearance was studied.
METHOD: Primary cultures of hippocampal and dopaminergic neurons both were injured with Aβ oligomers or αSyn PFF. Mitochondrial and lysosomal stress were carefully studied. At different timing accumulation of toxic protein was observed (by ICC and protein analysis). In vivo, aged mice (18 month old) were injured with Aβ or αSyn PFF by stereotaxic injection. Up to 6 weeks after the lesion, appearance of toxic proteins was following in different brain areas (SNpc, hippocampal area, amygdala, striatum).
RESULT: We observed a strong correlation between toxic αSyn aggregates and pTau accumulation. Similarly, aggregated αSyn was found after Aβ injections into the hippocampus. Appearance of these various toxic aggregates was always preceded by strong oxidative stress and by lysosome defects.
CONCLUSION: These results demonstrate the complexity of the relationships between these different proteins. We demonstrated that not only physical interaction are existing, but that each induced formation of the others leading to neuronal death.

DOI: https://doi.org/10.1002/alz70855_103110
Alzheimers Dement. 2025 Dec;21 Suppl 5 e098670

Drug Development.

Neil R Cashman, Steven S Plotkin, Scott Napper, Ebrima Gibbs, Beibei Zhao, Erin Scruten, Juliane Coutts, Johanne Kaplan.

BACKGROUND: Toxic misfolded proteins underlie the pathogenesis of neurodegenerative diseases such as Alzheimer's and Parkinson's disease (AD&PD), and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). Generation of therapeutic antibodies selectively targeting only disease-misfolded isoforms, while sparing normal or irrelevant isoforms, has not yet been successfully achieved by conventional immunization strategies.
METHOD: ProMIS Neurosciences has developed a computational platform to identify conformational epitopes that are uniquely exposed on toxic misfolded proteins, which can then be used to generate misfolding-specific antibodies or vaccine formulations.
RESULT: Application of the ProMIS platform produced PMN310, a clinical-stage, humanized monoclonal antibody highly selective for Abeta oligomers without significant reactivity with Abeta monomers or fibrils, thereby avoiding target distraction by these more abundant species, and reducing the risk of brain edema and microhemorrhages associated with the targeting of vascular/parenchymal amyloid. Similarly, specific epitopes for alpha-synuclein toxic oligomers/soluble fibrils that drive synucleinopathies, and for pathogenic TDP-43 in ALS/FTD have been identified and lead candidate antibodies generated. The small size and precise conformation of these epitopes have been translated into vaccines, enabling the specific targeting of pathogenic molecular species in preclinical models.
CONCLUSION: ProMIS has circumvented the specificity limitations of conventional immunizations to enable selective passive and active immunotherapies for neurodegenerative diseases.

DOI: https://doi.org/10.1002/alz70859_098670
J Neuroinflammation. 2025 Dec 22. 22(1): 293

Helicobacter pylori infection and α-synuclein pathology drive parallel neurodegenerative pathways in the substantia nigra.

Alejandro Soto-Avellaneda, Alice Prigent, Lindsay Meyerdirk, Noah Schautz, John Andrew Pospisilik, Lena Brundin, Michael X Henderson.

  Parkinson's disease is a common neurodegenerative disease related to both genetic and environmental insults. Epidemiological studies have linked Helicobacter pylori (H. pylori) infection to Parkinson's disease risk, but the underlying mechanisms of this association remain unclear. In this study, we investigated whether chronic infection with a pathogenic H. pylori strain could induce α-synuclein aggregation or neurodegeneration, and whether infection clearance mitigates these effects. We also assessed whether H. pylori infection exacerbates α-synuclein pathology and neuron loss when combined with seeding of α-synuclein pathology. We find that chronic H. pylori infection induces a sustained immune response in the gut and plasma that leads to mild brain inflammation and dopaminergic neuron loss, independent of α-synuclein pathology. These effects are attenuated by eradication of the infection. In mice with α-synuclein pathology induced by pre-formed fibrils, H. pylori does not further exacerbate the extent of pathology or neuronal death. Together, these results suggest that H. pylori infection can lead to neurodegeneration through inflammatory mechanisms independent of α-synuclein aggregation. Our findings offer mechanistic insights into how pathogens could influence the risk and progression of Parkinson's disease.

Keywords:  Helicobacter pylori; Infection; Inflammation; Parkinson’s disease; SNCA; T cells

DOI:  https://doi.org/10.1186/s12974-025-03596-z
Alzheimers Dement. 2025 Dec;21 Suppl 5 e100012

Drug Development.

Min Jung Lee, Sungsu Lim, Yun Kyung Kim, Kea Joo Lee, Bo-Ram Lee, Soo-Jung Choi, Hyangsoo Lee, Jun-Hwan Moon, Mi-Kyung Kim, Ae Nim Pae.

BACKGROUND: DA-7503 is a potential first-in-class, orally available small-molecule inhibitor of tau oligomerization, currently in clinical development for the treatment of Alzheimer's disease and primary tauopathies. The neurobehavioral and biochemical findings from AD and tauopathy mouse models revealed that DA-7503 improved memory and recognition, and reduced tau aggregation and hyperphosphorylation in the brain. This study aimed to elucidate the pharmacological properties of DA-7503, focusing on its potency and specificity for pathological tau isoforms, as well as its therapeutic effects on motor impairments and tau aggregation in the JNPL3 mouse model.
METHOD: The inhibitory potency of DA-7503 on aggregation of 4R and 3R tau isoforms was evaluated in tau-BiFC HEK293 cells. For in vivo studies, JNPL3 transgenic mice, expressing human P301L-mutant tau, were administrated with DA-7503 orally once daily for 4.5 months from 8 months of age. Therapeutic effects were assessed through motor impairment evaluations and analysis of pathological tau aggregation. Non-clinical toxicity and safety pharmacology studies, including 28-day rat and dog toxicity assessments, were conducted according to GLP principles.
RESULT: This study reports the non-clinical characteristics of DA-7503, a novel tau aggregation inhibitor, in terms of efficacy and safety. DA-7503 demonstrated comparable inhibitory potency against aggregation of both 4R tau and 3R tau under various tau aggregation-inducing conditions in tau-BiFC cells. In JNPL3 mice, DA-7503 treatment significantly improved motor function in several behavioral tests, including the open field, coat hanger, vertical grid, rotarod, and gait pattern analysis. Notably, a dose of 15 mg/kg was sufficient to reduce pathological tau aggregates in the brainstem and spinal cord of JNPL3 mice. Non-clinical toxicity studies revealed that DA-7503 has a favorable safety profile, supporting its clinical development.
CONCLUSION: Our findings suggest that DA-7503, a novel tau aggregation inhibitor with great potencies against pathological 3R and 4R tau isoforms and a favorable non-clinical safety profile, effectively restored motor function and reduced tau aggregates in the JNPL3 mouse model of tauopathy. These results highlight DA-7503's potential as a promising therapeutic candidate for Alzheimer's disease and primary tauopathies, including frontotemporal dementia, progressive supranuclear palsy and corticobasal degeneration. DA-7503 is currently undergoing a phase 1 clinical study.

DOI: https://doi.org/10.1002/alz70859_100012
Alzheimers Dement. 2025 Dec;21 Suppl 5 e106249

Drug Development.

Gregory M Cole, Cansheng Zhu, Kapil Manglani, Ke Hou, Alex Bombino, Mychica Jones, David S Eisenberg, Sally A Frautschy.

BACKGROUND: Pre-Fibrillar oligomeric and insoluble fibrillar aggregates of alpha-synuclein (aSyn) accumulate and contribute to the neurodegenerative decline in Parkinson Disease (PD) and other synucleinopathies and frequently occur as co-morbidities in the major tauopathy, Alzheimer Disease (AD). Familial autosomal dominant PD aSyn A53T mutations which promote aggregation cause age-related aSyn and tau pre-fibrillar oligomers and insoluble aSyn fibrillar deposits, neurodegeneration and motor deficits in hemizygous A53T aSyn transgenic mice.
METHOD: To test a candidate fibril structure-based therapeutic candidate we treated aSyn deposit-bearing 24 month old heterozygous A53T M83 mice for 6 weeks with a formulation of CNS11g, a small molecule designed to specifically fit an aSyn fibril site required for aggregation and previously demonstrated to disaggregate both pre-existing aSyn and tau fibrils in cell free systems.
RESULT: Oral gavage produced brain levels above the in vitro ED50 for disaggregation and ameliorated motor deficits with no evidence of toxicity compared with the vehicle group. CNS11g reduced levels of putatively neurotoxic, SDS-stable, high molecular weight soluble aSyn aggregates detected above 256kD by Western blot analysis in spinal cord and brainstem as well as tau oligomers in spinal cord. Quantitative ICC for p129S aSyn deposits and reactive glia, supported a significant treatment effect, but there was no effect on detergent insoluble p129S aSyn. Our late intervention results provide evidence for effective oral CNS11g delivery, safety and efficacy in reducing motor deficits and soluble p129S aSyn and tau oligomers and aSyn deposits by ICC without biochemical evidence for reducing pre-existing insoluble fibrillar aSyn deposits with this treatment paradigm.
CONCLUSION: While higher or longer dosing might disaggregate and clear insoluble fibrils, this initial study suggests oral dosing produces pleiotropic CNS activity against both aSyn and tau pre-fibrillar oligomers implicated in the neurotoxicity, seeding and spreading of two major proteinopathies.

DOI: https://doi.org/10.1002/alz70859_106249
Alzheimers Dement. 2025 Dec;21 Suppl 1 e104408

Basic Science and Pathogenesis.

Benjamin Falcon.

BACKGROUND: Neurodegenerative diseases are characterised by the accumulation of amyloid filaments of specific proteins in the central nervous system. Human genetic studies have established a causal role for amyloid filaments in neurodegeneration. However, the underlying molecular mechanisms remain poorly understood, which limits progress in targeting amyloid filaments for diagnostic and therapeutic benefit.
METHOD: We used electron cryo-microscopy (cryo-EM) to determine the atomic structures of amyloid filaments from the brains of individuals with neurodegenerative diseases.
RESULT: Unexpectedly, this approach directly revealed that TAR DNA-binding protein 43 (TDP-43) co-assembles with a second protein, annexin A11 (ANXA11), to form heteromeric amyloid filaments in specific neurodegenerative diseases. The atomic structures of these heteromeric filaments guide mechanistic studies into their formation.
CONCLUSION: This work establishes a central role for ANXA11 in neurodegenerative diseases. The unprecedented formation of heteromeric amyloid filaments in the human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.

DOI: https://doi.org/10.1002/alz70855_104408