Acta Neuropathologica最新文献

{"title":"LRRK2 kinase-mediated accumulation of lysosome-associated phospho-Rabs in tauopathies and synucleinopathies.","authors":"Silas A Buck,Tuyana Malankhanova,Samuel Strader,Eileen B Ma,Sarah Yim,Harrison W Pratt,John Ervin,Edward B Lee,Shih-Hsiu J Wang,Todd J Cohen,Andrew B West,Laurie H Sanders","doi":"10.1007/s00401-025-02951-x","DOIUrl":"https://doi.org/10.1007/s00401-025-02951-x","url":null,"abstract":"Parkinson's disease (PD) pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with endolysosomal dysfunction across cell types, and carriers of LRRK2 mutations variably present with phosphorylated tau and α-synuclein deposits in post-mortem analysis. LRRK2 mutations increase the phosphorylation of Rab substrates including Rab12 and Rab10. Rab12 and Rab10 are expressed in neuronal and non-neuronal cells with localization to membranes in the endolysosomal compartment, and lysosomal stress activates LRRK2 phosphorylation of Rabs. In this study, using antibodies directed to the LRRK2-mediated phosphorylation sites on Rab12 at amino acid Ser106 (pS106-Rab12) and Rab10 at amino acid Thr73 (pT73-Rab10), we test whether aberrant LRRK2 phosphorylation is associated with tau and/or α-synuclein pathology across clinically distinct neurodegenerative diseases. Analysis of brain tissue lysates and immunohistochemistry of pathology-susceptible brain regions demonstrate that pS106-Rab12 levels are increased in Alzheimer's disease (AD) and Lewy body disease (LBD), including PD with and without G2019S LRRK2 mutation. At early pathological stages, phosphorylated Rab12 localizes to granulovacuolar degeneration bodies (GVBs), which are thought to be active lysosomal-like structures, in neurons. pS106-Rab12-positive GVBs accumulate with pathological tau across brain tissues in AD and LBD, and in G2019S LRRK2 mutation carriers. In a mouse model of tauopathy, pS106-Rab12 localizes to GVBs during early tau deposition in an age-dependent manner. While GVBs are largely absent in neurons with mature protein pathology, subsets of both tau and α-synuclein inclusions appear to incorporate pS106-Rab12 at later pathological stages. Further, pS106-Rab12 labels GVBs in neurons and shows co-pathology with tau inclusions in primary tauopathies including Pick's disease, progressive supranuclear palsy, and corticobasal degeneration. Finally, pT73-Rab10 is elevated and localizes to GVBs, but not tau and α-synuclein inclusions, in AD and LBD, including G2019S LRRK2 mutation carriers. These results implicate LRRK2 kinase activity and Rab phosphorylation in endolysosomal dysfunction in tau- and α-synuclein-associated neurodegenerative diseases.","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"43 1","pages":"44"},"PeriodicalIF":12.7,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338962","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":"Genetic and proteomic analysis identifies BAG3 as an amyloid-responsive regulator of neuronal proteostasis","authors":"Zachary M. Augur,&nbsp;Garrett M. Fogo,&nbsp;Mason R. Arbery,&nbsp;Yi-Chen Hsieh,&nbsp;Nalini R. Rao,&nbsp;Kritika Goyal,&nbsp;Emily Dexter,&nbsp;David A. Bennett,&nbsp;Jeffrey N. Savas,&nbsp;Andrew M. Stern,&nbsp;Tracy L. Young-Pearse","doi":"10.1007/s00401-025-02947-7","DOIUrl":"10.1007/s00401-025-02947-7","url":null,"abstract":"<div><p>The autophagy–lysosome pathway (ALP) and the ubiquitin–proteasome system (UPS) are the primary protein degradative mechanisms maintaining proteostasis in neurons. However, the impact of human genetic variation on these pathways and the role of BAG3 are poorly understood, particularly in the context of Alzheimer’s disease, where proteostatic dysfunction is a defining hallmark. We utilized a large panel of iPSCs from deeply phenotyped cohorts to interrogate genetic contributions to baseline autophagic flux and UPS activity in human neurons, and protein turnover was assessed using SILAC-based quantitative proteomics. Across this panel of neurons, we observed substantial inter-individual differences in autophagic flux, which was inversely correlated with UPS activity. This reciprocal relationship extended to tau homeostasis, where higher autophagic flux resulted in reduced accumulation of aggregated, phosphorylated tau. Proteomic analyses revealed that global protein turnover dynamics stratified based on degradation pathway activity and could predict pathway-specific substrate dependencies. Interestingly, Bcl-2-associated athanogene 3 (BAG3), an important member of the chaperone-assisted selective autophagy pathway, emerged as a dynamically regulated autophagy chaperone, responsive to pharmacological inhibition of both the UPS and ALP. BAG3 knockout in neurons decreased autophagic flux and increased levels of high-molecular-weight phosphorylated tau. Notably, familial AD mutations and Aβ exposure induced BAG3 expression in neurons, while elevated BAG3 levels in human brain tissue were associated with higher neuropathological burden and disease progression. Our findings identify BAG3 as a key modulator of proteostasis in human neurons. Its regulation across genetic backgrounds and pathological stimuli suggests a central role in maintaining degradation activities in Alzheimer’s disease and related disorders.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02947-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283956","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":"Molecular characterization and clinical features of diffuse midline glioma in the pediatric precision oncology registry INFORM","authors":"Elke Pfaff,&nbsp;Kathrin Schramm,&nbsp;Mirjam Blattner-Johnson,&nbsp;Barbara C. Jones,&nbsp;Sebastian Stark,&nbsp;Gnana Prakash Balasubramanian,&nbsp;Christopher Previti,&nbsp;Robert J. Autry,&nbsp;Petra Fiesel,&nbsp;Felix Sahm,&nbsp;David Reuss,&nbsp;Andreas von Deimling,&nbsp;Cornelis M. van Tilburg,&nbsp;Kristian W. Pajtler,&nbsp;Till Milde,&nbsp;Uta Dirksen,&nbsp;Christof M. Kramm,&nbsp;André O. von Bueren,&nbsp;Caroline Hutter,&nbsp;Bram de Wilde,&nbsp;Jan Molenaar,&nbsp;Nicolas U. Gerber,&nbsp;Olli Lohi,&nbsp;Monica C. Munthe-Kaas,&nbsp;Kleopatra Georgantzi,&nbsp;Bernarda Kazanowska,&nbsp;Michal Zápotocký,&nbsp;Antonis Kattamis,&nbsp;Maria Filippidou,&nbsp;Iris Fried,&nbsp;Stefan M. Pfister,&nbsp;Olaf Witt,&nbsp;David T. W. Jones","doi":"10.1007/s00401-025-02945-9","DOIUrl":"10.1007/s00401-025-02945-9","url":null,"abstract":"<div><p>Diffuse midline glioma (DMG; a subtype of pediatric high-grade glioma) is a fatal disease in children, due to the localization in critical structures of the central nervous system, its invasive nature, and limited treatment options. Molecularly, DMG with loss of histone 3 K27 trimethylation (mostly through the typical K27M-mutation in histone 3) have been relatively well characterized, however, no unambiguous Achilles’ heel for targeted therapeutic approaches could be identified to date. This study integrates detailed molecular characteristics of pediatric DMGs with clinical data in a large, international cohort in order to contribute to a better understanding necessary for further development of therapeutic approaches. A total of 162 DMG tumors were analyzed within the INFORM registry from 01/2015 to 11/2023 using comprehensive molecular profiling (including exome, whole-genome and RNA next-generation sequencing approaches, complemented with DNA methylation analysis). Molecular results were correlated with clinical data of the respective patients including the treatment regimen applied and patients’ outcomes. This well-defined cohort of histone 3 K27-altered DMG according to the current WHO classification showed typical molecular alterations for this entity, with differences in frequencies in specific subgroups. The presence of <i>TP53</i> mutation and the absence of MAPK pathway alteration in the tumors were associated with worse outcomes. In a substantial proportion of patients, genetic alterations serving as targets for potential therapeutic approaches could be identified. This large, international, prospective DMG cohort combines comprehensive molecular characterization of the tumors with registry-level clinical data, thereby contributing to a better understanding of the underlying tumor biology, potential prognostic and predictive markers and the potential impact of targeted therapies.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02945-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261602","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":"Tumor-associated macrophages in meningiomas: a novel biomarker for poor survival outperforming the benefits of T cells","authors":"Catharina Lotsch,&nbsp;Rolf Warta,&nbsp;Fang Liu,&nbsp;Gerhard Jungwirth,&nbsp;Carmen Rommel,&nbsp;Mandy Barthel,&nbsp;Katrin Lamszus,&nbsp;Almuth F. Kessler,&nbsp;Niels Grabe,&nbsp;Mario Loehr,&nbsp;Ralf Ketter,&nbsp;Christian Senft,&nbsp;Sybren L. N. Maas,&nbsp;Philipp Sievers,&nbsp;Manfred Westphal,&nbsp;Sandro M. Krieg,&nbsp;Andreas Unterberg,&nbsp;Matthias Simon,&nbsp;Andreas von Deimling,&nbsp;Felix Sahm,&nbsp;David R. Raleigh,&nbsp;Christel Herold-Mende","doi":"10.1007/s00401-025-02948-6","DOIUrl":"10.1007/s00401-025-02948-6","url":null,"abstract":"<div><p>Tumor-associated macrophages (TAMs) represent the main immune cell population in various brain malignancies, but there is rare knowledge on the functional and, in particular, the prognostic role of TAMs in the meningioma (MGM) microenvironment. Here, we investigated TAM frequencies, activation state, survival-associated changes, and their association with tumor-infiltrating T lymphocytes (TILs) in two independent study samples comprising altogether 680 MGMs. To this end, we performed tissue cytometry analyses, quantified tissue cytokine levels, and integrated previously published TIL infiltration and microarray datasets in the discovery cohort comprising <i>n</i> = 195 clinically well-annotated cases. This was complemented by a DNA methylation-based deconvolution approach to predict TAM and TIL infiltration rates using immune cell-specific CpG sites as well as survival associations in an independent validation cohort of <i>n</i> = 485 MGMs. Our findings revealed substantial but heterogeneous TAM infiltration in newly diagnosed MGMs, with increased numbers of pro-tumoral TAMs in clinically aggressive tumors. Additional cytokine and transcriptome analyses corroborated the presence of an immunosuppressive niche in TAM-enriched MGMs. Importantly, a high frequency of pro-tumoral TAMs was associated with poor patient outcome, and high TAM infiltration was further identified as an independent prognostic factor for inferior survival, counteracting the beneficial prognostic effect of TILs. Moreover, methylation-based deconvolution analyses confirmed the opposing prognostic roles of TAMs and TILs in the validation cohort. Altogether, higher numbers of TAMs appear to be a hallmark of clinically aggressive behavior in newly diagnosed and recurrent MGMs. Unlike TILs, immunosuppressive TAMs seem to play a dominant role in the immunological landscape of MGMs with a significant negative impact on patient outcome, highlighting pro-tumoral TAMs to be an attractive treatment target in MGMs. Furthermore, our deconvolution approach presents a pipeline to computationally determine TAM and TIL infiltrates in the MGM microenvironment, which might be highly valuable for patient stratification for future immunotherapeutic treatments.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02948-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246914","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":"Primary age-related tauopathy","authors":"Timothy E. Richardson,&nbsp;Jamie M. Walker,&nbsp;Kurt Farrell,&nbsp;Tiago Gil Oliveira,&nbsp;Charles L. White III,&nbsp;John F. Crary","doi":"10.1007/s00401-025-02943-x","DOIUrl":"10.1007/s00401-025-02943-x","url":null,"abstract":"<div><p>Primary age-related tauopathy (PART) was proposed in 2014 as a neuropathological term to describe patients with Alzheimer’s-type medial temporal lobe neurofibrillary degeneration in the absence of significant β-amyloid pathology. Over the past decade, this designation has gained widespread adoption, helping to clarify the interpretation of biomarker profiles, delineate early-stage tauopathy in aging, and differentiate non-Alzheimer tauopathies from aging and classical Alzheimer disease. This review revisits PART ten years following its conception, critically evaluating its neuropathological features, clinical correlates, molecular underpinnings, and current limitations. We synthesize recent advances in neuroimaging, biomarkers, genetics, and epidemiology, explore the relationship between PART and other age-associated neurodegenerative processes, and propose revisions to the original PART criteria. While PART has served as a valuable framework for studying tau pathology in aging, key questions remain regarding its pathogenesis, clinical significance, and relationship to the broader spectrum of tauopathies. We highlight major gaps in knowledge and outline priorities for future research aimed at defining the mechanisms, biomarkers, and clinical criteria that will determine whether PART represents a distinct disease or a universal feature of human brain aging.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02943-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249289","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":"Impact of APOE on cerebrovascular lipid profile in Alzheimer’s disease","authors":"Yasuteru Inoue,&nbsp;Hu Wang,&nbsp;Michael G. Heckman,&nbsp;Yingxue Ren,&nbsp;Launia J. White,&nbsp;Wenyan Lu,&nbsp;Pengjiao Wang,&nbsp;Julia TCW,&nbsp;Shunsuke Koga,&nbsp;Alla Alnobani,&nbsp;Michael DeTure,&nbsp;Melissa E. Murray,&nbsp;Ronald C. Petersen,&nbsp;Dennis W. Dickson,&nbsp;Guojun Bu,&nbsp;Xianlin Han,&nbsp;Takahisa Kanekiyo","doi":"10.1007/s00401-025-02949-5","DOIUrl":"10.1007/s00401-025-02949-5","url":null,"abstract":"<div><p>Disturbances within the cerebrovascular system substantially contribute to the pathogenesis of age-related cognitive impairment and Alzheimer’s disease (AD). Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid-β (Aβ) in the leptomeningeal and cortical arteries and is highly prevalent in AD, affecting over 90% of cases. While the ε4 allele of apolipoprotein E (<i>APOE</i>) represents the strongest genetic risk factor for AD, it is also associated with cerebrovascular dysregulations. APOE plays a crucial role in brain lipid transport, particularly in the trafficking of cholesterol and phospholipids. Lipid metabolism is increasingly recognized as a critical factor in AD pathogenesis. However, the precise mechanism by which <i>APOE</i> influences cerebrovascular lipid signatures in AD brains remains unclear. In this study, we conducted non-targeted lipidomics on cerebral vessels isolated from the middle temporal cortex of 89 postmortem human AD brains, representing varying degrees of CAA and different <i>APOE</i> genotypes: <i>APOE</i> ε2/ε3 (N = 9), <i>APOE</i> ε2/ε4 (N = 14), <i>APOE</i> ε3/ε3 (N = 21), <i>APOE</i> ε3/ε4 (N = 23), and <i>APOE</i> ε4/ε4 (N = 22). Lipidomics detected 10 major lipid classes with phosphatidylcholine (PC) and phosphatidylethanolamine (PE) being the most abundant lipid species. While we observed a positive association between age and total acyl-carnitine (CAR) levels (p = 0.0008), the levels of specific CAR subclasses were influenced by the <i>APOE</i> ε4 allele. Notably, <i>APOE</i> ε4 was associated with increased PE (p = 0.049) and decreased sphingomyelin (SM) levels (p = 0.028) in the cerebrovasculature. Furthermore, cerebrovascular Aβ40 and Aβ42 levels showed associations with sphingolipid levels including SM (p = 0.0079) and ceramide (CER) (p = 0.024). Weighted correlation network analysis revealed correlations between total tau and phosphorylated tau and lipid clusters enriched for PE plasmalogen and lysoglycerophospholipids. Taken together, our results suggest that cerebrovascular lipidomic profiles offer novel insights into the pathogenic mechanisms of AD, with specific lipid alterations potentially serving as biomarkers or therapeutic targets for AD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02949-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246430","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":"Evolution of pilocytic astrocytoma to diffuse leptomeningeal glioneuronal tumor (DLGNT): bridging two distinct tumor types","authors":"Daniel C. Moreira,&nbsp;Soniya N. Pinto,&nbsp;Margit K. Mikkelsen,&nbsp;Xiaoyu Li,&nbsp;Yen-Chun Liu,&nbsp;Larissa V. Furtado,&nbsp;Jason Chiang","doi":"10.1007/s00401-025-02938-8","DOIUrl":"10.1007/s00401-025-02938-8","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246427","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":"Expansion of the spectrum of tumors diagnosed as myxopapillary ependymomas","authors":"Fuat Kaan Aras,&nbsp;Dennis Friedel,&nbsp;Felix Keller,&nbsp;Ferdinand Zettl,&nbsp;Rouzbeh Banan,&nbsp;Philipp Sievers,&nbsp;Abigail K. Suwala,&nbsp;Felix Hinz,&nbsp;Lukas Friedrich,&nbsp;Ivan Abdulrazak,&nbsp;Mozhgan Esmaeilibenvidi,&nbsp;Nima Etminan,&nbsp;Christel Herold-Mende,&nbsp;Wolfgang Wick,&nbsp;Sandro Krieg,&nbsp;Stefan M. Pfister,&nbsp;Andrey Korshunov,&nbsp;Isabell Bludau,&nbsp;Felix Sahm,&nbsp;David E. Reuss,&nbsp;Gianluca Sigismondo,&nbsp;Andreas von Deimling","doi":"10.1007/s00401-025-02944-w","DOIUrl":"10.1007/s00401-025-02944-w","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02944-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194520","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":"Neuropathological changes in the nucleus basalis of Meynert in people with type 1 or type 2 diabetes mellitus","authors":"Wei Jiang,&nbsp;Martin J. Kalsbeek,&nbsp;Felipe Correa-da-Silva,&nbsp;Han Jiao,&nbsp;Andries Kalsbeek,&nbsp;Dick F. Swaab,&nbsp;Sarah E. Siegelaar,&nbsp;Chun-Xia Yi","doi":"10.1007/s00401-025-02942-y","DOIUrl":"10.1007/s00401-025-02942-y","url":null,"abstract":"<div><p>People with type 1 or type 2 diabetes mellitus (T1DM or T2DM) often experience cognitive impairment. We profiled cells in the nucleus basalis of Meynert (NBM) in postmortem human brain tissue to investigate the neuropathological changes. Sixty-eight postmortem NBM samples were grouped as T1DM, T2DM, and controls without diabetes, with Braak stage 0–II or III–VI. T1DM subjects had only Braak stage 0–II and were thus compared only to controls with a similar Braak stage and not subjects with Braak stage III–VI. We analyzed neurons expressing choline acetyltransferase (ChAT), phosphorylated tau, amyloid-beta, glial cells, and vasculature with their respective markers. We found significantly lower neuronal expression of ChAT in T1DM individuals than in controls and T2DM individuals with Braak stage 0–II. Later-stage hyperphosphorylated tau levels were higher in T2DM compared to controls with Braak stage III–VI. Our results suggest that reduced acetylcholine production by NBM neurons may underlie the cognitive complaints of people with T1DM. In contrast, T2DM may exacerbate neuropathological changes associated with Alzheimer’s disease-like alterations.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190627","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":"Reversible tau hyperphosphorylation in hibernation: a blood biomarker and brain tissue study","authors":"Wagner S. Brum,&nbsp;Laia Montoliu-Gaya,&nbsp;Gunnar Brinkmalm,&nbsp;Diana Piotrowska,&nbsp;Elena Camporesi,&nbsp;Carsten Jäger,&nbsp;Helena S. Isaksson,&nbsp;Sven Martin,&nbsp;Jonas Kindberg,&nbsp;Juan Lantero-Rodriguez,&nbsp;João Pedro Ferrari-Souza,&nbsp;Alexis Moscoso,&nbsp;Andrea L. Benedet,&nbsp;Shorena Janelidze,&nbsp;Johan Gobom,&nbsp;Henrik Zetterberg,&nbsp;Oskar Hansson,&nbsp;Eduardo R. Zimmer,&nbsp;Nicholas J. Ashton,&nbsp;Thomas Arendt,&nbsp;Tammaryn Lashley,&nbsp;Jens T. Stieler,&nbsp;Max Holzer,&nbsp;Ole Fröbert,&nbsp;Kaj Blennow","doi":"10.1007/s00401-025-02930-2","DOIUrl":"10.1007/s00401-025-02930-2","url":null,"abstract":"<div><p>Tau hyperphosphorylation, a key neuropathological feature of tauopathies such as Alzheimer’s disease (AD), also occurs physiologically during mammalian hibernation and is fully reversed upon arousal, offering a unique translational model to study tau metabolism. However, limited data exist on insoluble and soluble tau alterations during hibernation and on patterns of tau fragment concentrations in the hibernating mammalian brain. We quantified tau biomarkers in plasma samples from ten free-ranging brown bears (<i>Ursus arctos</i>), captured during both their active summer period and hibernation in the winter, using clinically validated immunoassays and immunoprecipitation mass spectrometry (IP-MS) techniques. We also analyzed brain tissue from ten golden Syrian hamsters (<i>Mesocricetus auratus</i>) subjected to induced torpor (hibernation) versus euthermic (non-hibernating) states by quantifying multiple phosphorylated and non-phosphorylated tau peptides with an IP-MS method previously applied in human brain tissue. In brown bears, plasma levels of phosphorylated tau (p-tau) biomarkers p-tau181 and p-tau217 significantly increased during hibernation compared to summer (median increases of 362% and 294% by IP-MS, respectively), with similar increases found with immunoassays. Additional plasma p-tau biomarkers associated with AD pathology, including p-tau205 and p-tau231, were also increased during bear hibernation. In hamster brains, p-tau217, and p-tau231 were similarly elevated during torpor, while tau fragments from the microtubule-binding region (MTBR), associated with tangle aggregation, were not increased. In contrast, brain tissue from <i>n</i> = 10 AD patients, analyzed with the same IP-MS method, exhibited striking increases in p-tau (~ 50,000% for p-tau217) and MTBR fragments (~ 20,000% for MTBR tau354-369) compared with <i>n</i> = 10 human controls. We show that hibernation-linked tau hyperphosphorylation involves some of the same phospho-sites altered in AD, but occurs without MTBR tau aggregation. This highlights hibernation as a reversible, non-pathological model to study tau biology and mechanisms underlying AD due to its reversibility and lack of tau aggregation despite hyperphosphorylation in key AD tau phospho-sites.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02930-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189314","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}