Acta Neuropathologica最新文献

{"title":"Traumatic brain injury causes early aggregation of beta-amyloid peptides and NOTCH3 reduction in vascular smooth muscle cells of leptomeningeal arteries","authors":"Ilknur Özen,&nbsp;Sami Abu Hamdeh,&nbsp;Karsten Ruscher,&nbsp;Niklas Marklund","doi":"10.1007/s00401-025-02848-9","DOIUrl":"10.1007/s00401-025-02848-9","url":null,"abstract":"<div><p>Traumatic brain injury (TBI) often leads to impaired regulation of cerebral blood flow, which may be caused by pathological changes of the vascular smooth muscle cells (VSMCs) in the arterial wall. Moreover, these cerebrovascular changes may contribute to the development of various neurodegenerative disorders such as Alzheimer’s-like pathologies that include amyloid beta aggregation. Despite its importance, the pathophysiological mechanisms responsible for VSMC dysfunction after TBI have rarely been evaluated. Here, we show that acute human TBI resulted in early pathological changes in leptomeningeal arteries, closely associated with a decrease in VSMC markers such as NOTCH3 and alpha smooth muscle actin (α-SMA).These changes coincided with increased aggregation of variable-length amyloid peptides including Aβ_1-40/42, Aβ_1-16, and β-secretase-derived fragment (βCTF) (C99) caused by altered processing of amyloid precursor protein (APP) in VSMCs. The aggregation of Aβ_1-40/42 peptides were also observed in the leptomeningeal arteries of young TBI patients. These pathological changes also included higher β-secretase (BACE1) when compared to α-secretase A Disintegrin And Metalloprotease 10 (ADAM10) expression in the leptomeningeal arteries, plausibly caused by hypoxia and oxidative stress as shown using human VSMCs in vitro. Importantly, BACE1 inhibition not only restored NOTCH3 signalling but also normalized ADAM10 levels in vitro. Furthermore, we found reduced ADAM10 activity and decreased NOTCH3, along with increased βCTF (C99) levels in mice subjected to an experimental model of TBI. This study provides evidence of early post-injury changes in VSMCs of leptomeningeal arteries that can contribute to vascular dysfunction and exacerbate secondary injury mechanisms following TBI.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02848-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991990","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":"Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer’s disease, and late-onset Alzheimer’s disease","authors":"Mitchell Martá-Ariza,&nbsp;Dominique F. Leitner,&nbsp;Evgeny Kanshin,&nbsp;Jianina Suazo,&nbsp;Ana Giusti Pedrosa,&nbsp;Manon Thierry,&nbsp;Edward B. Lee,&nbsp;Orrin Devinsky,&nbsp;Eleanor Drummond,&nbsp;Juan Fortea,&nbsp;Alberto Lleó,&nbsp;Beatrix Ueberheide,&nbsp;Thomas Wisniewski","doi":"10.1007/s00401-025-02844-z","DOIUrl":"10.1007/s00401-025-02844-z","url":null,"abstract":"<div><p>Down syndrome (DS) is strongly associated with Alzheimer’s disease (AD) due to <i>APP</i> overexpression, exhibiting Amyloid-β (Aβ) and Tau pathology similar to early-onset (EOAD) and late-onset AD (LOAD). We evaluated the Aβ plaque proteome of DS, EOAD, and LOAD using unbiased localized proteomics on post-mortem paraffin-embedded tissues from four cohorts (<i>n</i> = 20/group): DS (59.8 ± 4.99 y/o), EOAD (63 ± 4.07 y/o), LOAD (82.1 ± 6.37 y/o), and controls (66.4 ± 13.04). We identified differentially abundant proteins when comparing Aβ plaques and neighboring non-plaque tissue (FDR &lt; 5%, fold-change &gt; 1.5) in DS (<i>n</i> = 132), EOAD (<i>n</i> = 192), and LOAD (<i>n</i> = 128), with 43 plaque-associated proteins shared across all groups. Positive correlations were observed between plaque-associated proteins in DS and EOAD (<i>R</i>² = .77), DS and LOAD (<i>R</i>² = .73), and EOAD and LOAD (<i>R</i>² = .67). Top gene ontology biological processes (GOBP) included lysosomal transport (<i>p</i> = 1.29 × 10⁻⁵) for DS, immune system regulation (<i>p</i> = 4.33 × 10⁻⁵) for EOAD, and lysosome organization (<i>p</i> = 0.029) for LOAD. Protein networks revealed a plaque-associated protein signature involving APP metabolism, immune response, and lysosomal functions. In DS, EOAD, and LOAD non-plaque vs. control tissue, we identified 263, 269, and 301 differentially abundant proteins, with 65 altered proteins shared across all cohorts. Non-plaque proteins in DS showed modest correlations with EOAD (<i>R</i>² = .59) and LOAD (<i>R</i>² = .33) compared to the correlation between EOAD and LOAD (<i>R</i>² = .79). Top GOBP term for all groups was chromatin remodeling (<i>p</i> &lt; 0.001), with additional terms for DS including extracellular matrix, and protein–DNA complexes and gene expression regulation for EOAD and LOAD. Our study reveals key functional characteristics of the amyloid plaque proteome in DS, compared to EOAD and LOAD, highlighting shared pathways in endo/lysosomal functions and immune responses. The non-plaque proteome revealed distinct alterations in ECM and chromatin structure, underscoring unique differences between DS and AD subtypes. Our findings enhance our understanding of AD pathogenesis and identify potential biomarkers and therapeutic targets.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02844-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988841","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":"Concurrent RB1 and P53 pathway disruption predisposes to the development of a primitive neuronal component in high-grade gliomas depending on MYC-driven EBF3 transcription","authors":"Francesca Pagani,&nbsp;Francesca Orzan,&nbsp;Sara Lago,&nbsp;Francesca De Bacco,&nbsp;Marta Prelli,&nbsp;Manuela Cominelli,&nbsp;Elena Somenza,&nbsp;Magdalena Gryzik,&nbsp;Piera Balzarini,&nbsp;Davide Ceresa,&nbsp;Daniela Marubbi,&nbsp;Claudio Isella,&nbsp;Giovanni Crisafulli,&nbsp;Maura Poli,&nbsp;Paolo Malatesta,&nbsp;Rossella Galli,&nbsp;Roberto Ronca,&nbsp;Alessio Zippo,&nbsp;Carla Boccaccio,&nbsp;Pietro Luigi Poliani","doi":"10.1007/s00401-025-02845-y","DOIUrl":"10.1007/s00401-025-02845-y","url":null,"abstract":"<div><p>The foremost feature of glioblastoma (GBM), the most frequent malignant brain tumours in adults, is a remarkable degree of intra- and inter-tumour heterogeneity reflecting the coexistence within the tumour bulk of different cell populations displaying distinctive genetic and transcriptomic profiles. GBM with primitive neuronal component (PNC), recently identified by DNA methylation-based classification as a peculiar GBM subtype (GBM-PNC), is a poorly recognized and aggressive GBM variant characterised by nodules containing cells with primitive neuronal differentiation along with conventional GBM areas. In addition, the presence of a PNC component has been also reported in <i>IDH-</i>mutant high-grade gliomas (HGGs), and to a lesser extent to other HGGs, suggesting that regardless from being <i>IDH</i>-mutant or <i>IDH</i>-wildtype, peculiar genetic and/or epigenetic events may contribute to the phenotypic skewing with the emergence of the PNC phenotype. However, a clear hypothesis on the mechanisms responsible for this phenotypic skewing is still lacking. We assumed that the biphasic nature of these entities represents a unique model to investigate the relationships between genetic alterations and their phenotypic manifestations. In this study we show that in HGGs with PNC features both components are highly enriched in genetic alterations directly causing cell cycle deregulation (<i>RB</i> inactivation or <i>CDK4</i> amplification) and p53 pathway inactivation (<i>TP53</i> mutations or <i>MDM2/4</i> amplification). However, the PNC component displays further upregulation of transcriptional pathways associated with proliferative activity, including overexpression of MYC target genes. Notably, the PNC phenotype relies on the expression of EBF3, an early neurogenic transcription factor, which is directly controlled by MYC transcription factors in accessible chromatin sites. Overall our findings indicate that the concomitant presence of genetic alterations, impinging on both cell cycle and p53 pathway control, strongly predisposes GBM to develop a concomitant poorly differentiated primitive phenotype depending on MYC-driven EBF3 transcription in a subset of glioma stem-like progenitor cells.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987940","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":"White matter pathology in FTLD caused by GRN mutations","authors":"Hyunwoo Lee,&nbsp;Simon Cheung,&nbsp;Jolien Perneel,&nbsp;Rosa Rademakers,&nbsp;G. Y. R. Hsiung,&nbsp;Ian R. A. Mackenzie","doi":"10.1007/s00401-025-02847-w","DOIUrl":"10.1007/s00401-025-02847-w","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981345","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":"Essential tremor with tau pathology features seeds indistinguishable in conformation from Alzheimer’s disease and primary age-related tauopathy","authors":"Nil Saez-Calveras,&nbsp;Jaime Vaquer-Alicea,&nbsp;Charles L. White III,&nbsp;Yogesh Tak,&nbsp;Stephanie Cosentino,&nbsp;Phyllis L. Faust,&nbsp;Elan D. Louis,&nbsp;Marc I. Diamond","doi":"10.1007/s00401-024-02843-6","DOIUrl":"10.1007/s00401-024-02843-6","url":null,"abstract":"<div><p>Neurodegenerative tauopathies are characterized by the deposition of distinct fibrillar tau assemblies, whose rigid core structures correlate with defined neuropathological phenotypes. Essential tremor (ET) is a progressive neurological disorder that, in some cases, is associated with cognitive impairment and tau accumulation. In this study, we explored tau assembly conformation in ET patients with tau pathology using cytometry-based tau biosensor assays. These assays quantify the tau seeding activity present in brain homogenates by detecting the conversion of intracellular tau-fluorescent protein fusions from a soluble to an aggregated state. Pathogenic tau assemblies exhibit seeding barriers, where a specific assembly structure cannot serve as a template for a native monomer if the amino acid sequences are incompatible. We recently leveraged this species barrier to define tauopathies systematically by substituting alanine (Ala) into the tau monomer and measuring its incorporation into seeded aggregates within biosensor cells. This Ala scan precisely classified the conformation of tau seeds from various tauopathies. In this study, we analyzed 18 ET patient brains with tau pathology, detecting robust tau seeding activity in 9 (50%) of the cases, predominantly localized to the temporal pole and temporal cortex. We further examined 8 of these ET cases using the Ala scan and found that the amino acid requirements for tau monomer incorporation into aggregates seeded from ET brain homogenates were identical to those of Alzheimer’s disease (AD) and primary age-related tauopathy (PART), and distinct from other tauopathies, such as corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), and progressive supranuclear palsy (PSP). These findings indicate that in a pathologically confined subset of ET cases with significant tau pathology, tau assembly cores are identical to those seen in AD and PART. This could facilitate more precise diagnosis and targeted therapies for ET patients presenting with cognitive impairment.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02843-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936293","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":"Detection of H3F3A K27M or BRAF V600E in liquid biopsies of brain tumor patients as diagnostic and monitoring biomarker: impact of tumor localization and sampling method","authors":"Sibylle Madlener,&nbsp;Natalia Stepien,&nbsp;Daniel Senfter,&nbsp;Lisa Mayr,&nbsp;Anna Laemmerer,&nbsp;Cora Hedrich,&nbsp;Alicia Baumgartner,&nbsp;Daniela Lötsch-Gojo,&nbsp;Jaroslav Sterba,&nbsp;Petra Pokorna,&nbsp;Barbara Kiesel,&nbsp;Georg Widhalm,&nbsp;Franziska Eckert,&nbsp;Matthias Preusser,&nbsp;Karl Rössler,&nbsp;Amedeo Azizi,&nbsp;Andreas Peyrl,&nbsp;Thomas Czech,&nbsp;Christine Haberler,&nbsp;Irene Slavc,&nbsp;Gregor Kasprian,&nbsp;Christian Dorfer,&nbsp;Julia Furtner,&nbsp;Johannes Gojo","doi":"10.1007/s00401-024-02842-7","DOIUrl":"10.1007/s00401-024-02842-7","url":null,"abstract":"<div><p>Gliomas are the most common brain tumor type in children and adolescents. To date, diagnosis and therapy monitoring for these tumors rely on magnetic resonance imaging (MRI) and histopathological as well as molecular analyses of tumor tissue. Recently, liquid biopsies (LB) have emerged as promising tool for diagnosis and longitudinal tumor assessment potentially allowing for a more precise therapeutic management. However, the optimal strategy for monitoring gliomas by LB remains to be determined. In this study, we analyzed circulating tumor DNA (ctDNA) from 78 liquid biopsies (plasma <i>n</i> = 44, cerebrospinal fluid <i>n</i> = 34 (CSF)) of 35 glioma patients, determining H3F3A K28M (K27M) and BRAF V600E mutation allele frequency using droplet digital PCR (ddPCR). All results were correlated to clinically relevant parameters including diagnostic imaging and CSF aspiration site (ventricular vs lumbar) with respect to tumor localization. Regarding diagnostic accuracy, the calculated sensitivity score in the H3F3A K27M cohort was 84.61% for CSF and 73.68% for plasma. In the BRAF V600E cohort, we determined a sensitivity of 83.3% in plasma and 80% in CSF. The overall specificity was 100%. With respect to the CSF aspiration, the intra-operatively obtained CSF demonstrated 100% detection rate, followed by ventricular CSF obtained via Ommaya Reservoir/shunt puncture (93%) and CSF obtained via lumbar puncture (66%). Notably, this further correlated with the proximity of the CSF site to tumor localization. Longitudinal CSF monitoring demonstrated a good correlation to clinical and radiological disease evolution. Importantly, we show for the first time that monitoring BRAF V600E by ddPCR could serve as treatment response assessment in gliomas. In summary, our observation may inform recommendations with regard to location of CSF aspiration when incorporating LB into future treatment protocols.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02842-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916847","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: Genome‑wide methylation profiling differentiates benign from aggressive and metastatic pituitary neuroendocrine tumors","authors":"Jelena Jotanovic,&nbsp;Henning Bünsow Boldt,&nbsp;Mark Burton,&nbsp;Marianne Skovsager Andersen,&nbsp;Daniel Bengtsson,&nbsp;Thomas Olsson Bontell,&nbsp;Bertil Ekman,&nbsp;Britt Edén Engström,&nbsp;Ulla Feldt-Rasmussen,&nbsp;Ansgar Heck,&nbsp;Antonia Jakovcevic,&nbsp;Jens Otto L. Jørgensen,&nbsp;Ivana Kraljevic,&nbsp;Jacek Kunicki,&nbsp;John R. Lindsay,&nbsp;Marco Losa,&nbsp;Paul Benjamin Loughrey,&nbsp;Dominique Maiter,&nbsp;Maria Maksymowicz,&nbsp;Emilija Manojlovic-Gacic,&nbsp;Jens Pahnke,&nbsp;Stephan Petersenn,&nbsp;Maria Petersson,&nbsp;Vera Popovic,&nbsp;Oskar Ragnarsson,&nbsp;Åse Krogh Rasmussen,&nbsp;Zita Reisz,&nbsp;Wolfgang Saeger,&nbsp;Camilla Schalin-Jäntti,&nbsp;David Scheie,&nbsp;Maria Rosa Terreni,&nbsp;Olli Tynninen,&nbsp;Ben Whitelaw,&nbsp;Pia Burman,&nbsp;Olivera Casar-Borota","doi":"10.1007/s00401-024-02838-3","DOIUrl":"10.1007/s00401-024-02838-3","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02838-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912827","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: Pyroptosis in Alzheimer’s disease: cell type‑specific activation in microglia, astrocytes and neurons","authors":"Sebastiaan Moonen,&nbsp;Marta J. Koper,&nbsp;Evelien Van Schoor,&nbsp;Jolien M. Schaeverbeke,&nbsp;Rik Vandenberghe,&nbsp;Christine A. F. von Arnim,&nbsp;Thomas Tousseyn,&nbsp;Bart De Strooper,&nbsp;Dietmar Rudolf Thal","doi":"10.1007/s00401-024-02841-8","DOIUrl":"10.1007/s00401-024-02841-8","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875209","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":"Amyloid-β oligomers increase the binding and internalization of tau oligomers in human synapses","authors":"Shrinath Kadamangudi,&nbsp;Michela Marcatti,&nbsp;Wen-Ru Zhang,&nbsp;Anna Fracassi,&nbsp;Rakez Kayed,&nbsp;Agenor Limon,&nbsp;Giulio Taglialatela","doi":"10.1007/s00401-024-02839-2","DOIUrl":"10.1007/s00401-024-02839-2","url":null,"abstract":"<div><p>In Alzheimer’s disease (AD), the propagation and spreading of CNS tau pathology closely correlates with cognitive decline, positioning tau as an attractive therapeutic target. Amyloid beta (Aβ) has been strongly implicated in driving tau spread, whereas primary tauopathies such as primary age-related tauopathy (PART)—which lack Aβ pathology—exhibit limited tau spread and minimal-to-no cognitive decline. Emerging evidence converges on a trans-synaptic mechanism of tau spread, facilitated by the transfer of misfolded tau aggregates (e.g. soluble oligomers). However, it is unclear whether Aβ oligomers modulate the binding and internalization of tau oligomers in human synapses. Our translationally focused paradigms utilize post-mortem brain specimens from Control, PART, and AD patients. Synaptosomes isolated from the temporal cortex of all three groups were incubated with preformed recombinant tauO (rtauO), ± preformed recombinant AβO (rAβO), and oligomer binding/internalization was quantified via flow cytometry following proteinase K (PK) digestion of surface-bound oligomers. TauO-synapse interactions were visualized using EM immunogold. Brain-derived tau oligomers (BDTO) from AD and PART PBS-soluble hippocampal fractions were co-immunoprecipitated and analyzed via mass spectrometry to compare synaptic tauO interactomes in primary and secondary tauopathies, thereby inferring the role of Aβ. AD synaptosomes, enriched in endogenous Aβ pathology, exhibited increased rtauO internalization compared to PART synaptosomes. This observation was mirrored in Control synaptosomes, where recombinant rAβO significantly increased rtauO binding and internalization. PK pre-treatment abolished this effect, implicating synaptic membrane proteins in AβO-mediated tauO internalization. While both PART and AD BDTO were broadly enriched in synaptic proteins, AD BDTO exhibited differential enrichment of endocytic proteins across pre- and post-synaptic compartments, whereas PART BDTO showed no significant synaptic enrichment. This study demonstrates that Aβ oligomers enhance tau oligomer binding and drive its internalization through synaptic membrane proteins. These findings offer novel mechanistic insights underlying pathological tau spreading directly within human synapses and emphasize the therapeutic potential of targeting Aβ-tau interactions.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02839-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826128","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":"TAM receptors mediate the Fpr2-driven pain resolution and fibrinolysis after nerve injury","authors":"Beate Hartmannsberger,&nbsp;Adel Ben-Kraiem,&nbsp;Sofia Kramer,&nbsp;Carolina Guidolin,&nbsp;Ida Kazerani,&nbsp;Kathrin Doppler,&nbsp;Dominique Thomas,&nbsp;Robert Gurke,&nbsp;Marco Sisignano,&nbsp;Pranav P. Kalelkar,&nbsp;Andrés J. García,&nbsp;Paula V. Monje,&nbsp;Michael Sammeth,&nbsp;Asma Nusrat,&nbsp;Alexander Brack,&nbsp;Susanne M. Krug,&nbsp;Claudia Sommer,&nbsp;Heike L. Rittner","doi":"10.1007/s00401-024-02840-9","DOIUrl":"10.1007/s00401-024-02840-9","url":null,"abstract":"<div><p>Nerve injury causes neuropathic pain and multilevel nerve barrier disruption. Nerve barriers consist of perineurial, endothelial and myelin barriers. So far, it is unclear whether resealing nerve barriers fosters pain resolution and recovery. To this end, we analysed the nerve barrier property portfolio, pain behaviour battery and lipidomics for precursors of specialized pro-resolving meditators (SPMs) and their receptors in chronic constriction injury of the rat sciatic nerve to identify targets for pain resolution by resealing the selected nerve barriers. Of the three nerve barriers—perineurium, capillaries and myelin—only capillary tightness specifically against larger molecules, such as fibrinogen, recuperated with pain resolution. Fibrinogen immunoreactivity was elevated in rats not only at the time of neuropathic pain but also in nerve biopsies from patients with (but not without) painful polyneuropathy, indicating that sealing of the vascular barrier might be a novel approach in pain treatment. Hydroxyeicosatetraenoic acid (15R-HETE), a precursor of aspirin-triggered lipoxin A4, was specifically upregulated at the beginning of pain resolution. Repeated local application of resolvin D1-laden nanoparticles or Fpr2 agonists sex-independently resulted in accelerated pain resolution and fibrinogen removal. Clearing macrophages (<i>Cd206)</i> were boosted and fibrinolytic pathways (<i>Plat)</i> were induced, while inflammation (<i>Tnfα)</i> and inflammasomes (<i>Nlrp3)</i> were unaffected by this treatment. Blocking TAM receptors (Tyro3, Axl and Mer) and tyrosine kinase receptors linking haemostasis and inflammation completely inhibited all the effects. In summary, nanoparticles can be used as transporters for fleeting lipids, such as SPMs, and therefore expand the array of possible therapeutic agents. Thus, the Fpr2–Cd206–TAM receptor axis may be a suitable target for strengthening the capillary barrier, removing endoneurial fibrinogen and boosting pain resolution in patients with chronic neuropathic pain.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02840-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142825154","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}