Acta Neuropathologica最新文献

{"title":"Microglial 5-LOX-activating protein antagonism alleviates leukotriene-driven neuroinflammation","authors":"Julia Konings,&nbsp;Fleur Mingneau,&nbsp;Serhii Chornyi,&nbsp;Cathrin E. Hansen,&nbsp;Rianne T. M. van der Brugt,&nbsp;Tessa G. van Elk,&nbsp;Laura Bolkaerts,&nbsp;Bo Batens,&nbsp;Gábor Tóth,&nbsp;Ingela Lanekoff,&nbsp;Frédéric M. Vaz,&nbsp;Alessio Cardilli,&nbsp;Marie Sels,&nbsp;Susanne M. A. van der Pol,&nbsp;Helga E. de Vries,&nbsp;Martin Giera,&nbsp;Oliver Werz,&nbsp;Sofie Kessels,&nbsp;Sanne G. S. Verberk,&nbsp;Jeroen F. J. Bogie,&nbsp;Merel Rijnsburger,&nbsp;Jerome J. A. Hendriks,&nbsp;Gijs Kooij","doi":"10.1007/s00401-026-03055-w","DOIUrl":"10.1007/s00401-026-03055-w","url":null,"abstract":"<div><p>In multiple sclerosis (MS), the chronic, unresolved nature of neuroinflammation within the central nervous system (CNS) remains a major obstacle for effective therapeutic intervention. This challenge arises primarily due to an incomplete understanding of the dysregulated inflammatory and pro-resolving pathways underlying MS lesion progression. Bioactive lipid mediators (LMs), biosynthesized through the coordinated actions of specific enzymes like lipoxygenases (LOX) and cyclooxygenases (COX), are key regulators of both the initiation and resolution of an inflammatory response; however, their spatial organization and functional role during MS pathology have not been fully elucidated. Here, by using pneumatically assisted nanospray desorption electrospray ionization (PA nano-DESI) mass spectrometry imaging and immunohistochemistry, we reveal an increase in the LM leukotriene B₄ (LTB₄) in human MS white matter compared to controls, with further enrichment in MS lesions relative to perilesional areas, alongside elevated microglial 5-LOX activating protein (FLAP) expression. Pharmacological antagonism of FLAP suppresses LTB₄ biosynthesis in human-induced pluripotent stem cell (iPSC)-derived microglia with only marginal effects on the microglia transcriptional phenotype as determined by RNA sequencing. Moreover, in vivo FLAP antagonism ameliorates disease severity and spinal cord inflammatory gene expression in the experimental autoimmune encephalomyelitis (EAE) model, an animal model of MS, in both a prophylactic and therapeutic settings. This coincided with reduced local LTB₄ biosynthesis and reduced levels of inflammatory monocytes within the spinal cord during EAE. Together these findings establish the FLAP/LTB₄ axis as a driver of neuroinflammation and a druggable therapeutic target for chronic inflammatory CNS disorders like MS.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13437591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148667945","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":"Improving T-cell engager efficacy in glioblastoma with multi-antigen targeting and novel delivery approaches","authors":"Arushi Tiwari,&nbsp;Kristen D. Pawlowski,&nbsp;Irina V. Balyasnikova","doi":"10.1007/s00401-026-03063-w","DOIUrl":"10.1007/s00401-026-03063-w","url":null,"abstract":"<div><p>Glioblastoma remains a challenging disease to approach with immunotherapy due to pronounced antigen heterogeneity, immunosuppressive tumor microenvironment, and barriers to effective molecule delivery within the central nervous system. T-cell engagers provide an off-the-shelf approach to redirect endogenous T cells toward tumor cells. However, bispecific formats are constrained by intra- and interpatient antigen heterogeneity, which can limit therapeutic efficacy. In this review, we examine trispecific T-cell engagers (TriTEs) as an emerging strategy to address this limitation by simultaneously targeting multiple tumor-associated antigens. We discuss principles guiding antigen selection in glioblastoma, summarize available preclinical evidence supporting multispecific engagement, and outline key design considerations, including molecular architecture, stability, half-life extension, and safety optimization. We further review delivery strategies, such as gene-encoded expression, cellular carriers, and blood–brain barrier modulation, that may improve tumor access and the durability of TriTEs. Together, these considerations position TriTEs as a modular immunotherapy platform relevant to glioblastoma and other heterogeneous solid tumors.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13433593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148663339","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":"Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE): genetics, mechanisms and precision therapy","authors":"James Spyrou,&nbsp;Paul J. Lockhart,&nbsp;Snezana Maljevic,&nbsp;Katherine B. Howell,&nbsp;Christopher A. Reid","doi":"10.1007/s00401-026-03059-6","DOIUrl":"10.1007/s00401-026-03059-6","url":null,"abstract":"<div><p>Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a recently defined malformation of cortical development that is an important cause of childhood-onset drug-resistant epilepsy. Clinically, the epilepsies associated with MOGHE are heterogeneous, with infantile epileptic spasms syndrome (IESS) being the most common manifestation. Histopathologically, MOGHE demonstrates subtle cortical dyslamination, heterotopic neurons in the white matter, hypomyelination, and a distinctive increase in the density and clustering of oligodendroglial cells, features that distinguish it from other malformations of cortical development such as focal cortical dysplasia (FCD). Recent genetic analyses of epileptogenic tissue resected from individuals with MOGHE have identified somatic mosaic loss-of-function variants in <i>SLC35A2</i>. This gene encodes the Golgi transmembrane UDP-galactose transporter, suggesting disrupted N-glycosylation as a distinct pathogenic mechanism underlying epilepsy in this disorder. In this review, we present the current clinical, histopathological, and molecular understanding of MOGHE, with a particular focus on recent insights gained from experimental rodent and human cellular models of SLC35A2 deficiency. We contextualise these findings against established models of mTORopathies including FCD type 2, placing MOGHE within the broader malformation of cortical development spectrum. Synthesising this evidence, we observe that neuronal activity in models of both MOGHE and mTORopathies such as FCD type 2 converge on reduced action potential firing, despite their distinct genetic aetiologies. Finally, we discuss how these findings inform our understanding of epileptogenesis, especially the emergence of infantile epileptic spasms, and the development of future precision therapeutic strategies across malformations of cortical development.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13429557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148652767","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":"Proteomic comparison of hippocampal neurofibrillary tangles in PART, intermediate Alzheimer’s disease and advanced Alzheimer’s disease","authors":"Manon Thierry,&nbsp;Dominique Leitner,&nbsp;Kaleah Balcomb,&nbsp;Tomas Kavanagh,&nbsp;Lauren Tang,&nbsp;Evgeny Kanshin,&nbsp;Christopher William,&nbsp;Derek Oakley,&nbsp;Bradley Hyman,&nbsp;Beatrix Ueberheide,&nbsp;Eleanor Drummond,&nbsp;Thomas Wisniewski","doi":"10.1007/s00401-026-03064-9","DOIUrl":"10.1007/s00401-026-03064-9","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) is characterised by the intraneuronal aggregation of phosphorylated Tau (pTau) into neurofibrillary tangles and by the extracellular deposition of β-amyloid (Aβ). Tau pathology restricted to the hippocampal formation is frequently observed in the elderly brain in the absence of any Aβ deposition and considered as “primary age-related tauopathy” (PART). Here, we applied an unbiased proteomic approach to determine how concomitant Aβ pathology modifies the neurofibrillary tangle proteome. Neurofibrillary tangles were isolated by dissecting Tau pSer202/pThr205 “AT8” immunopositive neuronal profiles, combining chromogenic immunohistochemistry with laser capture microdissection, from hippocampal sections of 17 <i>post-mortem</i> brains spanning three groups: PART (<i>n</i> = 5; A0, B1–2, C0 scores), intermediate AD (<i>n</i> = 6; A1–2, B2–3, C1–2 scores) and advanced AD (<i>n</i> = 6; A3, B3, C3 scores). A label-free quantitative liquid chromatography–mass spectrometry based proteomic analysis, using data independent acquisition (DIA) on a Bruker timsTOF, was performed. A conserved core of 63 proteins was identified as enriched in tangles across all groups, mostly associated with “RNA binding” and “regulation of mRNA metabolic process”, based on the Gene Ontology database. Group-specific signatures were also observed: 33 proteins were significantly enriched only in tangles collected from PART cases and were predominantly linked to “structural molecule activity”, whereas Aβ-positive cases showed specific enrichment of “RNA binding” and “cytoplasmic translation” pathways—with intermediate AD cases displaying a transitional profile. Our findings are consistent with PART having distinct tangle proteomic features; however, the majority of its proteomic signature is in common with tangles within the AD continuum. By addressing how Aβ accumulation alters the tangle proteome, this study provides mechanistic insights into the expansion of Tau pathology, paving the way towards the identification of biomarkers and therapeutic strategies that would allow for stabilisation of Tau pathology in the elderly.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13428778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148652818","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":"Retinal proteome changes mirror brain pathology and reveal synaptic and cytoskeletal dysfunction in Alzheimer’s disease","authors":"Jessica Santiago,&nbsp;Dovilė Pocevičiūtė,&nbsp;Teo Sällberg,&nbsp;Patrik Önnerfjord,&nbsp;The Netherlands Brain Bank,&nbsp;Jacob W. Vogel,&nbsp;Malin Wennström","doi":"10.1007/s00401-026-03054-x","DOIUrl":"10.1007/s00401-026-03054-x","url":null,"abstract":"<div><p>Visual dysfunction is increasingly recognized as an important feature of Alzheimer’s disease, and substantial retinal changes have been documented across multiple studies. Yet the molecular changes underlying retinal neurodegeneration and which retinal protein signatures best track cerebral pathology remain incompletely defined. Here, we performed comprehensive mass spectrometry-based proteomics on paired retinal and hippocampal tissue from the same postmortem donors (8 <span>AD</span>, 8 non-demented controls) to identify disease-associated molecular signatures and assess their overlap between these tissues. Using a sequential dual-extraction protocol, we identified 372 differentially abundant retinal proteins in AD, including established APP-processing regulators (SORL1, BACE1) and synaptic proteins. Retinal proteomes clearly separated AD from controls in principal component analysis, indicating robust AD-related molecular differences in the retina. Notably, 87% of proteins were detected in both retina and hippocampus, with 64 differentially abundant proteins shared between tissues, some of which showed strong cross-tissue correlation. Several retinal proteins also correlated with neuropathological disease stage. Functional enrichment analysis revealed convergent alterations in synaptic organization, cytoskeletal dynamics, mitochondrial function, cell adhesion, and APP metabolism in both tissues. Cell-type mapping using single-cell retinal reference data indicated that most proteomic changes were broadly distributed across cell types, though some proteins showed enrichment in specific populations, such as SORL1 in microglia and EYS in photoreceptors. The molecular changes identified here offer a potential basis for the retinal alterations previously documented through in vivo imaging and histological studies. Their similarities with brain pathology further support the retina as a promising window for assessing cerebral disease.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03054-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148614829","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":"Aquaporin-4’s dynamic expression and biological variations within the tumor obscure the paraneoplastic phenomenon in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder","authors":"Naga Pradyumna Kothapalli,&nbsp;Yong Guo,&nbsp;Nisa Vorasoot,&nbsp;Dean M. Wingerchuk,&nbsp;Eoin P. Flanagan,&nbsp;Divyanshu Dubey,&nbsp;Nanthaya Tisavipat,&nbsp;Fernando X. Cuascut,&nbsp;Hemali Y. Patel,&nbsp;Claudia F. Lucchinetti,&nbsp;Sean J. Pittock","doi":"10.1007/s00401-026-03053-y","DOIUrl":"10.1007/s00401-026-03053-y","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13401567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148590176","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":"Targeting chordoma via an isocitrate dehydrogenase-1-dependent susceptibility to redox metabolism","authors":"Matthew Pun,&nbsp;Akash Deogharkar,&nbsp;Siva Kumar Natarajan,&nbsp;Nicholas Nuechterlein,&nbsp;Wentao Tian,&nbsp;Sunjong Ji,&nbsp;Eleanor Young,&nbsp;Fusheng Yang,&nbsp;Debra Hawes,&nbsp;Anthony C. Andren,&nbsp;John Henry Owen,&nbsp;Sagar Rau,&nbsp;Fengyun Su,&nbsp;Xuhong Cao,&nbsp;Abhijit Parolia,&nbsp;Mark Prince,&nbsp;Joshua Fry,&nbsp;Paul A. Gardner,&nbsp;Rendong Yang,&nbsp;Alexander R. Judkins,&nbsp;Carl J. Koschmann,&nbsp;Andrew S. Venteicher,&nbsp;Costas A. Lyssiotis,&nbsp;Arul M. Chinnaiyan,&nbsp;Sriram Venneti","doi":"10.1007/s00401-026-03048-9","DOIUrl":"10.1007/s00401-026-03048-9","url":null,"abstract":"<div><p>Chordomas are rare cancers that arise along the axial skeleton. Alterations in metabolism are a hallmark of cancer, and we sought to identify metabolic vulnerabilities in chordoma. We discovered that the tricarboxylic acid (TCA)-related enzyme isocitrate dehydrogenase-1 (<i>IDH1</i>) was expressed highly in bulk and single-cell patient-derived chordomas and was associated with worse survival outcomes. IDH1 catalyzes the conversion of isocitrate and nicotinamide adenine dinucleotide phosphate (NADP+) to alpha-ketoglutarate (⍺-KG) and NADPH. This critical reaction influences TCA cycle metabolism, regulates epigenetic pathways, and affects redox balance. Both <i>IDH1</i> knockdown and treatment with an inhibitor targeting IDH1 were toxic to chordoma cells. An integrated analysis of the transcriptomic, chromatin, and metabolomic responses on IDH1 inhibition converged on deregulated glutathione metabolism. IDH1 inhibition was associated with increased expression and enrichment of activating H3K27ac at NRF2 (nuclear factor erythroid 2-related factor 2) signature genes including those in the glutathione biosynthetic pathway. This was accompanied by reduction of both NADPH/NADP+ and reduced/oxidized glutathione (GSH/GSSG) ratios. Importantly, IDH1 inhibitor-driven toxicity was rescued via media supplementation with the antioxidant <i>N</i>-acetylcysteine, suggesting that IDH1 inhibition in chordomas creates a redox-dependent metabolic vulnerability. Finally, IDH1 inhibitor treatment reduced tumor growth in two independent chordoma mouse xenograft models. Our findings suggest a potential therapeutic avenue for further exploration in chordoma.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13396039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148576533","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":"Validation of proposed cIMPACT-NOW update 12 molecular grading criteria for IDH-mutant astrocytoma","authors":"Timothy E. Richardson,&nbsp;Jorge Samanamud,&nbsp;Michael Christian Virata,&nbsp;Ema Mir,&nbsp;Shrishtee Kandoi,&nbsp;Cheyanne C. Slocum,&nbsp;Diana D. Shi,&nbsp;Milan R. Savani,&nbsp;Raquel T. Yokoda,&nbsp;Sachein Sharma,&nbsp;Raymund L. Yong,&nbsp;Joshua B. Bederson,&nbsp;Thenzing J. Silva-Hurtado,&nbsp;Phuong Nguyen,&nbsp;Satomi Hiya,&nbsp;Carolina Maldonado-Díaz,&nbsp;Kevin Clare,&nbsp;Meenakshi Vij,&nbsp;Yurika Nishikawa,&nbsp;Melissa Umphlett,&nbsp;Kimmo J. Hatanpaa,&nbsp;Steven Brem,&nbsp;Mariano S. Viapiano,&nbsp;Matija Snuderl,&nbsp;Dolores Hambardzumyan,&nbsp;Jamie M. Walker,&nbsp;Kalil G. Abdullah,&nbsp;Samuel K. McBrayer,&nbsp;Nadejda M. Tsankova","doi":"10.1007/s00401-026-03058-7","DOIUrl":"10.1007/s00401-026-03058-7","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03058-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148552225","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":"Cerebral amyloid angiopathy, brain iron concentrations, and cognitive decline in older people","authors":"Sonal Agrawal,&nbsp;Maude Wagner,&nbsp;Sue E. Leurgans,&nbsp;Puja Agarwal,&nbsp;Louise van der Weerd,&nbsp;David A. Bennett,&nbsp;Ashley I. Bush,&nbsp;Scott Ayton,&nbsp;Julie A. Schneider","doi":"10.1007/s00401-026-03056-9","DOIUrl":"10.1007/s00401-026-03056-9","url":null,"abstract":"<div><p>Cerebral amyloid angiopathy (CAA) is a common brain pathology in older people and has been recently recognized as a major risk factor for amyloid-related imaging abnormalities during anti-amyloid antibody therapy. CAA pathophysiology may involve iron released from ruptured vessels, but the association between postmortem CAA and brain iron is unclear. This study investigates the association between CAA and brain iron and whether elevated iron modifies the association between CAA and cognitive decline. We studied 626 Rush Memory and Aging Project decedents (mean age at death = 90 [SD = 6.1] years, 70% women) who completed baseline and longitudinal cognitive assessments and underwent detailed neuropathologic evaluation for CAA, Alzheimer’s disease neuropathologic changes (ADNC), and other brain pathologies. Brain iron content was assessed from the inferior temporal cortex using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Linear regression and mixed-effects models were used for analysis. CAA was common: 266 (42%) had mild, 153 (24%) had moderate, and 75 (12%) had severe CAA. In analyses adjusted for demographics, intermediate/high ADNC, and other pathologies, the presence and severity of CAA were associated with elevated cortical brain iron (Est = 0.033, SE = 0.011, <i>p</i> = 0.002; Est = 0.017, SE = 0.004, <i>p</i> &lt; 0.001, respectively). When examining associations with nonlinear cognitive change before death (mean follow-up = 7.7 [SD = 3.9] years), both CAA and elevated iron were independently associated with faster annual rates of decline in global cognition and semantic memory (all <i>p</i> &lt; 0.04). Elevated iron was also associated with faster declines in episodic and working memory and perceptual speed (all <i>p</i> &lt; 0.02). When exploring whether brain iron modulates the association of CAA with cognitive decline, we found that CAA had steeper decline in perceptual speed when elevated iron was present compared to when low iron was present (<i>p</i> = 0.03). Together, these findings suggest that brain iron may contribute to the clinical impact of CAA in older age.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03056-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148522392","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":"Complement dysregulation during the early phases of synucleinopathy","authors":"Hina Khan,&nbsp;Mary Gifford,&nbsp;Arash Kordbacheh,&nbsp;Asher Bury,&nbsp;Spencer Panoushek,&nbsp;Allyson Cole-Strauss,&nbsp;Christopher J. Kemp,&nbsp;Kelvin C. Luk,&nbsp;Kathy Steece-Collier,&nbsp;Nathan C. Kuhn,&nbsp;Nicholas M. Kanaan,&nbsp;Caryl E. Sortwell,&nbsp;Joseph R. Patterson,&nbsp;Matthew J. Benskey","doi":"10.1007/s00401-026-03057-8","DOIUrl":"10.1007/s00401-026-03057-8","url":null,"abstract":"<div><p>Parkinson’s disease (PD) is characterized by progressive degeneration of nigrostriatal dopamine neurons and synucleinopathy, which is the accumulation of aggregated α-synuclein (α-syn). Increasing evidence implicates α-syn-associated neuroinflammation as a contributor to PD pathogenesis, yet immune mechanisms linking synucleinopathy to neurodegeneration remain incompletely defined. Activation of the complement cascade occurs in PD and other synucleinopathies, but most studies report complement activation after overt neurodegeneration, making it difficult to conclude if complement is directly activated by pathological α-syn or secondarily following neurodegeneration. We used the rat α-syn preformed fibril (PFF) model, in vitro complement assays and postmortem human PD tissue to investigate whether pathological α-syn directly activates complement prior to overt neurodegeneration. The α-syn PFF model exhibits a protracted pathological time course and distinct temporal separation between peak α-syn aggregation and nigrostriatal degeneration. Thus, we quantified complement expression, activation, and regulation during the aggregation phase. Synucleinopathy caused complement activation prior to nigrostriatal degeneration, including upregulation of components of both the classical (<i>C1qa, C1r, C4b</i>) and alternative (<i>Cfd, Cfb</i>) pathways, the anaphylatoxin (<i>C3aR, C5aR</i>) and phagocytic (<i>CR3</i>) complement receptors, and activation of complement C3. During early synucleinopathy microglia upregulated C3, which significantly correlated with synucleinopathy burden across several brain regions, including the substantia nigra pars compacta (SNc) and cortex. Concurrently, complement regulators, including Cd55, Cd59, neuronal pentraxin-1 (Nptx1), and the neuronal pentraxin receptor were downregulated in the synucleinopathy-affected SNc. Importantly, increased levels of C1q and iC3b along with downregulation of CD55 and NPTX1 protein were also observed in human postmortem PD SNc tissue, supporting the translational relevance of our findings. Mechanistically, we demonstrate that aggregated, but not monomeric, α-syn directly binds C1q and activates the complement cascade in a C1q-dependent manner. These data provide the first in vivo evidence that synucleinopathy triggers complement activation and dysregulation prior to neurodegeneration.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13385250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148534887","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}