Acta Neuropathologica最新文献

{"title":"Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease","authors":"Clíona Farrell,&nbsp;Yazead Buhidma,&nbsp;Paige Mumford,&nbsp;Wendy E. Heywood,&nbsp;Jenny Hällqvist,&nbsp;Lisi Flores-Aguilar,&nbsp;Elizabeth J. Andrews,&nbsp;Negin Rahimzadah,&nbsp;Orjona Stella Taso,&nbsp;Eric Doran,&nbsp;Vivek Swarup,&nbsp;Elizabeth Head,&nbsp;Tammaryn Lashley,&nbsp;Kevin Mills,&nbsp;Christina E. Toomey,&nbsp;Frances K. Wiseman","doi":"10.1007/s00401-025-02889-0","DOIUrl":"10.1007/s00401-025-02889-0","url":null,"abstract":"<div><p>Trisomy of chromosome 21, the cause of Down syndrome (DS), is the most commonly occurring genetic cause of Alzheimer’s disease (AD). Here, we compare the frontal cortex proteome of people with Down syndrome–Alzheimer’s disease (DSAD) to demographically matched cases of early onset AD and healthy ageing controls. We find dysregulation of the proteome, beyond proteins encoded by chromosome 21, including an increase in the abundance of the key AD-associated protein, APOE, in people with DSAD compared to matched cases of AD. To understand the cell types that may contribute to changes in protein abundance, we undertook a matched single-nuclei RNA-sequencing study, which demonstrated that <i>APOE</i> expression was elevated in subtypes of astrocytes, endothelial cells, and pericytes in DSAD. We further investigate how trisomy 21 may cause increased APOE. Increased abundance of APOE may impact the development of, or response to, AD pathology in the brain of people with DSAD, altering disease mechanisms with clinical implications. Overall, these data highlight that trisomy 21 alters both the transcriptome and proteome of people with DS in the context of AD, and that these differences should be considered when selecting therapeutic strategies for this vulnerable group of individuals who have high risk of early onset dementia. </p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02889-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144084919","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":"Fyn-dependent Tau microcluster formation seeds and boosts extensive Tau pathology","authors":"Yingjie Li,&nbsp;Wending Qi,&nbsp;Le Chen,&nbsp;Fan Chu,&nbsp;Wenfeng Jiang,&nbsp;Zifeng Xu,&nbsp;Yuexin Luo,&nbsp;Xubo Hu,&nbsp;Jürgen Götz,&nbsp;Chuanzhou Li","doi":"10.1007/s00401-025-02887-2","DOIUrl":"10.1007/s00401-025-02887-2","url":null,"abstract":"<div><p>Tau seeding and propagation are defining features of all tauopathies, including Alzheimer’s disease, but the underlying molecular drivers remain incompletely understood. Here, we reveal that Fyn expression boosts massive Tau pathology in the mouse brain and enhances Tau seeding induced by pathological Tau seeds in biosensor cells. However, even in the absence of seeds, Fyn itself, via its palmitoylation, triggers the de novo formation of small, plasma membrane-anchored Tau microclusters, which initiate pronounced and diverse intra- and transcellular Tau seeding in vitro and in vivo. Mechanistically, membrane-associated Fyn phosphorylates Tau at its Tyr310 epitope and then recruits and activates GSK3β locally, which further phosphorylates Tau at Ser/Thr sites in the microclusters, eliciting their full seeding capacity. Our data suggest that Fyn not only serves as a master switch that initiates Tau pathogenesis on its own, but also augments a pre-existing Tau pathology, leading to a vicious cycle of Tau aggregation.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143944331","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":"Multiplatform molecular analyses reveal two molecular subgroups of NF2-related schwannomatosis vestibular schwannomas with distinct tumour microenvironment and therapeutic vulnerabilities","authors":"Fu Zhao,&nbsp;Xu-Fei Teng,&nbsp;Jing Zhang,&nbsp;Shi-Wei Li,&nbsp;Lei-Ming Wang,&nbsp;Han-Guang Zhao,&nbsp;Shun Zhang,&nbsp;Chi Zhao,&nbsp;Peng Li,&nbsp;Xiao-Bin Zhao,&nbsp;Shu-Hui Song,&nbsp;Pi-Nan Liu","doi":"10.1007/s00401-025-02883-6","DOIUrl":"10.1007/s00401-025-02883-6","url":null,"abstract":"<div><p><i>NF2</i>-related schwannomatosis (<i>NF2</i>-SWN) is a genetic predisposition syndrome characterized by the development of bilateral vestibular schwannomas (VSs). Despite their benign nature and consistent histopathological characteristics, these tumours display significant clinical and therapeutic heterogeneity. To elucidate the molecular heterogeneity within <i>NF2</i>-SWN schwannomas, we performed comprehensive molecular analyses on a cohort of 70 patients with <i>NF2</i>-SWN, including bulk RNA sequencing, whole genome or exome sequencing, single nuclear RNA (snRNA) sequencing and immunohistochemistry. Our analysis identified two distinct molecular subgroups: immune-enriched schwannomas (IESs) and immune-depleted schwannomas (IDSs). IESs were commonly diagnosed in adulthood, followed a favorable prognosis, and were characterized by abundant macrophage infiltration within the tumour microenvironment. In contrast, IDSs were predominantly composed of Schwann cells, harbored germline <i>NF2</i> mutations, occurred primarily during childhood and had poorer outcomes. Immunohistochemical staining for ionized calcium-binding adaptor molecule 1 (Iba1) and CD68, CD163 antibodies effectively differentiated these two subgroups of <i>NF2</i>-SWN schwannomas. Furthermore, we demonstrated that blockade of the colony stimulating factor 1 receptor (CSF1R) resulted in macrophage depletion and significantly suppressed tumour growth in both in vitro and in vivo models of IESs. Collectively, our study reveals two discrete molecular subgroups within <i>NF2</i>-SWN schwannomas, highlighting the importance of considering these subgroups in future therapeutic research and clinical trial design.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143925626","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":"Oligodendroglia vulnerability in the human dorsal striatum in Parkinson’s disease","authors":"Juan M. Barba-Reyes,&nbsp;Lisbeth Harder,&nbsp;Sergio Marco Salas,&nbsp;Methasit Jaisa-aad,&nbsp;Clara Muñoz-Castro,&nbsp;Leonardo D. Garma,&nbsp;Nima Rafati,&nbsp;Mats Nilsson,&nbsp;Bradley T. Hyman,&nbsp;Alberto Serrano-Pozo,&nbsp;Ana B. Muñoz-Manchado","doi":"10.1007/s00401-025-02884-5","DOIUrl":"10.1007/s00401-025-02884-5","url":null,"abstract":"<div><p>Oligodendroglia are the responsible cells for myelination in the central nervous system and their involvement in Parkinson’s disease (PD) is poorly understood. We performed sn-RNA-seq and image-based spatial transcriptomics of human caudate nucleus and putamen (dorsal striatum) from PD and control brain donors to elucidate the diversity of oligodendroglia and how they are affected by the disease. We profiled a total of ~ 200.000 oligodendroglial nuclei, defining 15 subclasses, from precursor to mature cells, 4 of which are disease-associated. These PD-specific populations are characterized by the overexpression of heat shock proteins, as well as distinct expression signatures related to immune responses, myelination alterations, and disrupted cell signaling pathways. We have also identified impairments in cell communication and oligodendrocyte development, evidenced by changes in neurotransmitter receptors expression and cell adhesion molecules. In addition, we observed significant disruptions in oligodendrocyte development, with aberrant differentiation trajectories and shifts in cell proportions, particularly in the transition from mature oligodendrocytes to disease-associated states. Quantitative immunohistochemical analysis revealed decreased myelin levels in the PD striatum, which correlated with transcriptomic alterations. Furthermore, spatial transcriptomics mapping revealed the distinct localization of disease-associated populations within the striatum, with evidence of impaired myelin integrity. Thus, we uncover oligodendroglia as a critical cell type in PD and a potential new therapeutic target for myelin-based interventions.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02884-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143908791","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":"DNA methylation identifies body segment origins of spinal ependymomas","authors":"Erika Yamazawa,&nbsp;Shota Tanaka,&nbsp;Genta Nagae,&nbsp;Takayoshi Umeda,&nbsp;Kenji Tatsuno,&nbsp;Taijun Hana,&nbsp;Phyo Kim,&nbsp;Toshihiro Takami,&nbsp;Keisuke Takai,&nbsp;Takashi Komori,&nbsp;Ryohei Otani,&nbsp;Fumi Higuchi,&nbsp;Hirokazu Takami,&nbsp;Keisuke Yamada,&nbsp;Masashi Nomura,&nbsp;Akitake Mukasa,&nbsp;Shunsaku Takayanagi,&nbsp;Hideaki Imai,&nbsp;Hiroyuki Aburatani,&nbsp;Nobuhito Saito","doi":"10.1007/s00401-025-02885-4","DOIUrl":"10.1007/s00401-025-02885-4","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143902748","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":"The interactome of tau phosphorylated at T217 in Alzheimer’s disease human brain tissue","authors":"Tomas Kavanagh,&nbsp;Manon Thierry,&nbsp;Kaleah Balcomb,&nbsp;Jackeline Ponce,&nbsp;Evgeny Kanshin,&nbsp;Alexander Tapia-Sealey,&nbsp;Glenda Halliday,&nbsp;Beatrix Ueberheide,&nbsp;Thomas Wisniewski,&nbsp;Eleanor Drummond","doi":"10.1007/s00401-025-02881-8","DOIUrl":"10.1007/s00401-025-02881-8","url":null,"abstract":"<div><p>Hyperphosphorylated tau (pTau) in Alzheimer’s disease (AD) brain tissue is a complex mix of multiple tau species that are variably phosphorylated. The emerging studies suggest that phosphorylation of specific residues may alter the role of tau. The role of specific pTau species can be explored through protein interactome studies. The aim of this study was to analyse the interactome of tau phosphorylated at T217 (pT217), which biomarker studies suggest is one of the earliest accumulating tau species in AD. pT217 interactors were identified in fresh-frozen human brain tissue from 10 cases of advanced AD using affinity purification-mass spectrometry. The cases included a balanced cohort of <i>APOE</i> ε3/ε3 and ε4/ε4 genotypes (<i>n</i> = 5 each) to explore how apolipoprotein E altered phosphorylated tau interactions. The results were compared to our previous interactome dataset that profiled the interactors of PHF1-enriched tau to determine if individual pTau species have different interactomes. 23 proteins were identified as <i>bona fide</i> pT217 interactors, including known pTau interactor SQSTM1. pT217 enriched tau was phosphorylated at fewer residues compared to PHF1-enriched tau, suggesting an earlier stage of pathology development. Notable pT217 interactors included five subunits of the CTLH E3 ubiquitin ligase (WDR26, ARMC8, GID8, RANBP9, MAEA), which has not previously been linked to AD. In <i>APOE</i> ε3/ε3 cases pT217 significantly interacted with 46 proteins compared to 28 in <i>APOE</i> ε4/ε4 cases, but these proteins were significantly overlapped. CTLH E3 ubiquitin ligase subunits significantly interacted with phosphorylated tau in both <i>APOE</i> genotypes. pT217 interactions with SQSTM1, WDR26 and RANBP9 were validated using co-immunoprecipitation and immunofluorescent microscopy of post-mortem human brain tissue, which showed colocalisation of both protein interactors with tau pathology. Our results report the interactome of pT217 in human Alzheimer’s disease brain tissue for the first time and highlight the CTLH E3 ubiquitin ligase complex as a significant novel interactor of pT217 tau.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02881-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143900828","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":"Abundant non-inclusion α-synuclein pathology in Lewy body-negative LRRK2-mutant cases","authors":"Nanna Møller Jensen,&nbsp;Zagorka Vitic,&nbsp;Mia R. Antorini,&nbsp;Tobias Bruun Viftrup,&nbsp;Laura Parkkinen,&nbsp;Poul Henning Jensen","doi":"10.1007/s00401-025-02871-w","DOIUrl":"10.1007/s00401-025-02871-w","url":null,"abstract":"<div><p>Lewy body diseases are common neurodegenerative diseases, including Parkinson’s disease (PD) and dementia with Lewy bodies, which lead to both motor and non-motor symptoms. They are neuropathologically characterized by loss of neuromelanized neurons in the substantia nigra pars compacta and α-synuclein-immunopositive inclusions (Lewy bodies) in several types of neurons in the brain. A fraction of monogenic PD cases, however, represent a conundrum, as they can present with clinical Lewy body disease but do not have Lewy bodies upon neuropathological examination. For LRRK2, the presence or absence of Lewy bodies is not related to any specific mutation in the gene and different clinical presentation and neuropathology can be present even in the same family. Here, we present the first evidence of widespread α-synuclein accumulation detected with proximity ligation assay (PLA) using the MJFR14-6-4-2 antibody in six Lewy body-negative LRRK2 cases and compare the levels with five patients with neuropathologically verified Lewy body disease and six healthy controls. We show that non-inclusion aggregated α-synuclein in the form of particulate PLA signal is dominant in the LRRK2 cases, while both Lewy-like and particulate PLA signal is found in late-stage Lewy body disease. Furthermore, LRRK2 cases displayed prominent particulate PLA signal in pontocerebellar tracts and inferior olivary nuclei in the brainstem, which was not seen in idiopathic Lewy body disease cases. These results suggest that Lewy-body negative LRRK2-related PD is not associated with a lack of α-synuclein aggregation in neurons but rather a deficiency in the formation of inclusions.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02871-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143896665","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":"LRRK2-associated Parkinson’s disease does have alpha-synuclein pathology","authors":"Nicolas Dzamko","doi":"10.1007/s00401-025-02874-7","DOIUrl":"10.1007/s00401-025-02874-7","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143896695","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":"Widespread distribution of α-synuclein oligomers in LRRK2-related Parkinson’s disease","authors":"Hiroaki Sekiya,&nbsp;Lukas Franke,&nbsp;Yuki Hashimoto,&nbsp;Mariko Takata,&nbsp;Katsuya Nishida,&nbsp;Naonobu Futamura,&nbsp;Kazuko Hasegawa,&nbsp;Hisatomo Kowa,&nbsp;Owen A. Ross,&nbsp;Pamela J. McLean,&nbsp;Tatsushi Toda,&nbsp;Zbigniew K. Wszolek,&nbsp;Dennis W. Dickson","doi":"10.1007/s00401-025-02872-9","DOIUrl":"10.1007/s00401-025-02872-9","url":null,"abstract":"<div><p>Mutations in leucine-rich repeat kinase 2 (<i>LRRK2</i>) are the most common cause of familial and sporadic Parkinson’s disease (PD). While the clinical features of patients with <i>LRRK2</i>-PD resemble those of typical PD, there are significant differences in the pathological findings. The pathological hallmark of definite PD is the presence of α-synuclein (αSYN)-positive Lewy-related pathology; however, approximately half of patients with <i>LRRK2</i>-PD do not have Lewy-related pathology. Lewy-related pathology is a late-stage αSYN aggregation that can be visualized with hematoxylin and eosin stains or conventional immunohistochemistry (IHC). Increasing evidence has indicated that αSYN oligomers, which represent the early-stage of αSYN aggregation, may have neurotoxicity. Visualization of αSYN oligomers requires specialized staining techniques, such as αSYN-proximity ligation assay (PLA). Distribution and severity of αSYN oligomers in the brain of patients with <i>LRRK2</i>-PD remain unknown. In this study, we performed phosphorylated αSYN-IHC and αSYN-PLA staining on postmortem brain sections of patients with three pathogenic LRRK2 mutants: p.G2019S (<i>n</i> = 5), p.I2020T (<i>n</i> = 5), and p.R1441C (<i>n</i> = 4). The severity of Lewy-related pathology and αSYN oligomers was assessed semi-quantitatively in the brainstem, limbic lobe, basal ganglia, and cerebral cortex. αSYN oligomers were detected in patients with <i>LRRK2</i>-PD even in those without Lewy-related pathology; a negative correlation was observed between Lewy-related pathology and αSYN oligomers (<i>r</i> = − 0.26 [− 0.39, − 0.12]; <i>P</i> &lt; 0.0001). Our findings suggest that αSYN oligomers may represent a common pathological feature of <i>LRRK2</i>-PD. Notably, patients harboring p.G2019S and p.I2020T had significantly higher levels of αSYN oligomers in those without Lewy-related pathology compared to those with Lewy-related pathology. These patients also had a trend toward shorter disease duration. These results imply that in <i>LRRK2</i>-PD, αSYN oligomers may initially accumulate in the brain but do not progress to form Lewy-related pathology. The present study suggests that targeting αSYN oligomers may be a therapeutic strategy for <i>LRRK2</i>-PD even if there is no Lewy-related pathology.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143896660","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":"CAA proteomics meta-analysis reveals novel targets, key players, and the effects of sex, APOE, and brain region in humans","authors":"Curran Varma,&nbsp;Cynthia A. Lemere","doi":"10.1007/s00401-025-02886-3","DOIUrl":"10.1007/s00401-025-02886-3","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02886-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884695","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}