Acta Neuropathologica Communications最新文献

{"title":"PIT-1/SF-1-positive pituitary tumors in patients with acromegaly: transcriptomic perspective.","authors":"Julia Rymuza, Qilin Zhang, Mateusz Bujko","doi":"10.1186/s40478-025-02091-z","DOIUrl":"10.1186/s40478-025-02091-z","url":null,"abstract":"<p><p>Neuroendocrine pituitary tumors (PitNETs) are classified based on clinical manifestation and expression of pituitary cell lineage-specific transcription factors (TFs) and hormones. A subtype of tumors in patients with acromegaly was found to express PIT-1 and SF-1 TFs, two markers of distinct pituitary cell lineages. These tumors have been described as multilineage or \"somatogonadotoph\" tumors. The aim of our study was to clarify their identity and cell type origin using extensive transcriptomic analysis. For this purpose, we analyzed the RNA sequencing (RNAseq) data from 546 PitNETs (including 193 tumors of patient with acromegaly) and single cell RNAseq data from somatotroph and gonadotroph tumors and normal pituitary tissue. Somatrotroph PitNETs co-expressing PIT-1 and SF-1 TFs were identified in each of the analyzed RNAseq dataset. Their transcriptomic profile and pituitary TF activity closely resembled those of other somatotroph tumors, while differing substantially from gonadotroph PitNETs, though they retained NR5A1 (SF-1) activity and expressed some SF-1-regulated genes (e.g., LHB and GNHRH). Notably, SF-1 appeared to regulate a slightly different set of genes in double positive somatotroph PitNETs and gonadotroph tumors. Analysis of scRNAseq data revealed a subcluster of normal gonadotroph cells expressing POU1F1 (PIT-1), but tumor cells from PIT-1/SF-1 PitNETs did not resemble this normal gonadotroph cell subtype. Genes expression profiles of three subtypes of somatotroph tumors were distinguished through analyses of both bulk- and scRNAseq data. From transcriptomic perspective - based on gene co-regulation and pituitary TF activity - PitNETs of patients with acromegaly that co-express PIT-1 and SF-1 represent a subtype of PIT-1 lineage tumors, and the molecular data do not support classifying them as multilineage tumors.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"174"},"PeriodicalIF":5.7,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854164","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: Reciprocal regulation of GPNMB/HIF-1α for inhibition of neuronal ferroptosis in delayed encephalopathy after acute carbon monoxide poisoning.","authors":"Zuolong Liu, Lanyue Sun, Nan Gao, Wei Li, Li Pang","doi":"10.1186/s40478-025-02088-8","DOIUrl":"10.1186/s40478-025-02088-8","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"173"},"PeriodicalIF":5.7,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12345093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844006","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":"Variably protease-sensitive prionopathy: mass spectrometry analysis of the pathogenic prion protein provides a new perspective.","authors":"S K Nemani, X Xiao, S Notari, I Cali, K Lundberg, L Cracco, B S Appleby, W K Surewicz, V L Sim, P Gambetti","doi":"10.1186/s40478-025-02079-9","DOIUrl":"10.1186/s40478-025-02079-9","url":null,"abstract":"<p><p>Variably protease-sensitive prionopathy (VPSPr) is a rare and complex prion disease that differs from sporadic Creutzfeldt-Jakob disease (sCJD) in its clinical and histopathological phenotypes. VPSPr also features a variety of fragments generated by the disease-causing prion protein (PrP^D). However, accurately determining the number and sequence of these fragments has been challenging when relying solely on epitope mapping with existing antibodies. To address these challenges, we performed mass spectrometry analyses and designed epitope mapping experiments to determine the primary structure and verify the presence or absence of the anchor in the VPSPr proteinase K-resistant and deglycosylated PrP^D fragments. All three N-terminus fragments, with reported molecular weights of 20, 17, and 7 kDa, likely share Ser97 as the N-terminal amino acid. The C-terminus of the internal 7 kDa fragment is ragged, extending from Phe141 to Met154, while the 20 kDa and 17 kDa fragments differ only in the absence of the anchor in the latter. The three fragments belonging to the C-terminus group have previously been reported to have electrophoretic mobilities of 18, 12/13, and 8-9 kDa. After deglycosylation, the 18 kDa fragment was not detected. The 12 kDa component of the 12/13 kDa fragment was found to have a ragged N-terminus between Tyr162 and Asp181 and the anchor, while the 8 kDa fragment represented the anchorless version of the 12 kDa fragment. Unexpectedly, a second approximately 8 kDa fragment was identified that bore the anchor but had a shorter, ragged N-terminus ranging from Gly195 to Phe198. Calculation based on sequencing data revealed that the actual molecular masses of the 20, 17, and 12 kDa fragments are 1-2 kDa lighter. Moreover, the primary structures of the 20, 17, and 12 kDa fragments match those of the 19, 17, and 12 kDa fragments associated with sCJD type 2. Our findings provide new insights into the characteristics of the deglycosylated, PK-resistant fragments in VPSPr, which will likely assist in interpreting future high-resolution studies of amyloid fibrils in this disease.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"172"},"PeriodicalIF":5.7,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12345132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833688","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":"Cerebrovascular p16^INK4A expression induces cerebral small vessel disease-related phenotypes.","authors":"Keiji Kawatani, Tomonori Aikawa, Zeynab Tabrizi, Yining Pan, Yingxue Ren, Ni Wang, Aishe Kurti, Toshihiko Nambara, Clark C Ikezu, Francis Shue, Michael Bamkole, Yasuteru Inoue, Tammee M Parsons, Guojun Bu, Qianqian Song, Oliver Bracko, Takahisa Kanekiyo","doi":"10.1186/s40478-025-02085-x","DOIUrl":"10.1186/s40478-025-02085-x","url":null,"abstract":"<p><p>Cerebral small vessel disease (cSVD) is the most common cause of vascular cognitive impairment and dementia (VCID) and highly associated with Alzheimer's disease pathogenesis. There is an urgent need to establish relevant animal models for cSVD. As aging is the strongest risk factor for these diseases, cerebrovascular senescence is implicated in cSVD pathogenesis. We investigated how AAV-based expression of senescence marker CDKN2A/p16^INK4A in cerebrovascular endothelial cells influences cSVD phenotypes in adult wild-type mice. A single intraperitoneal injection of the AAV carrying CDKN2A/p16^INK4A caused blood-brain barrier impairments, neurovascular uncoupling, and reduction of cerebral blood flow, accompanied with behavioral changes in mice. While single cell RNA-sequencing and immunostaining revealed the upregulation of VCAM1 in cerebrovascular endothelial cells, in vivo two-photon excitation microscopy detected aggravated leukocyte adhesions to capillaries. Our findings demonstrate the contributions of p16^INK4A in cerebrovascular endothelial cells to cSVD and VCID pathogenesis through new mouse model.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"171"},"PeriodicalIF":5.7,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12345092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833687","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":"Challenging CDKN2A assessment in BRAF-altered gliomas: lessons from a pleomorphic xanthoastrocytoma-enriched cohort.","authors":"Thibaut Wolf, Damien Reita, Marlène Deschuyter, Chinar Salmanli, Julie Buffa, Erwan Pencreach, Eric Guérin, Eric Jeandidier, Marguerite Miguet, Marie-Pierre Chenard, Lucas Geyer, Georges Noel, Julien Todeschi, Guillaume Gauchotte, Sophie Martin, Natacha Entz-Werlé, Benoît Lhermitte","doi":"10.1186/s40478-025-02089-7","DOIUrl":"10.1186/s40478-025-02089-7","url":null,"abstract":"<p><p>Detecting homozygous deletion (HD) of CDKN2A is critical in BRAF-altered gliomas, as this molecular alteration has both diagnostic and prognostic significance. It is predominantly associated with BRAF-altered high-grade gliomas and has been associated with poorer prognosis in certain BRAF-altered low-grade glioma tumor types. The 2021 WHO classification of central nervous system tumors therefore recommends screening for this alteration in most BRAF-altered gliomas, but it does not recommend one specific technique over another. Here, we compare the performance of several detection methods, including p16 immunohistochemistry, fluorescence in situ hybridization (FISH), droplet digital PCR, next-generation sequencing and DNA methylation profiling-derived copy-number variation (CNV) analysis, in a retrospective cohort of 25 BRAF-altered gliomas. Ten cases showed diffuse p16 immunohistochemical expression (10/25) with no associated CDKN2A HD, whereas 15 cases had complete absence of p16 expression (15/25). In the latter group, a high level of discrepancy in CDKN2A HD detection when considering FISH versus other techniques was observed, suggesting a high false-negative rate with FISH. Using an original bioinformatic pipeline leveraging genome alignment of routinely available CNV raw data, we identified among most false-negative cases (4/5) a large and undeleted region encompassing MTAP, which is targeted by most commercial CDKN2A FISH probes. This is likely due to non-specific probe hybridization. Our finding suggests that FISH probes targeting the entire 9p21 locus may have lower sensitivity than anticipated among BRAF-altered gliomas and emphasizes the critical need for appropriate probe selection.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"170"},"PeriodicalIF":5.7,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12337364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820319","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":"Divergent and convergent TMEM106B pathology in murine models of neurodegeneration and human disease.","authors":"Muzi Du, Suleyman C Akerman, Charlotte M Fare, Linhao Ruan, Svetlana Vidensky, Lyudmila Mamedova, Katie Koo, Joshua Lee, Jeffrey D Rothstein","doi":"10.1186/s40478-025-02087-9","DOIUrl":"10.1186/s40478-025-02087-9","url":null,"abstract":"<p><p>TMEM106B is a lysosome/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied in vivo using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of the endogenous TMEM106B protein in murine models of C9ORF72-related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy using an extensively validated TMEM106B antibody. We found profound correlations between the endogenous TMEM106B protein with known TDP-43 and tau pathology in murine models of C9-ALS/FTD and tauopathy, respectively. By using an antibody previously shown to recognize the pathologic TMEM106B C-terminal fragments, we then performed a similar analysis on postmortem brain tissues from patients with C9-ALS/FTD, Alzheimer's disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). Convergent evidence from both murine models and human patients links TMEM106B to TDP-43 nuclear clearance at the cellular level in C9-ALS. By characterizing endogenous TMEM106B in mice and human postmortem tissue, our work reveals essential considerations that must be taken when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"169"},"PeriodicalIF":5.7,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12335138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811605","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":"The association between WHO grading and the long-term outcomes and radiotherapy efficacy of intracranial solitary fibrous tumors.","authors":"Leihao Ren, Lingyang Hua, A O Feng, Jiaojiao Deng, Hiroaki Wakimoto, Tareq Juratli, Qing Xie, Ye Gong","doi":"10.1186/s40478-025-02086-w","DOIUrl":"10.1186/s40478-025-02086-w","url":null,"abstract":"<p><strong>Background: </strong>Intracranial solitary fibrous tumor (SFT) is a rare mesenchymal tumor of fibroblastic origin in the central nervous system (CNS). The 2021 WHO classification of CNS tumor has updated the entity and grading criterion of SFT. We aimed to compare the 2021 WHO grading criterion (2021-WGC) and 2016 WHO grading criterion (2016-WGC) for their value to predict prognosis and radiotherapy (RT) efficacy.</p><p><strong>Methods: </strong>This is a retrospective study involving 223 consecutive intracranial SFT patients who received tumor resection at our neurosurgical center from 2013 to 2021. Univariable and multivariable Cox regression analyses were utilized to identify prognosis-related factors and evaluate the efficacy of RT. A risk model was constructed to predict the long-term recurrence.</p><p><strong>Results: </strong>A total of 223 SFT patients were included in this study. During a median follow-up period of 4.67 years, 80 (35.9%) patients experienced tumor recurrence and 14 (6.3%) experienced extracranial metastasis. Patients with SFT who developed recurrence were significantly older at diagnosis and exhibited higher Ki-67 index and mitotic count. Of note, the PFS of 2016-WGC grade 3 tumors was worse than the comparable PFS of grade 1 and 2 tumors (P = 0.001), while the PFS of 2021-WGC grade 1 tumors was better than grade 2 and 3 tumors that showed similar PFS in the long term (P < 0.001). We further proposed a novel risk stratification method that demonstrated a superior prognostic value compared to the 2021-WGC and 2016-WGC. Additionally, RT significantly prolonged the PFS of SFT patients, especially beyond 3 years after surgery (P = 0.032). Further efficacy analysis showed that RT prolonged PFS in the 2016-grade 3 tumors. While with the 2021-WGC and novel risk stratification, RT prolonged PFS in the 2021-grade 2 and intermediate risk tumors, respectively.</p><p><strong>Conclusions: </strong>The 2016-WGC identified high-recurrence risk patients in grade 3 while the 2021-WGC identified low-recurrence risk patients in grade 1. RT significantly prolonged PFS in SFT patients, especially after 3 years post-surgery. Notably, RT significantly improved PFS in the 2016-grade 3, 2021-grade 2 and intermediate risk tumors.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"167"},"PeriodicalIF":5.7,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12329862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793125","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":"Integrated molecular and detailed anatomical profiling identifies a prognostically adverse subtype of posterior fossa meningiomas: high-risk copy number alterations are associated with midline predilection and predict poor prognosis.","authors":"Yudai Hirano, Satoru Miyawaki, Yu Sakai, Yu Teranishi, Motoyuki Umekawa, Takeru Hirata, Shotaro Ogawa, Daisuke Komura, Hiroto Katoh, Masako Ikemura, Satoshi Koizumi, Hideaki Ono, Tetsuo Ushiku, Shumpei Ishikawa, Nobuhito Saito","doi":"10.1186/s40478-025-02083-z","DOIUrl":"10.1186/s40478-025-02083-z","url":null,"abstract":"<p><p>Anatomical localization of meningiomas has been increasingly linked to their genetic alterations. However, studies focusing specifically on the genomic landscape and clinical implications of posterior fossa meningiomas remain limited. In this study, we investigated the genetic, anatomical, and clinical characteristics of posterior fossa meningiomas, aiming to clarify the association between genetic alterations, precise tumor localization, and prognosis. Whole-exome sequencing was performed on 132 consecutive tumors to identify driver mutations and copy number alterations (CNAs). Tumor localization was carefully assessed based on dural attachment, arterial supply, and intraoperative findings. Based on driver mutations and CNAs, tumors were classified into three molecular groups: Group A (no Merlin pathway alterations, n = 71 (54%)), Group B (NF2 mutation/22q loss without high-risk CNAs, n = 45 (34%)), and Group C (high-risk CNAs, n = 16 (12%)). Notably, Group C showed a strong anatomical predilection, with 81% arising from midline structures, including the medial incisura and clivus. Group C tumors were significantly associated with poor progression-free survival following gross total resection (P = 0.023), and this remained significant even when the analysis was anatomically restricted to tumors located in the medial incisura and clivus (P = 0.0003). In multivariable analysis, Group C (P = 0.020, HR 6.60) and preoperative tumor volume > 10 cc (P = 0.044, HR 9.41) independently predicted poor prognosis. Overall, the results demonstrated that approximately 10% of posterior fossa meningiomas harbored high-risk CNAs, predominantly in midline locations, and were associated with worse clinical outcomes. CNA profiling in addition to the identification of driver mutations may provide a valuable tool for risk stratification and decision-making regarding adjuvant therapy in posterior fossa meningiomas.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"168"},"PeriodicalIF":5.7,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12329998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797918","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":"Binding patterns of glycine receptor autoantibodies are related to clinical syndromes.","authors":"Inken Piro, Anna-Lena Wiessler, Eleni Kakavela, Betül Baykan, Erdem Tüzün, Carmen Villmann, Claudia Sommer","doi":"10.1186/s40478-025-02082-0","DOIUrl":"10.1186/s40478-025-02082-0","url":null,"abstract":"<p><p>Patients diagnosed with the rare autoimmune disease Stiff Person Syndrome (SPS) or the more severe form Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM) as well as patients with encephalitis or epilepsy may harbor autoantibodies against synaptic molecules, for example the glycine receptor (GlyR). These autoantibodies interfere with inhibitory signal transmission, which causes a variety of symptoms. How the underlying autoantibody associated pathomechanisms contribute to the variability of clinical presentations, is so far not understood. In this study, binding patterns of GlyR autoantibodies from patients with SPS, PERM and epilepsy to murine central nervous system (CNS) tissue samples were analyzed for disease- and patient-specificity patterns. Twelve GlyR autoantibody positive patients were grouped by the patients' primary diagnoses. Serum samples from these SPS, PERM and epilepsy patients were evaluated for autoantibody binding on transfected HEK-293 cells and murine spinal cord and various brain tissue samples. Autoantibody binding was further verified by co-localization with commercial antibodies binding to the GlyR and the synaptic marker synaptophysin. Immunochemistry revealed GlyRα1-specific autoantibody binding for all included patients on transfected HEK-293 cells and in the grey matter of murine spinal cord sections. Other CNS regions of enhanced autoantibody accumulation however varied among the groups of SPS, PERM and epilepsy patients and also within groups. Similarly, autoantibody deposits were detected in GlyR expressing higher brain areas for each patient. Even if variations between labeled areas and cell layers were rather patient-specific than group-specific, functionality of the labeled areas aligned with the patients' impaired functions. Labeled areas and cell layers differing between patients could thereby explain the variability of symptomatology between and within the diseases. The observed diversity suggests a necessity for a personalized approach correlating patient-specific autoantibody properties, phenotype and treatment approaches.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"166"},"PeriodicalIF":5.7,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12312451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752043","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":"Mitochondrial dysfunction mediated by ER-calcium dysregulation in neurons derived from Alzheimer's disease patients.","authors":"Sarah Mustaly-Kalimi, Wacey Gallegos, Daniel Steinbrenner, Smriti Gupta, Aiden J Houcek, David A Bennett, Robert A Marr, Daniel A Peterson, Israel Sekler, Grace E Stutzmann","doi":"10.1186/s40478-025-02023-x","DOIUrl":"10.1186/s40478-025-02023-x","url":null,"abstract":"<p><p>Tight regulation of mitochondrial Ca²⁺ is essential for neuronal bioenergetics and cellular metabolism. Ca²⁺ transfer from ER-localized ryanodine receptors (RyR) and inositol triphosphate receptors (IP₃R) to the mitochondria maintains a steady Ca²⁺ source that fuels oxidative phosphorylation and ATP production. In Alzheimer's disease (AD), RyR-evoked Ca²⁺ release is markedly increased, contributing to synaptic deficits, protein mishandling, and memory impairment. Here, we demonstrate dysregulated RyR-Ca²⁺ release in neurons from familial and sporadic AD patients, and this directly compromises mitochondrial activity and contributes to AD cellular pathology. We measured an array of mitochondrial functions using fluorescent biosensors and optical imaging in RyR2-expressing HEK cells and neurons derived from AD and nonAD individuals. In neurons from AD patients, resting mitochondrial Ca²⁺ levels were elevated alongside increased free radical production and higher caspase-3 activity relative to nonAD neurons. RyR-evoked Ca²⁺ release further potentiated pathogenic mitochondrial responses in AD neurons, with increased Ca²⁺ uptake and exaggerated mitochondrial membrane depolarization. Additionally, clearance of damaged mitochondria was impaired in AD neurons, demonstrating consequences from dysfunctional lysosomes. Notably, impairments to mitochondria in AD neurons were largely prevented with the RyR negative allosteric modulator, Ryanodex. These findings highlight how excess RyR-Ca²⁺ release broadly contributes to early cellular pathology in AD which includes a cascade of ER, lysosomal, and mitochondrial deficits culminating in neuronal decline and degeneration. Additionally, pharmacological suppression of RyR-Ca²⁺ release preserves mitochondrial, ER and lysosomal function, thus providing a novel and effective therapeutic strategy.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"165"},"PeriodicalIF":5.7,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12305934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726416","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}