Acta Neuropathologica最新文献

{"title":"Loss of the lysosomal lipid flippase ATP10B leads to progressive dopaminergic neurodegeneration and parkinsonian motor deficits.","authors":"María Sanchiz-Calvo, Elena Coccia, Christopher Cawthorne, Gustavo Morrone Parfitt, Teresa Torre-Muruzabal, George Tsafaras, Koen Van Laere, Diego Cabezudo, Ana Cascalho, Chris Van den Haute, Peter Vangheluwe, Joel Blanchard, Eduard Bentea, Veerle Baekelandt","doi":"10.1007/s00401-025-02908-0","DOIUrl":"10.1007/s00401-025-02908-0","url":null,"abstract":"<p><p>ATP10B, a transmembrane lipid flippase located in late endosomes and lysosomes, facilitates the export of glucosylceramide and phosphatidylcholine by coupling this process to ATP hydrolysis. Recently, loss-of-function mutations in the ATP10B gene have been identified in Parkinson's disease patients, pointing to ATP10B as a candidate genetic risk factor. Previous studies have shown compromised lysosomal functionality upon ATP10B knockdown in human cell lines and primary cortical neurons. To investigate the role of ATP10B in Parkinson's disease neuropathology, specifically in the nigrostriatal dopaminergic system, we induced ATP10B knockdown specifically in substantia nigra pars compacta neurons of rats using viral vector technology. Additionally, midbrain neuronal cultures derived from ATP10B knock-out human induced pluripotent stem cells clones were used to study the impact of ATP10B loss in dopaminergic neurons in a more translational model. Atp10b knockdown in rat brain induced parkinsonian motor deficits, and longitudinal striatal dopamine transporter ¹⁸F-FE-PE2I PET imaging revealed a progressive decrease in binding potential. Immunohistochemical analysis conducted one year post-injection confirmed the loss of dopaminergic terminals in the striatum, alongside a loss of dopaminergic neurons in the substantia nigra pars compacta. The expression of LAMP1, LAMP2a, cathepsin B and glucocerebrosidase was studied in dopaminergic neurons. A decrease in lysosomal numbers and an increase in lysosomal volume were observed more consistently in one of the knockdown constructs. The vulnerability of dopaminergic neurons to ATP10B loss-of-function was also observed in midbrain neuronal cultures derived from ATP10B knock-out human induced pluripotent stem cells clones, which showed a significant reduction in TH-positive neurons. Taken together, our findings demonstrate that ATP10B depletion detrimentally impacts the viability of dopaminergic neurons both in vivo and in vitro. Moreover, a broader impact on the functionality of the nigrostriatal pathway was evidenced as rats with Atp10b knockdown exhibited motor impairments similar to those observed in Parkinson's disease patients.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":"5"},"PeriodicalIF":9.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12271281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658073","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":"Amyloid-β plaque-associated microglia drive TSPO upregulation in Alzheimer's disease.","authors":"Daniel A Martinez-Perez,Jennifer L McGlothan,Alexander N Rodichkin,Karam Abilmouna,Zoran Bursac,Francisco Lopera,Carlos Andres Villegas-Lanau,Tomás R Guilarte","doi":"10.1007/s00401-025-02912-4","DOIUrl":"https://doi.org/10.1007/s00401-025-02912-4","url":null,"abstract":"Translocator protein 18 kDA (TSPO) imaging using positron emission tomography (PET) is widely used to assess neuroinflammation in Alzheimer's disease (AD). However, the significance of the increase in brain TSPO levels in AD pathophysiology is not known. Here, we show that in the 5XFAD transgenic mouse model, brain TSPO levels increase in an age-, brain region-, and sex-dependent fashion. TSPO levels were first increased in the subiculum at 1.5 months of age in male and female 5XFAD mice compared to wildtype mice. The TSPO increase in the subiculum of 1.5-month 5XFAD mice coincided with the appearance of Aβ aggregation and increased serum Aβ1-42/Aβ1-40 ratio which occurred prior to increased serum neurofilament light chain (Nfl) levels and well before cognitive function deficits. We also discovered that the brain TSPO increase was driven by an expansion of activated microglia in contact with Aβ-plaques, that also expressed higher TSPO levels per microglia than microglia not in contact with plaques. While overall, astrocytes were highly activated, the increased TSPO signal in the 5XFAD mouse brain did not increase in astrocytes. We also compared the 5XFAD mouse findings to postmortem human brain tissue from early-onset autosomal-dominant Presenilin 1 (PSEN1)-E280A mutation AD cases. The results in PSEN1-E280A cases confirmed the 5XFAD mouse findings relevant to increased TSPO levels and an increase in TSPO per microglia contacting Aβ-plaques. In summary, TSPO is an early biomarker of neuroinflammation in the AD brain that first increases in the subiculum simultaneously with increased Aβ aggregation and serum Aβ1-42/Aβ1-40 ratio. The increased TSPO response in the 5XFAD mouse brain and in the brain from PSEN1-E280A mutation AD cases reflects Aβ-plaque-associated microglia with a high TSPO content. This microglia subtype is likely to promote the progression of AD pathology, neurodegeneration, and cognitive decline and their high TSPO content may serve as a target for TSPO ligand-based therapy.","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"10 1","pages":"6"},"PeriodicalIF":12.7,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652840","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":"Primary papillary epithelial tumor of the sella harboring an EZH2 Y646F mutation.","authors":"Jawad Fares,Pouya Jamshidi,Harrshavasan T Congivaram,Daniel Oyon,Melissa Mejia Bautista,Robert C Kern,Daniel J Brat,Mark W Youngblood,James P Chandler","doi":"10.1007/s00401-025-02910-6","DOIUrl":"https://doi.org/10.1007/s00401-025-02910-6","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"36 1","pages":"4"},"PeriodicalIF":12.7,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639731","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":"Lipid mediated formation of antiparallel aggregates in cerebral amyloid angiopathy.","authors":"Ana Pacheco de Oliveira, Divya Baghel, Brooke Holcombe, William Chase, Tyler Ward, Shih-Hsiu J Wang, Ayanjeet Ghosh","doi":"10.1007/s00401-025-02911-5","DOIUrl":"10.1007/s00401-025-02911-5","url":null,"abstract":"<p><p>Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder marked by amyloid-β (Aβ) deposition in blood vessel walls, leading to hemorrhage and recurring stroke. Despite significant overlap with Alzheimer's disease (AD) through shared Aβ pathology, the specific structural characteristics of Aβ aggregates in CAA and their variations between stages of disease severity are yet to be fully understood. Traditional approaches relying on brain-derived fibrils can potentially overlook the polymorphic heterogeneity and chemical associations within vascular amyloids. This study utilizes sub-diffraction, label-free optical photothermal infrared (O-PTIR) spectroscopic imaging to directly probe the chemical structure and heterogeneity of vascular amyloid aggregates within human brain tissues across different CAA stages. Our results demonstrate a clear increase in β-sheet content within vascular Aβ deposits corresponding to disease progression. Crucially, we identify a significant presence of antiparallel β-sheet structures, particularly prevalent in moderate/severe CAA. The abundance of antiparallel structures correlates strongly with co-localized lipids, implicating a lipid-mediated aggregation mechanism. We substantiate the ex-vivo observations using nanoscale AFM-IR spectroscopy and demonstrate that Aβ40 aggregated in-vitro with brain-derived lipids adopts antiparallel structural distributions mirroring those found in CAA vascular lesions. This work provides critical insights into the structural distributions of Aβ aggregates in CAA, highlighting the presence of polymorphs typically associated with transient intermediates, which may lead to alternate mechanisms for neurotoxicity.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":"3"},"PeriodicalIF":9.3,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615780","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":"Subclinical detection of misfolded alpha-synuclein in the blood of M83 mice.","authors":"Lilian Bruyère-Ostells,Jérémy Verchère,Dominique Bétemps,Florian Almela,Thierry Baron,Daisy Bougard","doi":"10.1007/s00401-025-02909-z","DOIUrl":"https://doi.org/10.1007/s00401-025-02909-z","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"107 1","pages":"2"},"PeriodicalIF":12.7,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594100","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":"Oligosarcoma uniformly exhibits a HOX gene family hypermethylation signature.","authors":"Vinny Ha,Nicholas Nuechterlein,Mia Rivers,Drew Pratt,Patrick J Cimino","doi":"10.1007/s00401-025-02905-3","DOIUrl":"https://doi.org/10.1007/s00401-025-02905-3","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"2 1","pages":"1"},"PeriodicalIF":12.7,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533515","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":"CNS methylation classifiers may misclassify normal developing cerebellar cortex as medulloblastoma.","authors":"Jennifer A Cotter,Alexander L Markowitz,Everardo Castañeda,Chern-Yu Yen,Dejerianne Ostrow,Debra Hawes,Jianling Ji","doi":"10.1007/s00401-025-02907-1","DOIUrl":"https://doi.org/10.1007/s00401-025-02907-1","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"52 1","pages":"66"},"PeriodicalIF":12.7,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370311","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":"Transient receptor potential vanilloid channel 2 contributes to multi-modal endoplasmic reticulum and perinuclear space dilations that can also be observed in prion-infected mice.","authors":"Wenda Zhao, Shehab Eid, Chris Sackmann, Declan Williams, Xinzhu Wang, Yunqing Ouyang, Thomas Zerbes, Gerold Schmitt-Ulms","doi":"10.1007/s00401-025-02906-2","DOIUrl":"10.1007/s00401-025-02906-2","url":null,"abstract":"<p><p>Our recent work on the prion protein and Na⁺, K⁺-ATPases (NKAs) led us to revisit data from over 50 years ago, which suggested similarities between vacuolation phenotypes in rodents poisoned with cardiac glycosides (CGs) and spongiform degeneration in prion disease. At that time, this hypothesis was dismissed because the vacuolation observed in prion diseases affects neurons, whereas CG poisoning in rodent brains led to swellings of the endoplasmic reticulum (ER) in astrocytes. We speculated that this difference might be specific to rodents and document here that the vacuolation shifts to neurons in mice expressing a humanized NKA α1 subunit. Next, we investigated the molecular mechanisms that could cause similar ER vacuolation in human cells in vitro. We found that certain stressors-such as overexpression of NKA α subunits and exposure to specific toxins known to trigger the unfolded protein response-can induce a phenotype characterized by profound ER dilation that is most strikingly observed for the perinuclear space (PNS). The ion imbalance typically caused by functional NKAs does not contribute to this phenotype. In fact, it can occur even with the overexpression of catalytically inactive NKAs. Several lines of evidence, generated with pharmacological agents, ion-specific dyes, antagonists, and truncated expression constructs, suggest that a calcium leak channel in the ER, known as transient receptor potential vanilloid 2 (TRPV2), plays a role in this ER and PNS dilation. Additionally, we observed that the formation of these vacuoles coincides with a decrease in steady-state levels of the lipid kinase PIKFYVE, which is recognized for its role in endolysosomal fission and fusion processes. Finally, we found evidence of vacuoles in cryosectioned brains of prion-infected mice that can be filled with a fluorescent marker targeted at the ER and PNS. This raises the possibility that this vacuolation phenomenon contributes to spongiform degeneration seen in prion diseases.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":"68"},"PeriodicalIF":9.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473719","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":"Quantification of Lewy body pathology by cerebrospinal fluid endpoint dilution RT-QuIC in a neuropathological autopsy cohort of clinically heterogeneous participants.","authors":"Andrea Mastrangelo,Serena Caldera,Sophie E Mastenbroek,Erica Vittoriosi,Shorena Janelidze,Geidy E Serrano,Alireza Atri,Holly Shill,Erika Driver-Dunckley,Shyamal Mehta,Charles H Adler,Angela Mammana,Franco Magliocchetti,Simone Baiardi,Thomas G Beach,Oskar Hansson,Piero Parchi","doi":"10.1007/s00401-025-02904-4","DOIUrl":"https://doi.org/10.1007/s00401-025-02904-4","url":null,"abstract":"The identification of biomarkers predicting the burden of brain alpha-synuclein (α-syn) pathology in vivo represents a research priority in Lewy body disease (LBD). Recently, some kinetic parameters of seed amplification assays (SAAs) for α-syn showed associations with measures of clinical progression. However, preanalytical and analytical factors significantly affect these parameters, reducing reproducibility. The Endpoint Dilution (ED) SAA Real-time Quaking-induced Conversion (RT-QuIC) is emerging as an alternative, more accurate tool for seed quantification. Still, the approach needs validation in large patient cohorts. We applied the ED RT-QuIC to postmortem ventricular cerebrospinal fluid (CSF) samples from 357 brain donors, including 168 who showed LBD at neuropathologic examination. We estimated the seeding dose, yielding positive responses in 50% of replicate reactions (SD50), using the midSIN algorithm and correlated these values with postmortem synuclein pathology burden and clinical severity measures. LBD was staged through the Unified Staging System for Lewy Body Disorders and the Lewy pathology consensus criteria. The SD50 values (expressed in log10SD/ml) differed significantly among participants at different LBD stages (p < 0.0001), with those at a neocortical stage demonstrating higher values than those at a brainstem-predominant stage (p < 0.0001). The SD50 values were significantly associated with the LBD load evaluated through immunohistochemistry (Rho = 0.62, p < 0.0001). Participants showing higher SD50 values performed worse at the last available scores on clinical scales evaluating motor (Rho = 0.33, p < 0.0001) and olfactory functions (Rho = - 0.33, p < 0.0001). The SD50 scores accurately distinguished neocortical LBD participants from those at lower stages (area under the curve, 0.86; 95% confidence interval, 0.79-0.92). The CSF ED RT-QuIC measure of α-syn seeds correlated significantly with LBD burden and clinical severity scores. These findings validate the CSF ED RT-QuIC as a quantitative assay for misfolded brain α-syn in LBD. This novel approach may be clinically applied to identify individuals at different stages of LBD pathology in research settings.","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"19 1","pages":"67"},"PeriodicalIF":12.7,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370316","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 olfactory epithelium: a critical gateway for pathological tau propagation and a target for mitigating tauopathy in the central nervous system.","authors":"Marion Dourte,Esther Paître,Mongia Bouchoucha,Emilien Boyer,Sandra O Tomé,Emilie Doeraene,Caroline Huart,Karelle Leroy,Dietmar Rudolf Thal,Anabelle Decottignies,Bernard Hanseeuw,Nuria Suelves,Pascal Kienlen-Campard","doi":"10.1007/s00401-025-02902-6","DOIUrl":"https://doi.org/10.1007/s00401-025-02902-6","url":null,"abstract":"Olfactory impairment is a recognized early indicator of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD). Intracellular aggregates of hyperphosphorylated tau protein, referred to as neurofibrillary tangles (NFTs), are a hallmark of AD. NFTs are found in the olfactory bulb (OB) and entorhinal cortex (EC), both crucial for processing olfactory information. We explored the hypothesis that typical tau lesions could appear early and progress along olfactory regions to reach connected areas critically affected in AD (e.g., EC and hippocampal formation). To that end, we used transgenic PS19 mice expressing mutated human tau protein (1N4R isoform, P301S mutation). They recapitulate major phenotypes of AD, such as accumulation of NFTs, synaptic dysfunction, cognitive impairment, and neuronal loss. The presence of pathological hyperphosphorylated human tau protein (pTau) was monitored in olfactory regions: olfactory epithelium (OE), OB, piriform cortex (PC), and in connected regions of the hippocampal formation (hippocampus and EC). pTau was detected in the OE's middle stratum and in the OB's olfactory nerve layer (ONL) at 1.5 months. At 6 months of age, tau accumulations were found in the PC and EC, along with the CA3 region and dentate gyrus of the hippocampus. We found that olfactory function remained unaffected in PS19 mice, despite the presence of tau pathology in key regions of the olfactory system. Targeted treatments (ZnSO4 and AAVs) were applied at the OE level to assess the impact on tau pathology in the CNS. Complete stripping of the OE by intranasal administration of ZnSO4 led to a significant reduction in pretangle-like tau pathology within the PC, amygdala, and EC of 6-month-old PS19 mice. Finally, we observed in human postmortem samples that pTau signal was present in the olfactory regions (OE and OB) of patients at early Braak stages (I/II). Based on these observations, we propose that pTau could appear, due to aging or environmental agents, in the OE and subsequently spread in a prion-like manner to the hippocampal formation along neuroanatomical connections. These findings also indicate the interest of the OE as a target for intervention aimed at mitigating the progression of tauopathy in the CNS.","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"319 1","pages":"64"},"PeriodicalIF":12.7,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}