Acta Neuropathologica最新文献

{"title":"Idiotypic-susceptible Alzheimer’s disease: a clinically relevant, neurofibrillary tangle subtype","authors":"John L. Robinson,&nbsp;Helen Cai,&nbsp;Nicholas J. Loh,&nbsp;Omar Vazquez,&nbsp;Zahra Khodakaramimaghsoud,&nbsp;EunRan Suh,&nbsp;Vivianna M. Van Deerlin,&nbsp;Paul A. Yushkevich,&nbsp;Dawn Mechanic-Hamilton,&nbsp;Sharon X. Xie,&nbsp;Daniel T. Ohm,&nbsp;David A. Wolk,&nbsp;David J. Irwin,&nbsp;Jeffrey S. Phillips,&nbsp;Edward B. Lee","doi":"10.1007/s00401-026-03013-6","DOIUrl":"10.1007/s00401-026-03013-6","url":null,"abstract":"<div><p>Neurofibrillary tangles in Alzheimer’s disease (AD) stereotypically spread from the medial temporal lobe to association areas and then to idiotypic areas (i.e., primary motor, somatosensory, auditory, and visual). Previous studies have reported variable and clinically relevant tangle densities across the hippocampus and association cortices, but the idiotypic tangle burden is understudied. In this study, we measured tangle density using immunohistochemistry in three idiotypic cortices (primary motor, somatosensory, and visual), three association cortices (middle frontal, superior temporal, and inferior parietal), and two hippocampal sectors (CA1 and subiculum) in 144 cases with a high level of AD neuropathologic change. Clinical diagnoses included late-onset AD (LOAD, <i>n</i> = 50), early-onset AD (EOAD, <i>n</i> = 21), behavioral variant frontotemporal dementia (bvFTD, <i>n</i> = 19), corticobasal syndrome (CBS, <i>n</i> = 18), logopenic primary progressive aphasia (lvPPA, <i>n</i> = 21), and posterior cortical atrophy (PCA, <i>n</i> = 15). We algorithmically assigned cases outside the interquartile ranges of mean tangle ratios of association:hippocampal, idiotypic:association, and idiotypic:hippocampal to mutually exclusive subtypes: idiotypic-susceptible, associative-predominant, limbic-predominant, or typical Braak (for all remaining cases). Regional tangle burdens differentiated subtypes, while female sex, younger ages, and longer disease durations also influenced tangle severity. Compared to typical Braak cases, idiotypic-susceptible and associative-predominant cases exhibited shorter disease duration and younger age at death while limbic-predominant cases were older. The <i>MAPT</i> H1H1 haplotype also differed by subtype, being most prevalent in limbic-predominant and least common in idiotypic-susceptible and associative-predominant subtypes. Clinically, the idiotypic-susceptible subtype associated with CBS (56%), the associative-predominant subtype with bvFTD (53%), and the limbic-predominant subtype with LOAD (14%). The typical Braak subtype characterized 74–76% of amnestic AD cases and 32–53% of non-amnestic AD cases. Moreover, k-means clustering corroborated four clusters including the idiotypic-susceptible and associative-predominant patterns. Our results confirm previously described tau subtypes and describe an idiotypic-predominant subtype with clinical relevance and distinct demographic and genetic characteristics in AD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03013-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathogenic IgG from long COVID patients with neurological sequelae triggers sensitive but not cognitive impairments upon transfer into mice","authors":"Margaux Mignolet,&nbsp;Catherine Deroux,&nbsp;Thomas Florkin,&nbsp;Valéry Bielarz,&nbsp;Kathleen De Swert,&nbsp;Nicolas Halloin,&nbsp;Lindsay Sprimont,&nbsp;Aurélie Ladang,&nbsp;Fabienne George,&nbsp;Jacques Gilloteaux,&nbsp;Laurence Abeloos,&nbsp;Pierre Garin,&nbsp;Johan Van Weyenbergh,&nbsp;Marc Jamoulle,&nbsp;Claire Diederich,&nbsp;Nicolas Albert Gillet,&nbsp;Pierre Bulpa,&nbsp;Charles Nicaise","doi":"10.1007/s00401-026-03019-0","DOIUrl":"10.1007/s00401-026-03019-0","url":null,"abstract":"<div><p>Approximately 30% of long COVID patients still experience neurological symptoms (brain fog, pain, chronic fatigue) more than 4 months after the onset of COVID-19. This condition, known as ‘neurological long COVID’, remains poorly understood and might be explained by a persisting autoimmune response against nervous-derived self-antigens. The aim of this study is to determine whether IgG autoantibodies from long COVID patients with neurological sequelae can bind to central or peripheral nervous system epitopes and trigger neuropsychiatric symptoms upon passive transfer into mice, thereby mirroring patient-reported manifestations. Long COVID patients meeting the 2021 consensus WHO definition were included following a standardized neuropsychological assessment, while excluding patients with a medical history of autoimmune and neurological disorders. Age- and sex-matched asymptomatic individuals were used as healthy controls. Total IgGs were isolated using protein G purification and injected intraperitoneally into C57Bl6/J mice for four consecutive days. During the two weeks post-injections, behavioral tests assessed mechanical allodynia, thermal hyperalgesia, spatial working memory, depression, and anxiety. Mice injected with IgG from long COVID patients showed no difference with the control group in terms of anxiety or depression behaviors, short- or long-term spatial memories. However, they displayed a transient decrease of paw withdrawal threshold and thermal hypersensitivity during the first week. This effect was abolished when IgG-depleted serum or papain-digested IgGs were transferred. IgG from long COVID patients accumulated in the lumbar dorsal root ganglia of injected mice and colocalized with proprioceptive and nociceptive sensory neurons, without inducing local neuroinflammation or astrogliosis. When applied onto human <i>post-mortem</i> DRG tissue, patient-derived IgG also exhibited immunoaffinity for sensory neuron somata. These data demonstrate that IgGs from long COVID patients bind to peripheral sensory neurons and induce pain-related symptoms in mice. Our findings also support the hypothesis that autoantibodies mediate pain-related pathophysiology in the spectrum of long COVID symptoms.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03019-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The hypoxia-inflammation cycle as a key mechanism of smoldering inflammation and progression in multiple sclerosis","authors":"M. Missaglia,&nbsp;M. Filippi,&nbsp;F. Esposito,&nbsp;A. Giordano","doi":"10.1007/s00401-026-03021-6","DOIUrl":"10.1007/s00401-026-03021-6","url":null,"abstract":"<div><p>Disease progression in multiple sclerosis (MS) remains a major unmet clinical challenge, as it is driven by pathogenic mechanisms that are poorly targeted by currently available disease-modifying treatments. Whereas acute focal inflammation characterizes the relapsing–remitting phase, converging neuropathological, imaging and experimental evidence identifies a chronic low-grade compartmentalized inflammatory process, the so-called “smoldering” inflammation, as a central driver of disease progression in MS. Recent findings suggest that both tissue hypoxia (primarily resulting from vascular dysfunction) and virtual hypoxia (a state of metabolic supply–demand mismatch culminating in bioenergetic failure) may critically contribute to the onset, persistence and compartmentalization of smoldering inflammation. In this review, we first delineate the pathological mechanisms underlying smoldering inflammation, distinguishing between lesional and extra-lesional features. We then examine the processes leading to tissue and virtual hypoxia in MS. As a key link between smoldering inflammation and hypoxia, we focused on the Hypoxia-Inducible Factor (HIF) signaling, the master regulator of cellular responses to hypoxia. Particularly, we reviewed recent evidence supporting its role as a central immunometabolic hub shaping immune and glial cell function within the hypoxic microenvironment of smoldering inflammation in MS. Finally, we critically evaluate the potential of the HIF signaling as a therapeutic target to hamper smoldering inflammation and disease progression in MS.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel BEND2 monoclonal antibody enables highly specific immunohistochemical diagnosis of BEND2-fusion astroblastomas","authors":"Qianqian Sun,&nbsp;Yixing Shi,&nbsp;Leiming Wang,&nbsp;Lin Bai,&nbsp;Wanming Hu,&nbsp;Yuqiao Xu,&nbsp;Yueshan Piao,&nbsp;Xueling Qi,&nbsp;Jiang Liu,&nbsp;Hongzhi Guan,&nbsp;Wei Shi,&nbsp;Yang Yu","doi":"10.1007/s00401-026-03023-4","DOIUrl":"10.1007/s00401-026-03023-4","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A severe neurodevelopmental syndrome linked to a South Asian founder variant in the UFMylation adaptor CDK5RAP3","authors":"Michaela Yuen,&nbsp;Katharine Zhang,&nbsp;Rhett G. Marchant,&nbsp;Ryosuke Ishimura,&nbsp;Mark Graham,&nbsp;May Aung-Htut,&nbsp;Samantha Bryen,&nbsp;Rocio Rius,&nbsp;Lee Marshall,&nbsp;Nader Aryamanesh,&nbsp;Gregory Dziaduch,&nbsp;Himanshu Joshi,&nbsp;Ben Weisburd,&nbsp;Steve D. Wilton,&nbsp;Meredith Wilson,&nbsp;Russell Gear,&nbsp;Lucy Hennington,&nbsp;Stephanie Lau,&nbsp;Helen Doyle,&nbsp;Michael Krivanek,&nbsp;Richard J. Leventer,&nbsp;Susan M. White,&nbsp;Sarah A. Sandaradura,&nbsp;Masaaki Komatsu,&nbsp;Frances J. Evesson,&nbsp;Sandra T. Cooper","doi":"10.1007/s00401-026-03017-2","DOIUrl":"10.1007/s00401-026-03017-2","url":null,"abstract":"<div><p>We investigated the pathogenicity of a homozygous intronic variant in <i>CDK5RAP3</i>, a key UFMylation adapter, in three individuals from two unrelated families with a lethal neurodevelopmental disorder. <i>CDK5RAP3</i> variants have not been linked to human disorders to date; however, murine <i>Cdk5rap3</i> knockout is embryonic lethal and variants in five other UFMylation components cause severe neurodevelopmental conditions. A segregating homozygous variant, chr17(GRCh38):g.47974691G &gt; A, <i>CDK5RAP3</i> NM_176096.3:c.334 + 243G &gt; A, was identified by trio whole-genome and proband RNA sequencing in Family A and by trio whole-exome sequencing data reanalysis in Family B. Variant pathogenicity investigations included RT-PCR, Western blot, co-immunoprecipitation and (phospho)proteomics to assess transcript, protein and UFMylation complex effects. Antisense oligonucleotide-mediated rescue of <i>CDK5RAP3</i> expression combined with proteomics and phosphoproteomics defined the mechanistic impact of CDK5RAP3 deficiency and rescue in amniocytes from an affected individual. All three affected individuals showed foetal growth restriction, foetal akinesia, pontocerebellar hypoplasia, arthrogryposis and hepatic pathology. <i>CDK5RAP3</i> c.334 + 243G &gt; A activates a cryptic donor splice-site causing pseudoexon/intron inclusion triggering nonsense-mediated decay and deficiency of full-length CDK5RAP3 (NP_788276.1), while potentially allowing retained expression of C-terminal alternative isoforms. Co-immunoprecipitation revealed only full-length CDK5RAP3 binds UFL1, whereas C-terminal isoforms cannot. Primary amniocytes showed CDK5RAP3 deficiency was associated with impaired UFMylation of known substrates, RPL26 and UFBP1. Proteomic and phosphoproteomic analyses revealed dysregulation of extracellular matrix organisation, cell adhesion, mitotic/genome stability pathways, cytoskeletal networks and neuronal guidance, which were reversed by restoration of canonical <i>CDK5RAP3</i> expression via splice-correcting antisense oligonucleotides. Phosphoproteomic data implicate CDK5RAP3 as an upstream regulator of UFL1 S462 phosphorylation, known to be regulated by Ataxia-telangiectasia mutated (ATM) signalling. Our findings provide strong evidence linking deficiency of full-length CDK5RAP3 to severe neurodevelopmental, liver and muscle dysfunction. This study further highlights the therapeutic potential of ASO-based deep-intronic splicing defect correction.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03017-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147753248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of meningothelial identity and mesenchymal fate switching in NF2-mutant meningiomas","authors":"Ramin Rahmanzade,&nbsp;Leonille Schweizer,&nbsp;Simone Schmid,&nbsp;Tereza Lausová,&nbsp;Gianluca Sigismondo,&nbsp;Mozhgan Esmaeili Benvidi,&nbsp;Rushda Patel,&nbsp;Aras Fuat Kaan,&nbsp;Rouzbeh Banan,&nbsp;David Reuss,&nbsp;Natalie Jäger,&nbsp;Marie-Theresa Forster,&nbsp;Viktoria Zeller,&nbsp;Patricia Kohlhof-Meinecke,&nbsp;Annette Fisseler-Eckhoff,&nbsp;Barbara Carl,&nbsp;Patrick N. Harter,&nbsp;Katrin Lamszus,&nbsp;Ulrich Schüller,&nbsp;Michal Zapotocky,&nbsp;Till Acker,&nbsp;C. O. Hanemann,&nbsp;Jens Schittenhelm,&nbsp;Eva Brack,&nbsp;Uta Flucke,&nbsp;Gunhild Mechtersheimer,&nbsp;Luca Bertero,&nbsp;Christine Haberler,&nbsp;David Capper,&nbsp;Andreas von Deimling,&nbsp;Philipp Sievers,&nbsp;Felix Sahm","doi":"10.1007/s00401-026-03016-3","DOIUrl":"10.1007/s00401-026-03016-3","url":null,"abstract":"<div><p>Intracranial sarcomas can arise secondarily from primary brain tumors, including gliomas and meningiomas, either spontaneously or following radiotherapy. The current WHO classification recognizes sarcomatous transformation in several tumor entities; however, sarcomas arising from meningiomas remain poorly characterized and are regarded as a possible histological manifestation within the spectrum of anaplastic meningiomas. We analyzed nine matched meningioma–sarcoma pairs using integrated histopathological assessment and molecular profiling, including DNA methylation analysis, next-generation sequencing, copy number profiling, and proteomics. Although recurrent sarcomatous tumors were clonally related to their meningioma precursors—sharing identical NF2 alterations and overlapping chromosomal aberrations—they demonstrated pronounced divergence at the histological, immunophenotypic, and epigenetic levels. Importantly, sarcomatous transformation occurred in four cases without prior radiotherapy. Sarcomatous recurrences exhibited loss of meningothelial markers and acquired expression of cytokeratin and myogenic markers. DNA methylation profiling revealed a shift away from canonical meningioma signatures toward profiles resembling non-meningothelial mesenchymal tumors. Proteomic analysis showed consistent upregulation of SOX2 in sarcomatous tumors compared with their primary counterparts, suggesting acquisition of stem-like features during lineage divergence. Clinically, these tumors were associated with aggressive growth, early recurrence, and extracranial metastases, resembling malignant sarcomas more closely than anaplastic meningiomas. In addition, analysis of an institutional cohort of NF2-mutant intracranial tumors (n = 316) suggests that sarcomas with inactivating NF2 mutations may originate from meningiomas even in the absence of a clinically recognized precursor. Together, these findings suggest that sarcomatous transformation represents a rare evolutionary endpoint in NF2-mutant meningiomas, marked by clonal continuity but pronounced biological divergence. These results highlight limitations of morphology-based classification and emphasize the value of integrated molecular diagnostics in distinguishing these tumors from conventional high-grade meningiomas. Given their sarcoma-like behavior despite a meningioma ancestry, these tumors may not be adequately captured by current meningioma grading schemes.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03016-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147743850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered astrocyte–neuron crosstalk in progressive supranuclear palsy: integrated evidence from proteomics and magnetic resonance spectroscopy","authors":"Maiko Ono,&nbsp;Yuta Kumagai,&nbsp;Kosei Hirata,&nbsp;Yuki Maeda,&nbsp;Yurika Abe,&nbsp;Hironobu Endo,&nbsp;Hiroshi Shimizu,&nbsp;Akiyoshi Kakita,&nbsp;Yasuo Uchida,&nbsp;Yuhei Takado","doi":"10.1007/s00401-026-03020-7","DOIUrl":"10.1007/s00401-026-03020-7","url":null,"abstract":"<div><p>The anterior cingulate cortex (ACC), crucial for executive function, is frequently impaired in progressive supranuclear palsy (PSP), yet mechanisms underlying this selective vulnerability remain unclear. Given the integration of astrocytes into neural circuits, we hypothesized that astrocyte dysfunction and altered astrocyte–neuron crosstalk contribute to functional abnormalities in the ACC in PSP. To test this hypothesis, we conducted a multimodal analysis integrating SWATH-MS-based proteomics, histopathology, and in vivo magnetic resonance spectroscopy (MRS) in postmortem and living brains of patients with PSP and healthy controls (HCs). The astrocytic markers glial fibrillary acidic protein (GFAP) and aquaporin-4 (AQP4) were significantly elevated in the ACC of patients with PSP compared with those in HCs. Enhanced astrocytic Ca²⁺ signaling through the IP3-Ca²⁺ cascade was suggested in the ACC of patients with PSP, consistent with elevated myo-inositol levels on MRS. Proteomic data revealed reduced expression of pyruvate dehydrogenase complex components (DLD and PDHX) and oxidative phosphorylation-related proteins, including astrocyte-enriched genes such as ETFDH and UQCRC1. MRS also revealed significantly increased levels of lactate and glutamate in the ACC of patients with PSP compared with those in HCs. Notably, myo-inositol, lactate, and glutamate levels were positively correlated, indicating astrocyte-associated metabolic dysfunction. Expression of glutamate–glutamine cycle-related molecules and neuronal markers was negatively correlated with GFAP and AQP4 levels, suggesting that astrocytic dysfunction is associated with alterations in the excitatory/inhibitory balance in the ACC of patients with PSP. These findings demonstrate that multiple aspects of astrocyte–neuron crosstalk, including AQP4-mediated glymphatic clearance, energy metabolism, and neurotransmitter cycling, are altered in the ACC of patients with PSP. Such disruptions may contribute to neuronal dysfunction. Our study highlights astrocyte dysfunction as a central feature of the PSP pathophysiology.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147735550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tau oligomerization induces nuclear lamina invagination and chromatin remodeling in Alzheimer’s disease","authors":"Shuo Yuan,&nbsp;Nicholas Essepian,&nbsp;Rebecca Roberts,&nbsp;Eliana Sherman,&nbsp;Qingbo Wang,&nbsp;Alev Erisir,&nbsp;Lulu Jiang","doi":"10.1007/s00401-026-03018-1","DOIUrl":"10.1007/s00401-026-03018-1","url":null,"abstract":"<div><p>The aggregation of the microtubule-associated protein tau into oligomeric complexes is strongly correlated with the onset and progression of neurodegeneration in Alzheimer’s disease (AD). Increasing evidence implicates nuclear membrane disruption in AD and related tauopathies; however, whether this is a cause or consequence of neurodegeneration remains unresolved. Here, we show that nuclear lamina disruption emerges at the early Braak stages, coinciding with the initial formation of pathological tau aggregates in post-mortem AD brain tissue. Using the tauopathy mouse model (P301S PS19), we demonstrate that oligomeric tau (oTau) directly binds to the Lamin B Receptor (LBR), inducing nuclear envelope invaginations as revealed by electron microscopy. These structural alterations are accompanied by chromatin remodeling and gene expression dysregulation. To dissect the underlying mechanism, we employed a light-inducible OptoTau system (4R1N Tau::mCherry::Cry2Olig) in human iPSC-derived neurons, enabling real-time visualization of tau aggregation dynamics. This system revealed selective recruitment of oTau to the nuclear envelope and direct interactions with LBR and Lamin B2, leading to nuclear deformation and activation of the protein translational stress response. Together, these findings identify nuclear membrane disruption as an early and potentially causative event in tau-mediated neurodegeneration, establishing a mechanistic link between tau oligomerization, nuclear stress, and chromatin remodeling. Targeting nuclear destabilization may offer new therapeutic avenues for mitigating AD pathogenesis.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03018-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147731352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modification of early behavioural, physiological and neuropathological endpoints by syntaxin-6 knockout in a humanised P301S transgenic model of tauopathy","authors":"Elizabeth Hill,&nbsp;Jacqueline Linehan,&nbsp;Michael Farmer,&nbsp;Tatiana Jakubcova,&nbsp;Shyma Hamdan,&nbsp;Andrew Tomlinson,&nbsp;Silvia Purro,&nbsp;Fabio Argentina,&nbsp;Emma Jones,&nbsp;Nicholas Kaye,&nbsp;Craig Fitzhugh,&nbsp;Rohan de Silva,&nbsp;Sebastian Brandner,&nbsp;John Collinge,&nbsp;Thomas J. Cunningham,&nbsp;Simon Mead","doi":"10.1007/s00401-026-03009-2","DOIUrl":"10.1007/s00401-026-03009-2","url":null,"abstract":"<div><p>Genetically mediated increased expression of syntaxin-6, a SNARE protein involved in intracellular protein trafficking, is a proposed risk mechanism for progressive supranuclear palsy and sporadic prion disease. Increased syntaxin-6 protein levels are also causally associated with Alzheimer’s disease, suggesting it may have shared roles across multiple neurodegenerative diseases. However, no study has validated its functional role in tauopathies. To validate a role for syntaxin-6 in tauopathy pathogenesis, we knocked out syntaxin-6 in humanised P301S tauopathy mice. Mice underwent longitudinal rotarod testing, gait analysis, frailty and weight assessment, with neuropathological, biochemical and pathological analyses at 3 and 5 months. <i>Stx6</i>^+/+;h<i>Tau</i>^P301S/P301S mice showed motor impairment from 1 month of age, which was partially rescued by syntaxin-6 knockout from months 1 to 4, with additional protection of gait at 5.5 months. Physiologically, syntaxin-6 knockout exerted a protective effect on weight trajectories and measures of frailty. Reduced neurodegeneration in the superficial cortex was observed at 3 months, as well as higher synaptic coverage at 5 months of age, supporting preserved neuropathological measures related to function. We further observed localised increases in tau pathology in the spinal cord and defined brain regions in young <i>Stx6</i>^{<i>−/−</i>}<i>;</i>h<i>Tau</i>^P301S/P301S mice, despite total tau levels being comparable, in keeping with altered trafficking of pathological tau species with syntaxin-6 knockout. Despite a partial, early phenotypic rescue of functional measures, terminal endpoint comparisons were confounded by a 20% weight loss culling rule, as knockout mice maintained higher absolute weight. Taken together, this study functionally validates a role for syntaxin-6 in tauopathy pathogenesis, with syntaxin-6 knockout resulting in an early protective effect on multiple disease-relevant phenotypes in a humanised tauopathy model.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03009-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147731351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Primitive neuronal component is a frequent finding among IDH-mutant astrocytomas with RB1 alterations","authors":"Cheyanne C. Slocum,&nbsp;Jamal K. Benhamida,&nbsp;Scott Eckert,&nbsp;Erika Gedvilaite,&nbsp;Ryan Ptashkin,&nbsp;Viviane Tabar,&nbsp;Robert J. Young,&nbsp;Marc Ladanyi,&nbsp;Ingo K. Mellinghoff,&nbsp;Marc K. Rosenblum,&nbsp;A. Rose Brannon,&nbsp;Richard Hickman,&nbsp;Tejus A. Bale","doi":"10.1007/s00401-026-03014-5","DOIUrl":"10.1007/s00401-026-03014-5","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03014-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147719512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}