Acta Neuropathologica最新文献

{"title":"Neuropathological analysis of an ALS patient carrying a SOD1 missense variant and a C9orf72 repeat expansion","authors":"Tomoko Miki, Sibylle De Bertier, Maria-Del-Mar Amador, Mélusine Nicolas, Claire Guissart, Marion Deret, Elisa Teyssou, François Muratet, Delphine Bohl, Christian S. Lobsiger, Séverine Boillée, Florence Esselin, François Salachas, Stéphanie Millecamps, Danielle Seilhean","doi":"10.1007/s00401-026-03007-4","DOIUrl":"10.1007/s00401-026-03007-4","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03007-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147702160","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":"A model-based prion vaccine protects a transgenic mouse line carrying a Gerstmann–Sträussler–Scheinker disease mutation","authors":"Andrew Fang,&nbsp;Xinli Tang,&nbsp;Madeleine Fleming,&nbsp;Brian Tancowny,&nbsp;Xiongyao Wang,&nbsp;YongLiang Wang,&nbsp;Nathalie Daude,&nbsp;Lyudmyla Dorosh,&nbsp;Shelaine C. Fleck,&nbsp;Vineet Rathod,&nbsp;Virginie Coustou,&nbsp;Silvia A. Cervantes,&nbsp;Camilo Duque Velásquez,&nbsp;David Westaway,&nbsp;Judd Aiken,&nbsp;Debbie McKenzie,&nbsp;Glenn Telling,&nbsp;Maria Stepanova,&nbsp;Sven J. Saupe,&nbsp;Ansgar B. Siemer,&nbsp;Holger Wille","doi":"10.1007/s00401-026-03015-4","DOIUrl":"10.1007/s00401-026-03015-4","url":null,"abstract":"<div><p>Prion diseases are transmissible, fatal, neurodegenerative disorders driven by the conformational misfolding of the cellular prion protein (PrP^C) into an infectious, aggregation-prone conformer (PrP^Sc). While the accumulation of PrP^Sc represents the central pathogenic event, targeting it directly and specifically has proven difficult due to its structural heterogeneity and similarity to PrP^C. Consequently, previous immunization efforts have largely focused on PrP^C, though with limited success. Here, we employed a model-based approach to design a vaccine that specifically mimics immunogenic features hypothesized to be present on the surface of PrP^Sc. By mimicking predicted surface residues and using an innocuous, cross-beta fibril scaffold derived from the fungal protein HET-s (218–289), we were able to generate unique, conformation-dependent epitopes not found on PrP^C. We evaluated our vaccine by immunizing a genetic prion disease mouse model of Gerstmann–Sträussler–Scheinker disease, a genetic prion disorder. Vaccination was able to significantly delay the onset of disease in immunized mice (412 ± 88 days) compared to unimmunized (177 ± 17 days) and scaffold-immunized (161 ± 27 days) animals, and supplementation with adjuvants including Freund’s adjuvant (448 ± 39 days), QS-21 (479 ± 58 days), and Alum (506 ± 52 days) was able to further enhance the vaccine efficacy. To investigate the mechanism of neuroprotection, we derived a monoclonal antibody from a vaccinated mouse and mapped its discontinuous, conformation-specific epitope, comprising an aspartate–histidine pair that may be occluded in PrP^C, and confirmed the antibody’s ability to differentiate between infectious and uninfected prion samples. Our study demonstrates the feasibility of a model-based approach for prion vaccine design and targeting of the infectious prion protein, providing groundwork for future development of not only potential prion therapeutic interventions, but also targeting related neurodegenerative disorders characterized by protein misfolding.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03015-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147702162","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":"Consensus statement on microglial and macrophage functions in gliomas","authors":"Yuqi Zheng,&nbsp;Islam Alzoubi,&nbsp;Manuel B. Graeber,&nbsp;Atul Anand,&nbsp;Lara Barazzuol,&nbsp;Mario Dorostkar,&nbsp;Karl Frontzek,&nbsp;Anna Golebiewska,&nbsp;Costas G. Hadjipanayis,&nbsp;Tibor Hortobagyi,&nbsp;Azzam Ismail,&nbsp;Gerard H. Jansen,&nbsp;Bozena Kaminska,&nbsp;Daniel Kirschenbaum,&nbsp;Yoshihiro Komohara,&nbsp;Bjarne Winther Kristensen,&nbsp;Kevin S. Lee,&nbsp;Emilie Le Rhun,&nbsp;Q. Richard Lu,&nbsp;Kaspar Matiasek,&nbsp;Christian Mawrin,&nbsp;Alessandro Michelucci,&nbsp;Nicola Montemurro,&nbsp;Marc-André Mouthon,&nbsp;Quan Liu,&nbsp;Regina Reimann,&nbsp;Roman Sankowski,&nbsp;Alejandro Schcolnik-Cabrera,&nbsp;Michael Schulz,&nbsp;Christian M. Schürch,&nbsp;Marius Schwabenland,&nbsp;Aurélie Tchoghandjian,&nbsp;Indrė Valiulytė-Simaitė,&nbsp;Mariano S. Viapiano,&nbsp;Tobias Weiss,&nbsp;Michael Weller,&nbsp;Max Wintermark","doi":"10.1007/s00401-026-02999-3","DOIUrl":"10.1007/s00401-026-02999-3","url":null,"abstract":"<div><p>This international consensus statement synthesizes key findings on the complex roles of microglia and macrophages (tumor-associated microglia/macrophages or TAMs) in glioma progression and therapeutic resistance. Recent advances have highlighted the cellular, spatial, and temporal heterogeneity of TAMs, their functional plasticity, and the intricate interactions between TAMs, glioma stem cells, and the neuronal microenvironment, challenging the M1/M2 classification paradigm for TAMs in gliomas and other misconceptions. The statement emphasizes that glioma cells manipulate TAMs to suppress anti-tumor functions, while microglia-mediated modulation of neuron-glioma cell interactions promotes tumor progression. Furthermore, glioblastoma-derived extracellular vesicles (EVs) reprogram microglia to support tumor progression, offering novel therapeutic targets. To advance research and develop more effective treatments, the statement advocates for precision therapies targeting specific TAM subsets or functions, the use of bioengineered EVs as a therapeutic approach, and a shift away from simplistic terminology like “M1/M2” and “neuroinflammation”. Ultimately, this new understanding can support innovative strategies to modulate the tumor microenvironment, turning immunosuppression into immunostimulation and improving outcomes for patients with glioblastoma and other types of gliomas.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-02999-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147695200","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":"Ser423-phosphorylated MECP2 (MECP2-pS423) accumulates in human brain, cerebrospinal fluid and serum in sporadic Alzheimer’s disease","authors":"Qing-Rong Liu,&nbsp;Min Zhu,&nbsp;Kevin Perez,&nbsp;Qin Yao,&nbsp;Mark S. Horowitz,&nbsp;Qinghua Chen,&nbsp;Giovanna Fantoni,&nbsp;Yang An,&nbsp;Susan M. Resnick,&nbsp;Andrea Sedlock,&nbsp;Dragan Maric,&nbsp;Geidy E. Serrano,&nbsp;Josephine M. Egan,&nbsp;Christopher E. Ramsden","doi":"10.1007/s00401-026-03008-3","DOIUrl":"10.1007/s00401-026-03008-3","url":null,"abstract":"<div><p>Methyl-CpG-binding protein 2 (MECP2) is a nuclear protein that serves as a global epigenetic repressor. Activity-dependent Ser421-phosphorylation is permissive to translocation of mouse Mecp2 to the cytoplasm, thereby reducing the repressor functions and activating neurotrophins. Mecp2-pS421 levels increase in neuron soma of AD (APP/PS1) mouse model and ablating Mecp2 increases activity of glycogen synthase kinase 3 beta, implying a link between MECP2 phosphorylation and Tau pathology in Alzheimer’s disease (AD). It is currently unknown whether phosphorylation at the corresponding site of human MECP2-pS423 plays a role in AD. We developed an MECP2-pS423-specific antibody, and a quantitative selective reaction monitoring (SRM) assay based on LC–MS/MS analysis, and we used immunohistochemistry and proteomics to study MECP2-pS423 in human brain, cerebrospinal fluid (CSF), and serum specimens. In postmortem cortex and hippocampus, MECP2-pS423 expression increased across the clinicopathological spectrum of AD and correlated with histological progression and cognitive deficits. At the cellular level, MECP2-pS423 and pTau colocalized in granulovacuolar degeneration (GVD) bodies and neuritic plaques. Phosphoprotein levels of MECP2-pS423 increased in CSF and serum samples from patients clinically diagnosed as having AD premortem. Moreover, we found that a primate-specific and N-terminus truncated MECP2-E3 isoform mRNA was increased in postmortem middle temporal gyrus (MTG) of patients with AD. The results suggest that MECP2-pS423 is a promising mechanism-based biomarker and potential therapeutic target because its accumulations correlate with pathological and cognitive deficit in brain, CSF, and serum of human sporadic AD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147684815","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":"Contribution of health history and neuropathologic changes to the likelihood of dementia in those with intermediate/high Alzheimer’s pathology: findings from The 90 + Study","authors":"Zarui A. Melikyan,&nbsp;Zeinah Al-darsani,&nbsp;Luohua Jiang,&nbsp;Katherine A. Colcord,&nbsp;Annlia Paganini-Hill,&nbsp;Syed A. Bukhari,&nbsp;Thomas J. Montine,&nbsp;Claudia H. Kawas,&nbsp;María M. Corrada","doi":"10.1007/s00401-026-03010-9","DOIUrl":"10.1007/s00401-026-03010-9","url":null,"abstract":"<div><p>Although intermediate/high Alzheimer’s Disease Neuropathologic Change (ADNC) is associated with dementia in many older adults, some remain cognitively normal and are often referred to as resilient to ADNC. We aim to examine health, lifestyle, and neuropathologic factors that distinguish older adults with dementia vs. normal cognition in the presence of intermediate/high ADNC. Participants were from <i>The 90</i> + <i>Study</i>, a longitudinal study of aging in southern California. This cross-sectional analysis included participants with an intermediate/high ADNC on neuropathologic exam and normal cognition or dementia diagnosis on case conference. We analyzed 11 neuropathologic changes, both vascular and neurodegenerative, dichotomized as present/absent, and the total number of neuropathologies. To examine the association of health and lifestyle factors and neuropathologic changes (predictors) with cognitive diagnosis at consensus case conference, dementia vs. normal cognition, (outcome), we used logistic regression adjusted for demographics. Among 235 participants (mean age at death = 98 years, 70% women), 33% maintained normal cognition. Participants with heart disease (OR = 0.45; 95% CI = 0.25, 0.81) and hypertension (OR = 0.53; 95% CI = 0.29, 0.95) had lower likelihood of dementia. In contrast, participants with a history of transient ischemic attacks (OR = 3.00; 95% CI = 1.46, 6.18), Lewy Body Disease (OR = 2.73; 95% CI = 1.14, 6.58), hippocampal sclerosis (OR = 2.70; 95% CI = 1.06, 6.86), Limbic-predominant Age-related TDP-43 Encephalopathy neuropathologic change (OR = 2.80; 95% CI = 1.53, 5.12), and a high number of non-ADNCs (OR = 4.46; 95% CI = 2.01, 9.92) had higher likelihood of dementia. Arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, and microvascular lesions were not associated with dementia. In this study, the presence of neurodegenerative neuropathologic changes other than ADNC and the absence of hypertension distinguish oldest old individuals with dementia from those with normal cognition. Understanding mechanisms underlying normal cognition in those with ADNC may provide important clues to prevention and resilience to the effects of AD neuropathology.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03010-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147625824","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":"Alzheimer’s disease risk protein SorLA regulates ER homeostasis and lipid metabolism in human microglia, with conserved effects in neurons","authors":"Imdadul Haq,&nbsp;Jason C. Ngo,&nbsp;Nainika Roy,&nbsp;Emily Lee,&nbsp;Muniyat A. Choudhury,&nbsp;Rajesh K. Soni,&nbsp;Andrew F. Teich,&nbsp;Richard P. Mayeux,&nbsp;Philip L. De Jager,&nbsp;Ye He,&nbsp;Xuebing Wu,&nbsp;David A. Bennett,&nbsp;Marta Olah,&nbsp;Falak Sher","doi":"10.1007/s00401-026-03002-9","DOIUrl":"10.1007/s00401-026-03002-9","url":null,"abstract":"<div><p>Microglial dysfunction is a hallmark of Alzheimer’s disease (AD), yet the molecular mechanisms driving these impairments remain poorly defined. Genetic studies implicate several AD-associated genes in regulating microglial activity, including <i>SORL1</i>, which encodes the sorting receptor SorLA. Although SorLA is highly expressed in microglia, its functional role in cellular homeostasis has remained unclear. Here, we investigated SorLA function using human brain tissue, primary microglia from rapid autopsies, and CRISPR-engineered human iPSC-derived microglia and neurons. Integrated multi-omics analyses, including single-cell RNA sequencing, lipidomics, and proteomics, together with biochemical and functional assays, revealed that SorLA deficiency induces endoplasmic reticulum (ER) stress and interferon signaling, promotes lipid droplet accumulation, and impairs phagocytic and immune functions. Protein co-complex mapping and structural modeling identified ER-associated proteins co-enriched with SorLA, including SUN2, calnexin (CANX), and multiple COPI complex components (COPA, COPB1, COPG1, ARCN1), implicating SorLA in ER proteostasis and intracellular trafficking. Notably, <i>SORL1</i> deletion in iPSC-derived neurons recapitulated key phenotypes observed in microglia, including lipid droplet accumulation and SorLA–SUN2 co-immunoprecipitation, indicating that this ER-associated pathway operates across distinct brain cell types. Together, these findings identify an ER-related role for SorLA that extends beyond its established function in endocytic trafficking. Loss of SorLA triggers maladaptive stress responses, perturbs lipid handling, and compromises cellular resilience, thereby contributing to AD-relevant cellular dysfunction.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03002-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147625823","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":"Brachio-cervical inflammatory myopathy: multilevel clinical, histopathological and multi-omic analyses of a syndrome variably associated with systemic sclerosis","authors":"Felix Kleefeld,&nbsp;Joanna Teran Gamboa,&nbsp;Iago Pinal-Fernandez,&nbsp;Corinna Preusse,&nbsp;Christopher Nelke,&nbsp;Hans-Hilmar Goebel,&nbsp;Alexander Mensch,&nbsp;Agata Mossakowski,&nbsp;Mohi-Uddin Miah,&nbsp;Jordi Diaz-Manera,&nbsp;Eleonora Torchia,&nbsp;Sara Bortolani,&nbsp;Andreas Hentschel,&nbsp;Andreas Funke,&nbsp;Sarah Souvannanorath,&nbsp;François-Jérôme Authier,&nbsp;Edoardo Malfatti,&nbsp;Johannes Gehrig,&nbsp;Andrew L. Mammen,&nbsp;Maria Casal-Dominguez,&nbsp;Jonathan De Winter,&nbsp;Willem De Ridder,&nbsp;Tobias Ruck,&nbsp;Udo Schneider,&nbsp;Andreas Roos,&nbsp;Eduard Gallardo,&nbsp;Giorgio Tasca,&nbsp;Werner Stenzel","doi":"10.1007/s00401-026-03006-5","DOIUrl":"10.1007/s00401-026-03006-5","url":null,"abstract":"&lt;div&gt;&lt;p&gt;Brachio-cervical inflammatory myopathy (BCIM) is a rare and under-characterized subtype of idiopathic inflammatory myopathies (IIM), marked by prominent upper limb and neck muscle involvement. Since its initial description in 2006, few studies have addressed its clinical spectrum or pathogenesis, and its potential overlap with systemic sclerosis (SSc) remains a matter of debate. Here, we aimed to characterize the clinical, histopathological, and molecular features of BCIM in a large multicenter cohort and determine whether BCIM represents a characteristic clinico-pathological syndrome within the IIM spectrum or reflects an atypical presentation of SSc-associated myositis. We studied 26 patients with clinically and histologically confirmed BCIM from seven European centers. Clinical data, treatment responses, and autoantibody profiles were collected retrospectively from participating centers. Histopathological and immunohistochemical analyses were performed on muscle biopsies, and 12 muscle biopsy specimens underwent bulk RNA sequencing, including a comparison with 669 non-BCIM myositis datasets. Proteomic profiling was performed in an independent subset. Clinical overlap with SSc was defined using the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria. The cohort was predominantly female (88%) with a mean age of 51 years [standard deviation (SD) ± 15.0]. Core features included asymmetrical proximal upper limb weakness (100%), dropped head (62%), dysphagia (46%), and facial weakness (54%). Although 35% showed clinical overlap with SSc, 65% of patients did not meet SSc criteria. All patients received corticosteroids; 65% required additional immunosuppression, yet complete clinical remission was uncommon in this retrospective cohort, although outcome assessment was limited by heterogeneous follow-up. Histopathology revealed dense endomysial inflammation with T cell predominance and prominent endo- and perimysial B-cell/plasma-cell-rich clusters with variable fibrosis. CD45⁺ and CD8⁺ cells were more abundant in patients without SSc overlap. RNA sequencing revealed a strong B-cell/plasma-cell signature, M2-like macrophage polarization, and downregulation of mitochondrial gene expression. Proteomics highlighted broad alterations in oxidative phosphorylation, aerobic respiration, and ATP synthesis pathways. BCIM shows a characteristic constellation of clinical, histological, and molecular features within the IIM spectrum. While a subset of patients meets criteria for SSc overlap, many do not, and the consistent presence of B-cell-rich inflammation together with downregulation of mitochondrial transcripts and proteins highlights shared pathogenic mechanisms within the cohort. These findings support the concept of BCIM as a myositis syndrome with heterogeneous SSc association and highlight a prominent B-cell/plasma-cell signature in BCIM, which warrants further evaluation of B-cell-directed approaches in f","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03006-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147606406","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":"Correction: Intracellular trafficking SNARE protein, syntaxin-6, modifies prion cellular phenotypes and risk of disease development in vivo","authors":"Elizabeth Hill,&nbsp;Mitali M. Patel,&nbsp;Juan M. Ribes,&nbsp;Jacqueline Linehan,&nbsp;Fuquan Zhang,&nbsp;Tatiana Jakubcova,&nbsp;Shyma Hamdan,&nbsp;Andrew Tomlinson,&nbsp;Tiziana Ercolani,&nbsp;Christian Schmidt,&nbsp;Parvin Ahmed,&nbsp;George Thirlway,&nbsp;Fabio Argentina,&nbsp;Aline T. Marinho,&nbsp;Emma Jones,&nbsp;Nicholas Kaye,&nbsp;Craig Fitzhugh,&nbsp;Graham S. Jackson,&nbsp;Sebastian Brandner,&nbsp;Peter-Christian Klöhn,&nbsp;John Collinge,&nbsp;Thomas J. Cunningham,&nbsp;Simon Mead","doi":"10.1007/s00401-026-03003-8","DOIUrl":"10.1007/s00401-026-03003-8","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13035716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147580139","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":"Correction: Alterations in glutamate receptor 2/3 subunits and amyloid precursor protein expression during the course of Alzheimer’s disease and Lewy body variant","authors":"Veronika Thorns,&nbsp;Margaret Mallory,&nbsp;Lawrence Hansen,&nbsp;Eliezer Masliah","doi":"10.1007/s00401-026-02997-5","DOIUrl":"10.1007/s00401-026-02997-5","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147571867","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":"Preservation of miR-9-5p and miR-124-3p in ALS-resistant oculomotor neurons contrasts with their downregulation in vulnerable spinal motor neurons, irrespective of TDP-43 pathology","authors":"Crystal McLellan,&nbsp;Danae Campos-Melo,&nbsp;Robert Hammond,&nbsp;Michael J. Strong","doi":"10.1007/s00401-026-03005-6","DOIUrl":"10.1007/s00401-026-03005-6","url":null,"abstract":"<div><p>Selective vulnerability of motor neurons is a defining feature of amyotrophic lateral sclerosis (ALS) and provides a valuable framework for uncovering mechanisms that distinguish resilient from vulnerable neuronal populations. We investigated whether dysregulation of neuroprotective microRNAs (miRNAs), miR-9-5p and miR-124-3p, contributes to the differential susceptibility of motor neuron subtypes. We focused on cervical spinal motor neurons (SMNs), which undergo drastic degeneration in ALS, and oculomotor neurons (OMNs), which remain functionally intact and rarely degenerate, allowing preservation of eye movement in ALS patients. Using a modified multiplexed fluorescent in situ hybridization protocol combined with immunofluorescence, we quantified the expression of miR-9-5p and miR-124-3p in cervical SMNs and OMNs from ALS and control cases. We observed significant downregulation of both miRNAs in ALS SMNs, while their expression was maintained in ALS OMNs. Stratification of ALS SMNs by TDP-43 pathological status revealed similarly reduced miRNA expression in neurons with and without cytoplasmic inclusions, suggesting that miRNA downregulation occurs independently of visible TDP-43 pathology. We assessed the localization of the Dicer cofactor TRBP and found that it colocalized with TDP-43 inclusions in ALS SMNs, suggesting that TRBP sequestration could prevent proper miRNA processing. However, TRBP remained normally localized in neurons without cytoplasmic inclusions, indicating that sequestration cannot fully account for miRNA reduction across all ALS motor neurons. These findings support a model in which early or subtle disruptions, preceding visible pathology, may also contribute to miRNA downregulation in ALS. By identifying preserved miRNA networks as correlates of oculomotor neuron resilience in ALS, this work also exposes new therapeutic targets potentially capable of reinstating miRNA expression and reprogramming vulnerable SMNs.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"151 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03005-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147518432","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}