Acta Neuropathologica最新文献

{"title":"The olfactory epithelium: a critical gateway for pathological tau propagation and a target for mitigating tauopathy in the central nervous system","authors":"Marion Dourte,&nbsp;Esther Paître,&nbsp;Mongia Bouchoucha,&nbsp;Emilien Boyer,&nbsp;Sandra O. Tomé,&nbsp;Emilie Doeraene,&nbsp;Caroline Huart,&nbsp;Karelle Leroy,&nbsp;Dietmar Rudolf Thal,&nbsp;Anabelle Decottignies,&nbsp;Bernard Hanseeuw,&nbsp;Nuria Suelves,&nbsp;Pascal Kienlen-Campard","doi":"10.1007/s00401-025-02902-6","DOIUrl":"10.1007/s00401-025-02902-6","url":null,"abstract":"<div><p>Olfactory impairment is a recognized early indicator of neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD). Intracellular aggregates of hyperphosphorylated tau protein, referred to as neurofibrillary tangles (NFTs), are a hallmark of AD. NFTs are found in the olfactory bulb (OB) and entorhinal cortex (EC), both crucial for processing olfactory information. We explored the hypothesis that typical tau lesions could appear early and progress along olfactory regions to reach connected areas critically affected in AD (e.g., EC and hippocampal formation). To that end, we used transgenic PS19 mice expressing mutated human tau protein (1N4R isoform, P301S mutation). They recapitulate major phenotypes of AD, such as accumulation of NFTs, synaptic dysfunction, cognitive impairment, and neuronal loss. The presence of pathological hyperphosphorylated human tau protein (pTau) was monitored in olfactory regions: olfactory epithelium (OE), OB, piriform cortex (PC), and in connected regions of the hippocampal formation (hippocampus and EC). pTau was detected in the OE’s middle stratum and in the OB’s olfactory nerve layer (ONL) at 1.5 months. At 6 months of age, tau accumulations were found in the PC and EC, along with the CA3 region and dentate gyrus of the hippocampus. We found that olfactory function remained unaffected in PS19 mice, despite the presence of tau pathology in key regions of the olfactory system. Targeted treatments (ZnSO₄ and AAVs) were applied at the OE level to assess the impact on tau pathology in the CNS. Complete stripping of the OE by intranasal administration of ZnSO₄ led to a significant reduction in pretangle-like tau pathology within the PC, amygdala, and EC of 6-month-old PS19 mice. Finally, we observed in human <i>postmortem</i> samples that pTau signal was present in the olfactory regions (OE and OB) of patients at early Braak stages (I/II). Based on these observations, we propose that pTau could appear, due to aging or environmental agents, in the OE and subsequently spread in a prion-like manner to the hippocampal formation along neuroanatomical connections. These findings also indicate the interest of the OE as a target for intervention aimed at mitigating the progression of tauopathy in the CNS.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02902-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320337","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":"Role of CSF flow and meningeal barriers in the development of inflammatory lesions at the CNS–PNS transition zone of cranial nerves in autoimmune demyelinating diseases","authors":"Li Xin,&nbsp;Hideaki Nishihara,&nbsp;Adrian Madarasz,&nbsp;Petr Pleskac,&nbsp;Linh Tran,&nbsp;Daniela C. Ivan,&nbsp;Fumitaka Shimizu,&nbsp;Simone Aleandri,&nbsp;Giuseppe Locatelli,&nbsp;Paola Luciani,&nbsp;Steven T. Proulx","doi":"10.1007/s00401-025-02896-1","DOIUrl":"10.1007/s00401-025-02896-1","url":null,"abstract":"<div><p>Patients with autoimmune inflammatory demyelinating diseases have been shown to present with trigeminal and cochlear nerve lesions restricted at the root transition zone, which contrasts with the relatively extensive distribution of lesions in optic neuritis. To better understand the mechanism underlying the different distribution pattern for cranial nerve lesions in these autoimmune neuroinflammatory diseases, we focused on the CNS–PNS transition zone (TZ) of the trigeminal and cochlear nerves in a MOG-driven active EAE model. These nerves were found to exhibit unique arrangements of anatomical barrier layers including the arachnoid and glia limitans, which affected cerebrospinal fluid (CSF) tracer distribution as well as CCR2⁺ immune cell infiltration. Our data demonstrated that CCR2⁺ immune cells accumulate at the TZ on both CNS side and PNS side of the trigeminal nerve and cochlear nerve, which mirror the locations of cranial nerve pathology observed clinically in patients with inflammatory demyelinating disease. On the other hand, the optic and olfactory nerves, which both lack a TZ, did not exhibit restrictions in immune cell localization. Overall, our results reconcile with the hypothesis that the segment of the cranial nerve that is exposed to CSF flow is more susceptible to CCR2⁺ immune cell infiltration.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02896-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320379","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":"Characterization of prion strains and peripheral prion infectivity patterns in E200K genetic CJD patients","authors":"Tomás Barrio,&nbsp;Jean-Yves Douet,&nbsp;Dana Žáková,&nbsp;Hasier Eraña,&nbsp;Alvina Huor,&nbsp;Hervé Cassard,&nbsp;Oihane Alzuguren,&nbsp;Séverine Lugan,&nbsp;Naïma Aron,&nbsp;Patrice Péran,&nbsp;Joaquín Castilla,&nbsp;Olivier Andréoletti","doi":"10.1007/s00401-025-02903-5","DOIUrl":"10.1007/s00401-025-02903-5","url":null,"abstract":"<div><p>The mutation E200K in the prion protein gene (<i>PRNP</i>) is the most common variant in genetic Creutzfeldt–Jakob disease (gCJD). The clinical and pathological features observed in patients with E200K gCJD led to the hypothesis that the prion strains responsible for this form of the disease may be related to those involved in sporadic CJD (sCJD). In this study, we characterized the prion strains responsible for E200K gCJD cases from Slovakia (<i>n</i> = 12), Spain (<i>n</i> = 9), and France (<i>n</i> = 3) using transgenic mouse models expressing human prion protein (PrP). The cohort included patients with various <i>PRNP</i> genotypes: E200K-Met₁₂₉/Met₁₂₉, E200K-Met₁₂₉/E200K-Met₁₂₉, E200K-Met₁₂₉/Val₁₂₉, and E200K-Val₁₂₉/Val₁₂₉. Prion strain characterization revealed that the strains isolated from E200K gCJD cases corresponded to the two most common strains identified in sCJD cases: M1^CJD and V2^CJD. Depending on the individual, these strains were either present as pure M1^CJD or V2^CJD, or as a mixture of both (M1^CJD + V2^CJD). Additionally, peripheral tissues from E200K-Met₁₂₉/Met₁₂₉ patients (<i>n</i> = 4) and one E200K-Met₁₂₉/Val₁₂₉ case were analyzed for prion infectivity and seeding activity. Similar to sCJD patients, low but detectable levels of prions were found in various peripheral tissues of E200K gCJD cases. Overall, our findings suggest that the prion strains and their distribution in the body are highly similar between E200K gCJD and sCJD patients. These similarities indicate that individuals carrying the E200K mutation may serve as a valuable model for understanding CJD pathogenesis during the preclinical phase of the disease.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02903-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295667","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":"Divergent host–pathogen interactions in neurolisteriosis: cytosolic replication vs. phagosomal dormancy of Listeria monocytogenes in CNS macrophages","authors":"Leticia Tavares-Gomes,&nbsp;Margherita Polidori,&nbsp;Camille Monney,&nbsp;Géraldine Neuhaus,&nbsp;Beatriz Vidondo,&nbsp;Guillaume Witz,&nbsp;Andrew Hemphill,&nbsp;Anna Oevermann","doi":"10.1007/s00401-025-02900-8","DOIUrl":"10.1007/s00401-025-02900-8","url":null,"abstract":"<div><p>Bacterial infections of the central nervous system (CNS) pose a significant threat to public health, especially with the growing challenge of antimicrobial resistance. Among these, <i>Listeria monocytogenes</i> (<i>Lm</i>) stands out as a key pathogen, responsible for often fatal neurolisteriosis in humans and cattle. Emerging evidence highlights the distinct roles played by microglia, the resident macrophages of the CNS, and infiltrating monocyte-derived macrophages (MDM) during neuroinflammation. Using bovine models, we investigated the interactions between these two macrophage populations and <i>Lm</i> during infection. Our results show that <i>Lm</i> thrives in the cytosol of microglia, driving productive infection and facilitating bacterial spread. In contrast, MDM effectively sequesters <i>Lm</i> within the phagolysosomal system, limiting its replication and inducing a viable but non-culturable (VBNC) state without completely eliminating the pathogen. Listeriolysin O contributes to the dichotomy of <i>Lm</i> fate, determining whether <i>Lm</i> escapes into the cytosol or transitions to the VBNC state. These findings underscore the complexity of <i>Lm</i>-host dynamics in neurolisteriosis, emphasizing the distinct yet complementary roles of microglia and MDM in shaping CNS infection. By elucidating these mechanisms, our study offers new perspectives on the neurolisteriosis pathogenesis and opens avenues for innovative therapeutic approaches to combat bacterial neuroinfections.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02900-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295669","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":"Outcome-associated factors in a molecularly defined cohort of central neurocytoma","authors":"Maja Krech,&nbsp;Amos Muench,&nbsp;Daniel Teichmann,&nbsp;Peter Kuzman,&nbsp;Abigail K. Suwala,&nbsp;Franziska M. Ippen,&nbsp;Michael Müther,&nbsp;Katharina J. Weber,&nbsp;Katharina Wenger-Alakmeh,&nbsp;Julia Onken,&nbsp;Peter Vajkoczy,&nbsp;Felix Behling,&nbsp;Sven-Axel May,&nbsp;Georgios Ntoulias,&nbsp;Joachim K. Krauss,&nbsp;Oday Atallah,&nbsp;Majid Esmaeilzadeh,&nbsp;Wolf C. Mueller,&nbsp;Frank L. Heppner,&nbsp;Helena Radbruch,&nbsp;Carsten Dittmayer,&nbsp;Werner Stenzel,&nbsp;Arend Koch,&nbsp;David Capper,&nbsp;David Kaul,&nbsp;Werner Paulus,&nbsp;Karl H. Plate,&nbsp;Joachim P. Steinbach,&nbsp;Markus Czabanka,&nbsp;Rudi Beschorner,&nbsp;Andreas von Deimling,&nbsp;Michael Bockmayr,&nbsp;Julia E. Neumann,&nbsp;Sebastian Brandner,&nbsp;Teresa Krieger,&nbsp;Christian Hartmann,&nbsp;Christian Thomas,&nbsp;Leonille Schweizer","doi":"10.1007/s00401-025-02894-3","DOIUrl":"10.1007/s00401-025-02894-3","url":null,"abstract":"<div><p>Central neurocytomas (CN) are intraventricular brain tumors predominantly occurring in young adults. Although prognosis is usually favorable, tumor recurrence is common, particularly following subtotal resection (STR). Currently, the risk of progression is evaluated using atypical features and an elevated Ki67 proliferation index. However, these markers lack consistent definitions, raising the need for objective criteria. Genome-wide DNA methylation profiles were examined in 136 tumors histologically classified as CN. Clinical/histopathological characteristics were assessed in 93/90 cases, and whole-exome sequencing was conducted in 12 cases. Clinical and molecular characteristics were integrated into a survival model to predict progression-free survival (PFS). A diagnosis of CN was epigenetically confirmed in 125 of 136 cases (92%). No DNA methylation subgroups were identified, but global DNA hypomethylation emerged as a hallmark feature of CN associated with higher recurrence risk. Risk stratification based on histological features of atypia and Ki67 proliferation index was not reproducible across neuropathologists. Hypomethylation at the <i>FGFR3</i> locus, accompanied by increased FGFR3 protein expression, was observed in 97% of cases. Gross total resection was associated with significantly improved PFS compared to STR, while patients undergoing STR receiving radiotherapy had a better outcome (<i>p</i> = 0.0001). Younger patients were identified as having a higher risk of recurrence (<i>p</i> = 0.026). Patient age and treatment strategy were key factors associated with survival outcomes in this cohort. These findings underscore the importance of closer follow-up for younger patients and radiotherapy for STR cases. Furthermore, <i>FGFR3</i> represents a hallmark feature and potential therapeutic target, warranting further investigation.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12158839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265031","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":"Molecular signatures of regional vulnerability to tauopathy in excitatory cortical neurons","authors":"Diede W. M. Broekaart,&nbsp;Abhijeet Sharma,&nbsp;Aarthi Ramakrishnan,&nbsp;Anjalika Chongtham,&nbsp;Dorothee M. Günther,&nbsp;Saraswathi Subramaniyan,&nbsp;Minghui Wang,&nbsp;Vishwendra Patel,&nbsp;Bin Zhang,&nbsp;Lea T. Grinberg,&nbsp;Robert D. Blitzer,&nbsp;Eric F. Schmidt,&nbsp;Li Shen,&nbsp;Patrick R. Hof,&nbsp;Ana C. Pereira","doi":"10.1007/s00401-025-02879-2","DOIUrl":"10.1007/s00401-025-02879-2","url":null,"abstract":"<div><p>Tauopathies are characterized by the aggregation and accumulation of hyperphosphorylated tau proteins that correlates with cognitive impairment in affected individuals. The presence of tauopathy follows a temporospatial spreading pattern in which certain neuronal cell types in specific brain regions are more vulnerable to tau accumulation and atrophy. However, the mechanisms underlying the selective vulnerability of these neurons and regions to pathological tau accumulation are not fully understood. Here, we characterized the presence of phosphorylated tau in excitatory and inhibitory neurons in post-mortem prefrontal cortex of tauopathy patients, including Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration, and frontotemporal lobar dementia due to a MAPT mutation. We observed that neuronal tau accumulation across these tauopathies occurs predominantly in excitatory neurons compared to inhibitory neurons. Next, we performed viral translating ribosome affinity purification (vTRAP) from vulnerable and resistant brain regions on vGLUT1^CRE+ and GAD2^CRE+ PS19 mice to understand molecular signatures of tau vulnerability. We observed that both vulnerable regions and vulnerable neurons are characterized by alterations in synaptic transmission and neuronal excitability. Transcription factor Mef2c (myocyte enhancer factor 2c) was identified as an upstream regulator affecting myelination and synaptic organization in vulnerable brain regions in PS19 mice. The relevance of these findings was validated in human tauopathies via coexpression network analysis. Concordantly, we observed tau-induced changes in spontaneous postsynaptic currents of excitatory neurons in mice especially in the prefrontal cortex. Taken together, we conclude that selective vulnerability to tau could arise from changes in neurotransmission and synaptic compositions, potentially due to an altered Mef2c transcriptional network.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245599","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":"Analysis of the splicing landscape of the frontal cortex in FTLD-TDP reveals subtype specific patterns and cryptic splicing","authors":"Júlia Faura,&nbsp;Bavo Heeman,&nbsp;Cyril Pottier,&nbsp;Matthew C. Baker,&nbsp;Mariely DeJesus-Hernandez,&nbsp;Fahri Küçükali,&nbsp;Laura Heiß,&nbsp;Sarah Wynants,&nbsp;Marleen Van den Broeck,&nbsp;Peter De Rijk,&nbsp;Tim De Pooter,&nbsp;Geert Joris,&nbsp;NiCole A. Finch,&nbsp;Yan Asmann,&nbsp;Mojca Strazisar,&nbsp;Melissa E. Murray,&nbsp;Leonard Petrucelli,&nbsp;Björn Oskarsson,&nbsp;Kristel Sleegers,&nbsp;Keith A. Josephs,&nbsp;Aivi T. Nguyen,&nbsp;R. Ross Reichard,&nbsp;Ronald C. Petersen,&nbsp;Bradley F. Boeve,&nbsp;Neill R. Graff-Radford,&nbsp;Dennis W. Dickson,&nbsp;Marka van Blitterswijk,&nbsp;Rosa Rademakers","doi":"10.1007/s00401-025-02901-7","DOIUrl":"10.1007/s00401-025-02901-7","url":null,"abstract":"<div><p>Dysregulation of TDP-43 as seen in TDP-43 proteinopathies leads to specific RNA splicing dysfunction. While discovery studies have explored novel TDP-43-driven splicing events in induced pluripotent stem cell (iPSC)-derived neurons and TDP-43 negative neuronal nuclei, transcriptome-wide investigations in frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP) brains remain unexplored. Such studies hold promise for identifying widespread novel and relevant splicing alterations in FTLD-TDP patient brains. We conducted the largest differential splicing analysis (DSA) using bulk short-read RNAseq data from frontal cortex (FCX) tissue of 127 FTLD-TDP (A, B, C, <i>GRN</i> and <i>C9orf72</i> carriers) and 22 control subjects (Mayo Clinic Brain Bank), using Leafcutter. In addition, long-read bulk cDNA sequencing data were generated from FCX of 9 FTLD-TDP and 7 controls and human <i>TARDBP</i> wildtype and knock-down iPSC-derived neurons. Publicly available RNAseq data (MayoRNAseq, MSBB and ROSMAP studies) from Alzheimer’s disease patients (AD) was also analyzed. Our DSA revealed extensive splicing alterations in FTLD-TDP patients with 1881 differentially spliced events, in 892 unique genes. When evaluating differences between FTLD-TDP subtypes, we found that <i>C9orf72</i> repeat expansion carriers carried the most splicing alterations after accounting for differences in cell-type proportions. Focusing on cryptic splicing events, we identified <i>STMN2</i> and <i>ARHGAP32</i> as genes with the most abundant and differentially expressed cryptic exons between FTLD-TDP patients and controls in the brain, and we uncovered a set of 17 cryptic events consistently observed across studies, highlighting their potential relevance as biomarkers for TDP-43 proteinopathies. We also identified 16 cryptic events shared between FTLD-TDP and AD brains, suggesting potential common splicing dysregulation pathways in neurodegenerative diseases. Overall, this study provides a comprehensive map of splicing alterations in FTLD-TDP brains, revealing subtype-specific differences and identifying promising candidates for biomarker development and potential common pathogenic mechanisms between FTLD-TDP and AD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232851","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":"Multifactorial etiology of progressive supranuclear palsy (PSP): the genetic component","authors":"Ulrich Müller,&nbsp;Günter Höglinger,&nbsp;Dennis W. Dickson","doi":"10.1007/s00401-025-02898-z","DOIUrl":"10.1007/s00401-025-02898-z","url":null,"abstract":"<div><p>Progressive supranuclear palsy (PSP) is mainly a sporadic disease. It has a multifactorial etiology and an interaction between environmental and genetic factors causes disease. While elucidation of environmental risks for PSP is still in its infancy, much has been learned about the genetic etiological component of PSP during the past few years. This article reviews genes that convey risk for PSP. All genes have been identified in association studies. Only those genes with the standard threshold for genome-wide significance of <i>P</i> &lt; 5E-8 are covered. These genes include <i>MAPT, KANSL1, PLEKHM1, STX6, MOBP, EIF2AK3, SLC01 A2, DUSP10, APOE, RUNX2, TRIM11, NFASC/CNTN2</i> and <i>LRRK2.</i> The physiologic function of these genes is described and their potential role in the etiology of PSP is discussed.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214530","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":"Immunohistochemical evaluation of a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease","authors":"Charles D. Chen,&nbsp;Erin E. Franklin,&nbsp;Yan Li,&nbsp;Nelly Joseph-Mathurin,&nbsp;Aime L. Burns,&nbsp;Diana A. Hobbs,&nbsp;Austin A. McCullough,&nbsp;Stephanie A. Schultz,&nbsp;Chengjie Xiong,&nbsp;Guoqiao Wang,&nbsp;Mario Masellis,&nbsp;Ging-Yuek Robin Hsiung,&nbsp;Serge Gauthier,&nbsp;Sarah B. Berman,&nbsp;Erik D. Roberson,&nbsp;Lawrence S. Honig,&nbsp;Roger Clarnette,&nbsp;John M. Ringman,&nbsp;James E. Galvin,&nbsp;William Brooks,&nbsp;Kazushi Suzuki,&nbsp;Sandra Black,&nbsp;Johannes Levin,&nbsp;Neelum T. Aggarwal,&nbsp;Mathias Jucker,&nbsp;Matthew P. Frosch,&nbsp;Julia K. Kofler,&nbsp;Charles White III,&nbsp;C. Dirk Keene,&nbsp;Jie Chen,&nbsp;Alisha Daniels,&nbsp;Brian A. Gordon,&nbsp;Laura Ibanez,&nbsp;Celeste M. Karch,&nbsp;Jorge Llibre-Guerra,&nbsp;Eric McDade,&nbsp;John C. Morris,&nbsp;Charlene Supnet-Bell,&nbsp;Ricardo F. Allegri,&nbsp;Jae-Hong Lee,&nbsp;Gregory S. Day,&nbsp;Francisco Lopera,&nbsp;Jee Hoon Roh,&nbsp;Peter R. Schofield,&nbsp;Susan Mills,&nbsp;Tammie L. S. Benzinger,&nbsp;Randall J. Bateman,&nbsp;Richard J. Perrin,&nbsp;For the DIAN-TU Study Team,&nbsp;For the DIAN-Obs Study Team","doi":"10.1007/s00401-025-02890-7","DOIUrl":"10.1007/s00401-025-02890-7","url":null,"abstract":"<div><p>Clinical trials of anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer disease (AD) infer target engagement from Aβ positron emission tomography (PET) and/or fluid biomarkers such as cerebrospinal fluid (CSF) Aβ42/40. However, these biomarkers measure brain Aβ deposits indirectly and/or incompletely. In contrast, neuropathologic assessments allow direct investigation of treatment effects on brain Aβ deposits—and on potentially myriad ‘downstream’ pathologic features. From a clinical trial of anti-Aβ monoclonal antibodies in dominantly inherited AD (DIAD), in the largest study of its kind, we measured immunohistochemistry area fractions (AFs) for Aβ deposits (10D5), tauopathy (PHF1), microgliosis (IBA1), and astrocytosis (GFAP) in 10 brain regions from 10 trial cases—gantenerumab (<i>n</i> = 4), solanezumab (<i>n</i> = 4), placebo/no treatment (<i>n</i> = 2)—and 10 DIAD observational study cases. Strikingly, in proportion to total drug received, Aβ deposit AFs were significantly lower in the gantenerumab arm versus controls in almost all areas examined, including frontal, temporal, parietal, and occipital cortices, anterior cingulate, hippocampus, caudate, putamen, thalamus, and cerebellar gray matter; only posterior cingulate and cerebellar white matter comparisons were non-significant. In contrast, AFs of tauopathy, microgliosis, and astrocytosis showed no differences across groups. Our results demonstrate with direct histologic evidence that gantenerumab treatment in DIAD can reduce parenchymal Aβ deposits throughout the brain in a dose-dependent manner, suggesting that more complete removal may be possible with earlier and more aggressive treatment regimens. Although AFs of tauopathy, microgliosis, and astrocytosis showed no clear response to partial Aβ removal in this limited autopsy cohort, future examination of these cases with more sensitive techniques (e.g., mass spectrometry) may reveal more subtle ‘downstream’ effects.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12133910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207352","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":"Anti-pyroglutamate-3 Aβ immunotherapy engages microglia and inhibits amyloid accumulation in transgenic mouse models of Aβ amyloidosis","authors":"Fan Liao,&nbsp;Maria Calvo-Rodriguez,&nbsp;Meha Chhaya,&nbsp;Julian P Sefrin,&nbsp;Erik I Charych,&nbsp;Mario Mezler,&nbsp;Diana Clausznitzer,&nbsp;Emily J McGlame,&nbsp;Karen Zhao,&nbsp;Allison Rodgers,&nbsp;Yang Cao,&nbsp;Philipp F Secker,&nbsp;Laura Fernandez Garcia-Agudo,&nbsp;Lili Huang,&nbsp;Corinna Klein,&nbsp;Tammy Dellovade,&nbsp;Eric Karran","doi":"10.1007/s00401-025-02892-5","DOIUrl":"10.1007/s00401-025-02892-5","url":null,"abstract":"<div><p>Alzheimer disease (AD) is the most common form of dementia affecting more than 6 million people in the United States. Currently, 3 monospecific antibodies targeting different Amyloid β (Aβ) species have been approved by the US FDA as disease modifying therapeutics for treatment in early AD patients with amyloid pathology. ABBV-916 is a clinical stage human IgG1 monoclonal antibody which binds to N-terminal truncated, pyroglutamate-modified at amino acid position 3, Aβ (Aβ_pE3). The current study characterized ABBV-916 using human tissue samples and amyloid precursor protein (APP) transgenic mice. ABBV-916 selectively bound to recombinant Aβ_pE3-42 fibrils and native amyloid plaques in unfixed AD brain tissue but did not bind targets in human CSF. ABBV-916 significantly reduced dense plaques from brain tissue that were co-cultured with hiPSC-derived phagocytes. In APPPS1-21 mice, ABBV‑916 bound plaques in a dose-dependent manner after a single intravenous injection. In addition, three months of weekly administration of ABBV-916 murine surrogate antibody significantly decreased amyloid plaques in APPPS1-21 mice. <i>In vivo</i> two-photon imaging revealed that the murine version of ABBV-916 inhibited the growth of the plaques in APPPS1-21 mice. ABBV-916 murine surrogate antibody recruited microglia to plaques within 24-48 hours after a single intraperitoneal injection in Cx3cr1-tdTomato/APPPS1-21 mice. Importantly, in contrast to a positive control antibody, ABBV‑916 murine precursor antibody did not cause microhemorrhage in aged APPPS1-21 mice. Taken together, our results suggest that ABBV-916 is a promising drug candidate. Clinical testing is on-going to evaluate the plaque removal and safety profiles of ABBV-916 in AD patients.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12130127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198028","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}