Acta Neuropathologica Communications最新文献

{"title":"Neuronal TDP-43 aggregation drives changes in microglial morphology prior to immunophenotype in amyotrophic lateral sclerosis.","authors":"Molly E V Swanson, Miran Mrkela, Clinton Turner, Maurice A Curtis, Richard L M Faull, Adam K Walker, Emma L Scotter","doi":"10.1186/s40478-025-01941-0","DOIUrl":"10.1186/s40478-025-01941-0","url":null,"abstract":"<p><p>Microglia are the innate immune cells of the brain with the capacity to react to damage or disease. Microglial reactions can be characterised in post-mortem tissues by assessing their pattern of protein expression, or immunophenotypes, and cell morphologies. We recently demonstrated that microglia have a phagocytic immunophenotype in early-stage ALS but transition to a dysfunctional immunophenotype by end stage, and that these states are driven by TAR DNA-binding protein 43 (TDP-43) aggregation in the human brain. However, it remains unclear how microglial morphologies are changed in ALS. Here we examine the relationship between microglial immunophenotypes and morphologies, and TDP-43 pathology in motor cortex tissue from people with ALS and from a TDP-43-driven ALS mouse model. Post-mortem human brain tissue from 10 control and 10 ALS cases was analysed alongside brain tissue from the bigenic NEFH-tTA/tetO-hTDP-43∆NLS (rNLS) mouse model of ALS at distinct disease stages. Sections were immunohistochemically labelled for microglial markers (HLA-DR, CD68, and Iba1) and phosphorylated TDP-43 (pTDP-43). Single-cell microglial HLA-DR, CD68, and Iba1 average intensities, and morphological features (cell body area, process number, total outgrowth, and branch number) were measured using custom image analysis pipelines. In human ALS motor cortex, we identified a significant change in microglial morphologies from ramified to hypertrophic, which was associated with increased Iba1 and CD68 levels. In the rNLS mouse motor cortex, the microglial morphologies changed from ramified to hypertrophic and increased Iba1 levels occurred in parallel with pTDP-43 aggregation, prior to increases in CD68 levels. Overall, the evidence presented in this study demonstrates that microglia change their morphologies prior to immunophenotype changes. These morphological changes may prime microglia near neurons with pTDP-43 aggregation for phagocytosis, in turn triggering immunophenotype changes; first, to a phagocytic state then to a dysfunctional one.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"39"},"PeriodicalIF":6.2,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human induced pluripotent stem cell-derived myotubes to model inclusion body myositis.","authors":"Judith Cantó-Santos, Laura Valls-Roca, Ester Tobías, Francesc Josep García-García, Mariona Guitart-Mampel, Félix Andújar-Sánchez, Adrià Vilaseca-Capel, Anna Esteve-Codina, Beatriz Martín-Mur, Joan Padrosa, Emma Peruga, Irene Madrigal, Paula Segalés, Carmen García-Ruiz, José Carlos Fernández-Checa, Pedro J Moreno-Lozano, Albert Selva O'Callaghan, Ana Sevilla, José César Milisenda, Glòria Garrabou","doi":"10.1186/s40478-025-01933-0","DOIUrl":"10.1186/s40478-025-01933-0","url":null,"abstract":"<p><p>Inclusion body myositis (IBM) is an inflammatory myopathy that displays proximal and distal muscle weakness. At the histopathological level, the muscles of IBM patients show inflammatory infiltrates, rimmed vacuoles and mitochondrial changes. The etiology of IBM remains unknown, and there is a lack of validated disease models, biomarkers and effective treatments. To contribute to unveil disease underpins we developed a cell model based on myotubes derived from induced pluripotent stem cells (iPSC-myotubes) from IBM patients and compared the molecular phenotype vs. age and sex-paired controls (n = 3 IBM and 4 CTL). We evaluated protein histological findings and the gene expression profile by mRNA-seq, alongside functional analysis of inflammation, degeneration and mitochondrial function. Briefly, IBM iPSC-myotubes replicated relevant muscle histopathology features of IBM, including aberrant expression of HLA, TDP-43 and COX markers. mRNA seq analysis identified 1007 differentially expressed genes (DEGs) (p-value adj < 0.01; 789 upregulated and 218 downregulated), associated with myopathy, muscle structure and developmental changes. Among these, 1 DEG was related to inflammation, 28 to autophagy and 28 to mitochondria. At the functional level, inflammation was similar between the IBM and CTL groups under basal conditions (mean cytokine expression in IBM 4.6 ± 1.4 vs. 6.7 ± 3.4 in CTL), but increased in IBM iPSC-myotubes after lipopolysaccharide treatment (72.5 ± 21.8 in IBM vs. 13.0 ± 6.7 in CTL). Additionally, autophagy was disturbed, with 40.14% reduction in autophagy mediators. Mitochondrial dysfunction was strongly manifested, showing a conserved respiratory profile and antioxidant capacity, but a 56.33% lower cytochrome c oxidase/citrate synthase ratio and a 66.59% increase in lactate secretion. Overall, these findings support patient-derived iPSC-myotubes as a relevant model for IBM, reflecting the main muscle hallmarks, including inflammation, autophagy dysfunction and mitochondrial alterations at transcriptomic, protein and functional levels.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"38"},"PeriodicalIF":6.2,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinctive autophagy/mitophagy biomarker profiles in frontotemporal lobar degeneration and Alzheimer's disease.","authors":"Kateřina Veverová, Alžběta Katonová, Hana Horáková, Jan Laczó, Francesco Angelucci, Jakub Hort, Sofie Lautrup, Evandro Fei Fang, Martin Vyhnálek","doi":"10.1186/s40478-025-01954-9","DOIUrl":"10.1186/s40478-025-01954-9","url":null,"abstract":"<p><p>Maintaining cellular homeostasis by removing damaged and senescent mitochondria, a process termed mitophagy, is crucial in preventing Alzheimer's disease (AD) and represents a promising therapeutic target. Our previous research revealed altered mitophagy biomarkers, such as increased CSF and serum PINK1 and serum BNIP3L and decreased serum TFEB levels, indicating impaired autophagy-lysosomal degradation in the AD continuum. However, the role of autophagy/mitophagy in frontotemporal lobar degeneration (FTLD) remains unclear. This study investigated the biomarkers of autophagy/mitophagy and lysosomal biogenesis (PINK1, ULK1, BNIP3L, and TFEB) in biofluids (CSF and serum) from 308 biomarker-defined individuals across the FTLD continuum (FTLD-dementia, n = 29; FTLD-MCI, n = 33) and compared them with those across the AD continuum (MCI-AD, n = 100; AD-dementia, n = 100) and cognitively unimpaired (CU) controls (n = 46) recruited from Czech Brain Aging Study. Additionally, we compared the mitophagy biomarkers across different FTLD clinical subtypes (frontal, semantic and nonfluent variant) with CU, and explored the association between mitophagy biomarkers and clinical phenotypes of FTLD (biomarkers of tau, biomarkers of neurodegeneration, cognition and ATN profile).Our findings indicated a significantly lower CSF PINK1 and ULK1 levels in FTLD compared to AD, with FTLD dementia showing particularly low CSF PINK1 levels compared to AD-dementia. Conversely, CSF ULK1 levels were higher in FTLD-MCI compared to AD-dementia. Serum analyses revealed lower PINK1 and higher TFEB levels in FTLD dementia compared to AD dementia. This study provides compelling evidence of distinct alterations in autophagy/mitophagy biomarkers between FTLD and AD, indicating that these neurodegenerative diseases may affect the cellular waste disposal system through different pathways. This is the first study to explore mitophagy biomarkers in human CSF and serum in FTLD, opening avenues for further research and potential clinical applications.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"37"},"PeriodicalIF":6.2,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Gene-expression profiling of individuals resilient to Alzheimer's disease reveals higher expression of genes related to metallothionein and mitochondrial processes and no changes in the unfolded protein response.","authors":"Luuk E de Vries, Aldo Jongejan, Jennifer Monteiro Fortes, Rawien Balesar, Annemieke J M Rozemuller, Perry D Moerland, Inge Huitinga, Dick F Swaab, Joost Verhaagen","doi":"10.1186/s40478-025-01931-2","DOIUrl":"10.1186/s40478-025-01931-2","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"36"},"PeriodicalIF":6.2,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial analysis of a complete DIPG-infiltrated brainstem reveals novel ligand-receptor mediators of tumour-to-TME crosstalk.","authors":"Anja Kordowski, Onkar Mulay, Xiao Tan, Tuan Vo, Ulrich Baumgartner, Mellissa K Maybury, Timothy Hassall, Lachlan Harris, Quan Nguyen, Bryan W Day","doi":"10.1186/s40478-025-01952-x","DOIUrl":"10.1186/s40478-025-01952-x","url":null,"abstract":"<p><p>Previous studies have highlighted the capacity of brain cancer cells to functionally interact with the tumour microenvironment (TME). This TME-cancer crosstalk crucially contributes to tumour cell invasion and disease progression. In this study, we performed spatial transcriptomic sequencing analysis of a complete annotated tumour-infiltrated brainstem from a single diffuse intrinsic pontine glioma (DIPG) patient. Gene signatures from ten sequential tumour regions were analysed to assess mechanisms of disease progression and oncogenic interactions with the TME. We identified four distinct tumour subpopulations and assessed respective ligand-receptor pairs that actively promote DIPG tumour progression via crosstalk with endothelial, neuronal and immune cell communities. Our analysis found potential targetable mediators of tumour-to-TME communication, including members of the complement component system and the neuropeptide/GPCR ligand-receptor pair ADCYAP1-ADCYAP1R1. These interactions could influence DIPG tumour progression and represent novel therapeutic targets.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"35"},"PeriodicalIF":6.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Density and entropy of immune cells within the tumor microenvironment of primary tumors and matched brain metastases.","authors":"Markus Kleinberger, Didem Çifçi, Christina Paiato, Erwin Tomasich, Maximilian J Mair, Ariane Steindl, Zoltán Spiró, Zunamys I Carrero, Luzia Berchtold, Johannes Hainfellner, Leonhard Müllauer, Gerwin Heller, Matthias Preusser, Jakob Niklas Kather, Anna Sophie Berghoff","doi":"10.1186/s40478-025-01939-8","DOIUrl":"10.1186/s40478-025-01939-8","url":null,"abstract":"<p><strong>Background: </strong>Tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) have increasingly been reported to impact the brain metastatic process of solid tumors. However, data on intra-individual differences between primary tumor and brain metastasis (BM), as well as their correlation with clinical outcome parameters, is scarce.</p><p><strong>Methods: </strong>We retrospectively identified patients who received resection of the primary tumor and BM between 01/1990 and 10/2022. Density quantification of TAMs (CD68⁺, CD163⁺) and TILs (CD3⁺, CD8⁺, CD45RO⁺, FOXP3⁺) was performed by immunohistochemical staining of matched tumor tissue samples. Images were processed with QuPath software and heterogeneity of generated heatmaps was measured by Shannon Entropy. Time-to-BM (TTBM) was defined as the time from diagnosis of the primary tumor until the first diagnosis of BM.</p><p><strong>Results: </strong>In total, 104 patients (46.2% female; median age 57.3 years at BM diagnosis) were included: 78/104 (75%) non-small cell lung cancer, 18/104 (17%) breast cancer, 8/104 (8%) renal cell carcinomas. Densities of CD3⁺ (p < 0.001) and CD8⁺-TILs (p < 0.001) were higher in primary tumor samples, while CD68⁺ (p = 0.035) and CD163⁺-TAM densities (p < 0.001) were higher in the matched BM. Higher CD3⁺, CD8⁺-TILs and CD163⁺-TAMs densities in primary tumors were associated with shorter TTBM (p = 0.005, p = 0.015 and p = 0.006, respectively). Higher entropies of CD3⁺ (p < 0.001) and FOXP3⁺ (p = 0.011) TILs were observed in primary tumors compared to BM. Longer TTBM was associated with higher entropy of FOXP3⁺ TILs (p = 0.024) and lower entropy in CD163⁺ TAMs (p = 0.039). No significant associations of immune cell densities or entropies with OS after BM diagnosis were found.</p><p><strong>Discussion: </strong>By utilizing a unique cohort of matched primary tumor and BM tissue samples, we could demonstrate higher TIL densities in primary tumors and higher TAM densities in BM, respectively. Higher cell densities of CD3⁺, CD8⁺-TILs and CD163⁺-TAMs in primary tumors were associated with shorter TTBM, while a larger difference between CD3⁺ and CD8⁺ densities between primary tumor and BM was associated with longer TTBM. These findings highlight the potential of targeting TAMs as a therapeutic strategy to mitigate the development of brain metastases.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"34"},"PeriodicalIF":6.2,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blocking peptidyl arginine deiminase 4 confers neuroprotective effect in the post-ischemic brain through both NETosis-dependent and -independent mechanisms.","authors":"Song-I Seol, Sang-A Oh, Dashdulam Davaanyam, Ja-Kyeong Lee","doi":"10.1186/s40478-025-01951-y","DOIUrl":"10.1186/s40478-025-01951-y","url":null,"abstract":"<p><p>Peptidylarginine deiminase 4 (PAD4) is an enzyme that modifies proteins by converting positively charged arginine residues to neutral citrulline residues. This process, termed citrullination, has been known to trigger NETosis, a neutrophil cell death pathway involving the release of neutrophil extracellular traps (NETs). Abnormal PAD4 activity and protein citrullination have been linked to various diseases, including those affecting the central nervous system. Herein we investigated the profile of PAD4 expression in an animal model of stroke induced by middle cerebral artery occlusion (MCAO). PAD4 levels were significantly elevated in the ischemic core and penumbra of the affected hemisphere at 3-6 and 6-48 h post-MCAO, respectively. Notably, NETosis induction, indicated by the upregulation of CitH3 (citrullinated histone H3, a NETosis marker), was observed between 48 and 96 h post-MCAO, peaking at 96 h. While PAD4 was present in most brain cell types of sham controls, strong PAD4 induction was primarily observed in neurons during the peak PAD4 induction period (12-24 h post-MCAO). Importantly, intranasal administration of the PAD4 inhibitor BB-Cl-amidine (BBCA) significantly reduced infarct volume and improved neurological and functional outcomes at 24 h post-MCAO, demonstrating a strong protective effect of PAD4 inhibition in ischemic stroke. Staining with an antibody that recognizing citrullinated proteins (F95) revealed an accumulation of these proteins, especially degenerating neurons, however, BBCA treatment significantly suppressed this accumulation in dying neurons. These findings indicate that PAD4-mediated protein citrullination in neurons plays a critical role in promoting ischemic brain damage. Furthermore, delayed administration of BBCA (at 48/72 h post-MCAO) suppresses the NETosis induction observed at 96 h post-MCAO, potentially ameliorating repair processes such as blood vessel regeneration. Collectively, these findings suggest a complex role of PAD4 in cerebral ischemia, with neuroprotective effects (NETosis-independent function) during the acute to subacute period and NETosis-suppressive effects at later time points.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"33"},"PeriodicalIF":6.2,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bradykinesia and postural instability in a model of prodromal synucleinopathy with α-synuclein aggregation initiated in the gigantocellular nuclei.","authors":"Vasileios Theologidis, Sara A Ferreira, Nanna M Jensen, Diana Gomes Moreira, Ole A Ahlgreen, Mads W Hansen, Emilie D Rosenberg, Mette Richner, Islam Faress, Hjalte Gram, Poul Henning Jensen, Per Borghammer, Jens R Nyengaard, Marina Romero-Ramos, Christian B Vægter, Wilma D J van de Berg, Nathalie Van Den Berge, Asad Jan","doi":"10.1186/s40478-025-01948-7","DOIUrl":"10.1186/s40478-025-01948-7","url":null,"abstract":"<p><p>α-Synuclein (aSyn) accumulation within the extra-nigral neuronal populations in the brainstem, including the gigantocellular nuclei (GRN/Gi) of reticular formation, is a recognized feature during the prodromal phase of Parkinson disease (PD). Accordingly, there is a burgeoning interest in animal model development for understanding the pathological significance of extra-nigral synucleinopathy, in relation to motor and/or non-motor symptomatology in PD. Here, we report an experimental paradigm for the induction of aSyn aggregation in brainstem, with stereotaxic delivery of pre-formed fibrillar (PFF) aSyn in the pontine GRN of transgenic mice expressing the mutant human Ala53Thr aSyn (M83 line). Our data show that PFF aSyn-induced aggregate pathology in GRN and distinct nuclei of subcortical motor system leads to progressive decline in home cage activity, which was accompanied by postural instability and impaired motor coordination. The progressive accumulation of aSyn pathology in brainstem and motor neurons in lumbar spinal cord heralded the onset of a moribund stage, which culminated in impaired survival. Collectively, our observations suggest an experimental framework for studying the pathological significance of aSyn aggregation in GRN in relation to features of movement disability in PD. With further refinements, we anticipate that this model holds promise as a test-bed for translational research in PD and related disorders.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"32"},"PeriodicalIF":6.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retinal ganglion cell vulnerability to pathogenic tau in Alzheimer's disease.","authors":"Miyah R Davis, Edward Robinson, Yosef Koronyo, Elena Salobrar-Garcia, Altan Rentsendorj, Bhakta P Gaire, Nazanin Mirzaei, Rakez Kayed, Alfredo A Sadun, Alexander V Ljubimov, Lon S Schneider, Debra Hawes, Keith L Black, Dieu-Trang Fuchs, Maya Koronyo-Hamaoui","doi":"10.1186/s40478-025-01935-y","DOIUrl":"10.1186/s40478-025-01935-y","url":null,"abstract":"<p><p>Pathological tau isoforms, including hyperphosphorylated tau at serine 396 (pS396-tau) and tau oligomers (Oligo-tau), are elevated in the retinas of patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and AD dementia. These patients exhibit significant retinal ganglion cell (RGC) loss, however the presence of tau isoforms in RGCs and their impact on RGC integrity, particularly in early AD, have not been studied. Here, we analyzed retinal superior temporal cross-sections from 25 MCI or AD patients and 16 age- and sex-matched cognitively normal controls. Using the RGC marker ribonucleic acid binding protein with multiple splicing (RBPMS) and Nissl staining, we found a 46-56% reduction in RBPMS⁺ RGCs and Nissl⁺ neurons in the ganglion cell layer (GCL) of MCI and AD retinas (P < 0.05-0.001). RGC loss was accompanied by soma hypertrophy (10-50% enlargement, P < 0.05-0.0001), nuclear displacement, apoptosis (30-50% increase, P < 0.05-0.01), and prominent expression of granulovacuolar degeneration (GVD) bodies and GVD-necroptotic markers. Both pS396-tau and Oligo-tau were identified in RGCs, including in hypertrophic cells. PS396-tau⁺ and Oligo-tau⁺ RGC counts were significantly increased by 2.1-3.5-fold in MCI and AD retinas versus control retinas (P < 0.05-0.0001). Tauopathy-laden RGCs strongly inter-correlated (r_P=0.85, P < 0.0001) and retinal tauopathy associated with RGC reduction (r_P=-0.40-(-0.64), P < 0.05-0.01). Their abundance correlated with brain pathology and cognitive deficits, with higher tauopathy-laden RGCs in patients with Braak stages (V-VI), clinical dementia ratings (CDR = 3), and mini-mental state examination (MMSE ≤   26) scores. PS396-tau⁺ RGCs in the central and mid-periphery showed the closest associations with disease status, while Oligo-tau⁺ RGCs in the mid-periphery exhibited the strongest correlations with brain pathology (NFTs, Braak stages, ABC scores; r_S=0.78-0.81, P < 0.001-0.0001) and cognitive decline (MMSE; r_S=-0.79, P = 0.0019). Overall, these findings identify a link between pathogenic tau in RGCs and RGC degeneration in AD, involving apoptotic and GVD-necroptotic cell death pathways. Future research should validate these results in larger and more diverse cohorts and develop RGC tauopathy as a potential noninvasive biomarker for early detection and monitoring of AD progression.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"31"},"PeriodicalIF":6.2,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blood biomarker fingerprints in a cohort of patients with CHRNE-related congenital myasthenic syndrome.","authors":"Adela Della Marina, Andrie Koutsoulidou, Daniel Natera-de Benito, Lars-Oliver Tykocinski, Marios Tomazou, Kristia Georgiou, Andreas Laner, Heike Kölbel, Andres Nascimento, Carlos Ortez, Angela Abicht, Basant Kumar Thakur, Hanns Lochmüller, Leonidas A Phylactou, Tobias Ruck, Ulrike Schara-Schmidt, Dipali Kale, Andreas Hentschel, Andreas Roos","doi":"10.1186/s40478-025-01946-9","DOIUrl":"10.1186/s40478-025-01946-9","url":null,"abstract":"<p><p>Mutations in CHRNE encoding the epsilon subunit of acetylcholine receptor result in impaired neuromuscular transmission and congenital myasthenic syndrome (CMS) with variying severity of symptoms. Although the pathophysiology is well-known, blood biomarker signatures enabling a patient-stratification are lacking. This retrospective two-center-study includes 19 recessive CHRNE-patients (AChR deficiency; mean age 14.8 years) from 13 families which were clinically characterized according to disease severity. 15 patients were classified as mildly and 4 patients as moderate to severely affected. Seven known pathogenic and one unreported variant (c.1032 + 2_1032 + 3delinsGT) were identified. Biomarker discovery was carried out on blood samples: proteomics was performed on white blood cells (WBC; n = 12) and on extracellular vesicles (EV) purified from serum samples (n = 7) in addition to amino acid profiling (n = 9) and miRNA screening (n = 18). For miRNA studies, 7 patients with other CMS-subtypes were moreover included. WBC-proteomics unveiled a significant increase of 7 and a decrease of 36 proteins. In silico studies of these proteins indicated affection of secretory granules and the extracellular space. Comparison across patients unveiled increase of two vesicular transport proteins (SCAMP2 and SNX2) in severely affected patients and indeed EV-proteomics revealed increase of 7 and decrease of 13 proteins. Three of these proteins (TARSH, ATRN & PLEC) are known to be important for synaptogenesis and synaptic function. Metabolomics showed decrease of seven amino acids/ amino acid metabolites (aspartic and glutamic acids, phosphoserine, amino adipate, citrulline, ornithine, and 1-methyhistidine). miRNA-profiling showed increase miR - 483 - 3p, miR-365a-3p, miR - 365b - 3p and miR-99a, and decrease of miR-4433b-3p, miR-6873-3p, miR-182-5p and let-7b-5p in CHRNE-patients whereas a comparison with other CMS subtypes showed increase of miR - 205 - 5p, miR - 10b - 5p, miR-125a-5p, miR-499-5p, miR-3120-5p and miR - 483 - 5p and decrease of miR - 1290. Our combined data introduce a molecular fingerprint on protein, metabolic and miRNA level with some of those playing different roles along the neuromuscular axis.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"29"},"PeriodicalIF":6.2,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}