Acta Neuropathologica最新文献

{"title":"Lipid storage myopathy associated with sertraline treatment is an acquired mitochondrial disorder with respiratory chain deficiency","authors":"Carola Hedberg-Oldfors,&nbsp;Ulrika Lindgren,&nbsp;Kittichate Visuttijai,&nbsp;Yan Shen,&nbsp;Andreea Ilinca,&nbsp;Sara Nordström,&nbsp;Christopher Lindberg,&nbsp;Anders Oldfors","doi":"10.1007/s00401-024-02830-x","DOIUrl":"10.1007/s00401-024-02830-x","url":null,"abstract":"<div><p>Lipid storage myopathies are considered inborn errors of metabolism affecting the fatty acid metabolism and leading to accumulation of lipid droplets in the cytoplasm of muscle fibers. Specific diagnosis is based on investigation of organic aids in urine, acylcarnitines in blood and genetic testing. An acquired lipid storage myopathy in patients treated with the antidepressant drug sertraline, a serotonin reuptake inhibitor, has recently emerged as a new tentative differential diagnosis. We analyzed the muscle biopsy tissue in a group of 11 adult patients with muscle weakness and lipid storage myopathy which developed at a time when they were on sertraline treatment. This group comprise most patients with lipid storage myopathies in western Sweden during the recent nine-year period. By enzyme histochemistry, electron microscopy, quantitative proteomics, immunofluorescence of the respiratory chain subunits, western blot and genetic analyses we demonstrate that muscle tissue in this group of patients exhibit a characteristic morphological and proteomic profile. The patients also showed an acylcarnitine profile in blood suggestive of multiple acyl-coenzyme A dehydrogenase deficiency, but no genetic explanation was found by whole genome or exome sequencing. By proteomic analysis the muscle tissue revealed a profound loss of Complex I subunits from the respiratory chain and to some extent also deficiency of Complex II and IV. Most other components of the respiratory chain as well as the fatty acid oxidation and citric acid cycle were upregulated in accordance with the massive mitochondrial proliferation. The respiratory chain deficiency was verified by immunofluorescence analysis, western blot analysis and enzyme histochemistry. The typical ultrastructural changes of the mitochondria included pleomorphism, dark matrix and frequent round osmiophilic inclusions. Our results show that lipid storage myopathy associated with sertraline treatment is a mitochondrial disorder with respiratory chain deficiency and is an important differential diagnosis with characteristic features.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02830-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142712528","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":"SMOC1 colocalizes with Alzheimer’s disease neuropathology and delays Aβ aggregation","authors":"Kaleah Balcomb,&nbsp;Caitlin Johnston,&nbsp;Tomas Kavanagh,&nbsp;Dominique Leitner,&nbsp;Julie Schneider,&nbsp;Glenda Halliday,&nbsp;Thomas Wisniewski,&nbsp;Margaret Sunde,&nbsp;Eleanor Drummond","doi":"10.1007/s00401-024-02819-6","DOIUrl":"10.1007/s00401-024-02819-6","url":null,"abstract":"<div><p>SMOC1 has emerged as one of the most significant and consistent new biomarkers of early Alzheimer’s disease (AD). Recent studies show that SMOC1 is one of the earliest changing proteins in AD, with levels in the cerebrospinal fluid increasing many years before symptom onset. Despite this clear association with disease, little is known about the role of SMOC1 in AD or its function in the brain. Therefore, the aim of this study was to examine the distribution of SMOC1 in human AD brain tissue and to determine if SMOC1 influenced amyloid beta (Aβ) aggregation. The distribution of SMOC1 in human brain tissue was assessed in 3 brain regions (temporal cortex, hippocampus, and frontal cortex) using immunohistochemistry in a cohort of 73 cases encompassing advanced AD, mild cognitive impairment (MCI), preclinical AD, and cognitively normal controls. The Aβ- and phosphorylated tau-interaction with SMOC1 was assessed in control, MCI, and advanced AD human brain tissue using co-immunoprecipitation, and the influence of SMOC1 on Aβ aggregation kinetics was assessed using Thioflavin-T assays and electron microscopy. SMOC1 strongly colocalized with a subpopulation of amyloid plaques in AD (43.8 ± 2.4%), MCI (32.8 ± 5.4%), and preclinical AD (28.3 ± 6.4%). SMOC1 levels in the brain strongly correlated with plaque load, irrespective of disease stage. SMOC1 also colocalized with a subpopulation of phosphorylated tau aggregates in AD (9.6 ± 2.6%). Co-immunoprecipitation studies showed that SMOC1 strongly interacted with Aβ in human MCI and AD brain tissue and with phosphorylated tau in human AD brain tissue. Thioflavin-T aggregation assays showed that SMOC1 significantly delayed Aβ aggregation in a dose-dependent manner, and electron microscopy confirmed that the Aβ fibrils generated in the presence of SMOC1 had an altered morphology. Overall, our results emphasize the importance of SMOC1 in the onset and progression of AD and suggest that SMOC1 may influence pathology development in AD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02819-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697105","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":"BAG3’s dual roles in Parkinson’s disease and cardiomyopathy: benefit or liability?","authors":"Hui-Qi Qu,&nbsp;Hakon Hakonarson","doi":"10.1007/s00401-024-02837-4","DOIUrl":"10.1007/s00401-024-02837-4","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694804","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":"Pathologic and clinical correlates of region-specific brain GFAP in Alzheimer’s disease","authors":"Jared M. Phillips,&nbsp;Rebecca L. Winfree,&nbsp;Mabel Seto,&nbsp;Julie A. Schneider,&nbsp;David A. Bennett,&nbsp;Logan C. Dumitrescu,&nbsp;Timothy J. Hohman","doi":"10.1007/s00401-024-02828-5","DOIUrl":"10.1007/s00401-024-02828-5","url":null,"abstract":"<div><p>Plasma glial fibrillary acidic protein (GFAP) is an emerging biomarker of Alzheimer’s disease (AD), with higher blood GFAP levels linked to faster cognitive decline, particularly among individuals with high brain amyloid burden. However, few studies have examined brain GFAP expression to clarify if peripheral associations reflect brain changes. This study aimed to correlate region-specific GFAP mRNA expression (<i>n</i> = 917) and protein abundance (n=386) with diverse neuropathological measures at autopsy in the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP) and to characterize the interaction between brain GFAP and brain amyloid burden on downstream outcomes. We assessed GFAP gene expression in the dorsolateral prefrontal cortex, caudate nucleus, and posterior cingulate cortex with respect to core AD pathology (amyloid-β and tau), cerebrovascular (microinfarcts, macroinfarcts, and cerebral amyloid angiopathy [CAA]), proteinopathic (TDP-43, Lewy bodies), and cognitive outcomes. These associations were further examined at the protein level using tandem-mass tag proteomic measurements from the dorsolateral prefrontal cortex. We also assessed GFAP interactions with AD neuropathology on downstream outcomes. Cortical GFAP gene and protein expression were significantly upregulated in participants with a neuropathologically confirmed AD diagnosis at autopsy (all P_FDR &lt; 3.5e−4), but not in individuals positive for tau pathology and negative for amyloid pathology (all P_FDR &gt; 0.05). Higher cortical GFAP levels were associated with increased amyloid pathology, CAA pathology, and faster cognitive decline (all P_FDR &lt; 3.3e−3). GFAP’s associations with phosphorylated tau burden and cognition were influenced by amyloid burden, being most pronounced among amyloid-positive individuals, confirming previous in vivo biomarker observations. No associations were observed between <i>GFAP</i> gene expression and outcomes in the caudate nucleus. Our results support previous biomarker findings and suggest that higher brain GFAP levels are associated with higher brain amyloid burden and faster cognitive decline among amyloid-positive individuals.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02828-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142691968","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":"Neuronal and oligodendroglial, but not astroglial, tau translates to in vivo tau PET signals in individuals with primary tauopathies","authors":"Luna Slemann,&nbsp;Johannes Gnörich,&nbsp;Selina Hummel,&nbsp;Laura M. Bartos,&nbsp;Carolin Klaus,&nbsp;Agnes Kling,&nbsp;Julia Kusche-Palenga,&nbsp;Sebastian T. Kunte,&nbsp;Lea H. Kunze,&nbsp;Amelie L. Englert,&nbsp;Yunlei Li,&nbsp;Letizia Vogler,&nbsp;Sabrina Katzdobler,&nbsp;Carla Palleis,&nbsp;Alexander Bernhardt,&nbsp;Alexander Jäck,&nbsp;Andreas Zwergal,&nbsp;Franziska Hopfner,&nbsp;Sebastian N. Roemer-Cassiano,&nbsp;Gloria Biechele,&nbsp;Sophia Stöcklein,&nbsp;Gerard Bischof,&nbsp;Thilo van Eimeren,&nbsp;Alexander Drzezga,&nbsp;Osama Sabri,&nbsp;Henryk Barthel,&nbsp;Gesine Respondek,&nbsp;Timo Grimmer,&nbsp;Johannes Levin,&nbsp;Jochen Herms,&nbsp;Lars Paeger,&nbsp;Marie Willroider,&nbsp;Leonie Beyer,&nbsp;Günter U. Höglinger,&nbsp;Sigrun Roeber,&nbsp;Nicolai Franzmeier,&nbsp;Matthias Brendel","doi":"10.1007/s00401-024-02834-7","DOIUrl":"10.1007/s00401-024-02834-7","url":null,"abstract":"<div><p>Tau PET has attracted increasing interest as an imaging biomarker for 4-repeat (4R)-tauopathy progressive supranuclear palsy (PSP). However, the translation of in vitro 4R-tau binding to in vivo tau PET signals is still unclear. Therefore, we performed a translational study using a broad spectrum of advanced methodologies to investigate the sources of [¹⁸F]PI-2620 tau PET signals in individuals with 4R-tauopathies, including a pilot PET autopsy study in patients. First, we conducted a longitudinal [¹⁸F]PI-2620 PET/MRI study in a 4-repeat-tau mouse model (PS19) and detected elevated [¹⁸F]PI-2620 PET signals in the presence of high levels of neuronal tau. An innovative approach involving cell sorting after radiotracer injection in vivo revealed higher tracer uptake in single neurons than in the astrocytes of PS19 mice. Regional [¹⁸F]PI-2620 tau PET signals during the lifetime correlated with the abundance of fibrillary tau and with autoradiography signal intensity in PSP patients and disease controls who underwent autopsy 2–63 months after tau PET. In autoradiography, tau-positive neurons and oligodendrocytes with a high AT8 density, but not tau-positive astrocytes, were the drivers of [¹⁸F]PI-2620 autoradiography signals in individuals with PSP. The high tau abundance in oligodendrocytes at the boundary of gray and white matter facilitated the identification of an optimized frontal lobe target region to detect the tau burden in patients with PSP. In summary, neuronal and oligodendroglial tau constitutes the dominant source of tau PET radiotracer binding in 4-repeat-tauopathies, translating to an in vivo signal.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02834-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692025","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":"Genome-wide methylation profiling differentiates benign from aggressive and metastatic pituitary neuroendocrine tumors","authors":"Jelena Jotanovic,&nbsp;Henning Bünsow Boldt,&nbsp;Mark Burton,&nbsp;Marianne Skovsager Andersen,&nbsp;Daniel Bengtsson,&nbsp;Thomas Olsson Bontell,&nbsp;Bertil Ekman,&nbsp;Britt Edén Engström,&nbsp;Ulla Feldt-Rasmussen,&nbsp;Ansgar Heck,&nbsp;Antonia Jakovcevic,&nbsp;Jens Otto L. Jørgensen,&nbsp;Ivana Kraljevic,&nbsp;Jacek Kunicki,&nbsp;John R. Lindsay,&nbsp;Marco Losa,&nbsp;Paul Benjamin Loughrey,&nbsp;Dominique Maiter,&nbsp;Maria Maksymowicz,&nbsp;Emilija Manojlovic-Gacic,&nbsp;Jens Pahnke,&nbsp;Stephan Petersenn,&nbsp;Maria Petersson,&nbsp;Vera Popovic,&nbsp;Oskar Ragnarsson,&nbsp;Åse Krogh Rasmussen,&nbsp;Zita Reisz,&nbsp;Wolfgang Saeger,&nbsp;Camilla Schalin-Jäntti,&nbsp;David Scheie,&nbsp;Maria Rosa Terreni,&nbsp;Olli Tynninen,&nbsp;Ben Whitelaw,&nbsp;Pia Burman,&nbsp;Olivera Casar-Borota","doi":"10.1007/s00401-024-02836-5","DOIUrl":"10.1007/s00401-024-02836-5","url":null,"abstract":"<div><p>Aggressive pituitary neuroendocrine tumors (PitNETs)/adenomas are characterized by progressive growth despite surgery and all standard medical therapies and radiotherapy. A subset will metastasize to the brain and/or distant locations and are termed metastatic PitNETs (pituitary carcinomas). Studies of potential prognostic markers have been limited due to the rarity of these tumors. A few recurrent somatic mutations have been identified, and epigenetic alterations and chromosomal rearrangements have not been explored in larger cohorts of aggressive and metastatic PitNETs. In this study, we performed genome-wide methylation analysis, including copy-number variation (CNV) calculations, on tumor tissue specimens from a large international cohort of 64 patients with aggressive (48) and metastatic (16) pituitary tumors. Twelve patients with non-invasive pituitary tumors (Knosp 0–2) exhibiting an indolent course over a 5 year follow-up served as controls. In an unsupervised hierarchical cluster analysis, aggressive/metastatic PitNETs clustered separately from benign pituitary tumors, and, when only specimens from the first surgery were analyzed, three separate clusters were identified: aggressive, metastatic, and benign PitNETs. Numerous CNV events affecting chromosomal arms and whole chromosomes were frequent in aggressive and metastatic, whereas benign tumors had normal chromosomal copy numbers with only few alterations. Genome-wide methylation analysis revealed different CNV profiles and a clear separation between aggressive/metastatic and benign pituitary tumors, potentially providing biomarkers for identification of these tumors with a worse prognosis at the time of first surgery. The data may refine follow-up routines and contribute to the timely introduction of adjuvant therapy in patients harboring, or at risk of developing, aggressive or metastatic pituitary tumors.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02836-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142691856","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":"Unsuccessful transmissions of atypical genetic Creutzfeldt–Jakob disease (PRNP p.T183A-129M) in transgenic mice","authors":"Simone Baiardi,&nbsp;Claudia Marina Vargiu,&nbsp;Shirou Mohri,&nbsp;Otto Windl,&nbsp;Jochen Herms,&nbsp;Sabina Capellari,&nbsp;Tetsuyuki Kitamoto,&nbsp;Piero Parchi","doi":"10.1007/s00401-024-02825-8","DOIUrl":"10.1007/s00401-024-02825-8","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142672519","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":"Pure LATE-NC: Frequency, clinical impact, and the importance of considering APOE genotype when assessing this and other subtypes of non-Alzheimer’s pathologies","authors":"Yuriko Katsumata,&nbsp;Xian Wu,&nbsp;Khine Zin Aung,&nbsp;David W. Fardo,&nbsp;Davis C. Woodworth,&nbsp;S. Ahmad Sajjadi,&nbsp;Sandra O. Tomé,&nbsp;Dietmar Rudolf Thal,&nbsp;Juan C. Troncoso,&nbsp;Koping Chang,&nbsp;Charles Mock,&nbsp;Peter T. Nelson","doi":"10.1007/s00401-024-02821-y","DOIUrl":"10.1007/s00401-024-02821-y","url":null,"abstract":"<div><p>Pure limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (pure LATE-NC) is a term used to describe brains with LATE-NC but lacking intermediate or severe levels of Alzheimer’s disease neuropathologic changes (ADNC). Focusing on pure LATE-NC, we analyzed data from the National Alzheimer’s Coordinating Center (NACC) Neuropathology Data Set, comprising clinical and pathological information aggregated from 32 NIH-funded Alzheimer’s Disease Research Centers (ADRCs). After excluding subjects dying with unusual conditions, n = 1,926 autopsied subjects were included in the analyses. For &gt; 90% of these participants, apolipoprotein E (<i>APOE)</i> allele status was known; 46.5% had at least one <i>APOE</i> 4 allele. In most human populations, only 15–25% of people are <i>APOE</i> ε4 carriers. ADRCs with higher documented AD risk allele (<i>APOE</i> or <i>BIN1</i>) rates had fewer participants lacking ADNC, and correspondingly low rates of pure LATE-NC. Among <i>APOE</i> ε4 non-carries, 5.3% had pure LATE-NC, 37.0% had pure ADNC, and 3.6% had pure neocortical Lewy body pathology. In terms of clinical impact, participants with pure LATE-NC tended to die after having received a diagnosis of dementia: 56% died with dementia among <i>APOE</i> ε4 non-carrier participants, comparable to 61% with pure ADNC. LATE-NC was associated with increased Clinical Dementia Rating Sum of Boxes (CDR-SOB) scores, i.e. worsened global cognitive impairments, in participants with no/low ADNC and no neocortical Lewy body pathology (p = 0.0023). Among pure LATE-NC cases, there was a trend for higher LATE-NC stages to be associated with worse CDR-SOB scores (p = 0.026 for linear trend of LATE-NC stages). Pure LATE-NC was not associated with clinical features of disinhibition or primary progressive aphasia. In summary, LATE-NC with no or low levels of ADNC was less frequent than pure ADNC but was not rare, particularly among individuals who lacked the <i>APOE</i> 4 allele, and in study cohorts with <i>APOE</i> 4 frequencies similar to those in most human populations.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02821-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637182","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":"Microglia contribute to the production of the amyloidogenic ABri peptide in familial British dementia","authors":"Charles Arber,&nbsp;Jackie M. Casey,&nbsp;Samuel Crawford,&nbsp;Naiomi Rambarack,&nbsp;Umran Yaman,&nbsp;Sarah Wiethoff,&nbsp;Emma Augustin,&nbsp;Thomas M. Piers,&nbsp;Matthew Price,&nbsp;Agueda Rostagno,&nbsp;Jorge Ghiso,&nbsp;Patrick A. Lewis,&nbsp;Tamas Revesz,&nbsp;John Hardy,&nbsp;Jennifer M. Pocock,&nbsp;Henry Houlden,&nbsp;Jonathan M. Schott,&nbsp;Dervis A. Salih,&nbsp;Tammaryn Lashley,&nbsp;Selina Wray","doi":"10.1007/s00401-024-02820-z","DOIUrl":"10.1007/s00401-024-02820-z","url":null,"abstract":"<div><p>Mutations in <i>ITM2B</i> cause familial British, Danish, Chinese, and Korean dementias. In familial British dementia (FBD), a mutation in the stop codon of the <i>ITM2B</i> gene (also known as <i>BRI2</i>) causes a C-terminal cleavage fragment of the ITM2B/BRI2 protein to be extended by 11 amino acids. This fragment, termed amyloid-Bri (ABri), is highly insoluble and forms extracellular plaques in the brain. ABri plaques are accompanied by tau pathology, neuronal cell death and progressive dementia, with striking parallels to the aetiology and pathogenesis of Alzheimer’s disease. The molecular mechanisms underpinning FBD are ill-defined. Using patient-derived induced pluripotent stem cells, we show that expression of <i>ITM2B/BRI2</i> is 34-fold higher in microglia than neurons and 15-fold higher in microglia compared with astrocytes. This cell-specific enrichment is supported by expression data from both mouse and human brain tissue. ITM2B/BRI2 protein levels are higher in iPSC-microglia compared with neurons and astrocytes. The ABri peptide was detected in patient iPSC-derived microglial lysates and conditioned media but was undetectable in patient-derived neurons and control microglia. The pathological examination of post-mortem tissue supports the presence of ABri in microglia that are in proximity to pre-amyloid deposits. Finally, gene co-expression analysis supports a role for ITM2B/BRI2 in disease-associated microglial responses. These data demonstrate that microglia are major contributors to the production of amyloid forming peptides in FBD, potentially acting as instigators of neurodegeneration. Additionally, these data also suggest ITM2B/BRI2 may be part of a microglial response to disease, motivating further investigations of its role in microglial activation. These data have implications for our understanding of the role of microglia and the innate immune response in the pathogenesis of FBD and other neurodegenerative dementias including Alzheimer’s disease.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02820-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142636668","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":"Correction: Multiciliated ependymal cells: an update on biology and pathology in the adult brain","authors":"Adam M. R. Groh,&nbsp;Yeji Lori Song,&nbsp;Fiona Tea,&nbsp;Brianna Lu,&nbsp;Stephanie Huynh,&nbsp;Elia Afanasiev,&nbsp;Maxime Bigotte,&nbsp;Marc R. Del Bigio,&nbsp;Jo Anne Stratton","doi":"10.1007/s00401-024-02826-7","DOIUrl":"10.1007/s00401-024-02826-7","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611885","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}