Acta Neuropathologica最新文献

{"title":"The microglial translocator protein (TSPO) in Alzheimer’s disease reflects a phagocytic phenotype","authors":"Emma F. Garland,&nbsp;Henrike Antony,&nbsp;Laura Kulagowska,&nbsp;Thomas Scott,&nbsp;Charlotte Rogien,&nbsp;Michel Bottlaender,&nbsp;James A. R. Nicoll,&nbsp;Delphine Boche","doi":"10.1007/s00401-024-02822-x","DOIUrl":"10.1007/s00401-024-02822-x","url":null,"abstract":"<div><p>Translocator protein (TSPO) is a mitochondrial protein expressed by microglia, ligands for which are used as a marker of neuroinflammation in PET studies of Alzheimer’s disease (AD). We previously showed increasing TSPO load in the cerebral cortex with AD progression, consistent with TSPO PET scan findings. Here, we aim to characterise the microglial phenotype associated with TSPO expression to aid interpretation of the signal generated by TSPO ligands in patients. Human post-mortem sections of temporal lobe (TL) and cerebellum (Cb) from cases classified by Braak group (0–II, III–IV, V–VI; each <i>n</i> = 10) were fluorescently double labelled for TSPO and microglial markers: Iba1, HLA-DR, CD68, MSR-A and CD64. Quantification was performed on scanned images using QuPath software to assess the microglial phenotype of TSPO. Qualitative analysis was also performed for TSPO with GFAP (astrocytes), CD31 (endothelial cells) and CD163 (perivascular macrophages) to characterise the cellular profile of TSPO. The percentage of CD68⁺TSPO⁺ double-labelled cells was significantly higher than for other microglial markers in both brain regions and in all Braak stages, followed by MSR-A⁺TSPO⁺ microglia. Iba1⁺TSPO⁺ cells were more numerous in the cerebellum than the temporal lobe, while CD64⁺TSPO⁺ cells were more numerous in the temporal lobe. No differences were observed for the other microglial markers. TSPO expression was also detected in endothelial cells, but not detected in astrocytes nor in perivascular macrophages. Our data suggest that TSPO is mainly related to a phagocytic profile of microglia (CD68⁺) in human AD, potentially highlighting the ongoing neurodegeneration.</p></div>","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":"https://link.springer.com/content/pdf/10.1007/s00401-024-02822-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610349","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":"No sex difference in the extent of acute mechanical blood–brain barrier disruption after experimental concussion","authors":"Hailong Song,&nbsp;Eashwar Kantemneni,&nbsp;Yue Qiu,&nbsp;Jean-Pierre Dolle,&nbsp;D. Kacy Cullen,&nbsp;William Stewart,&nbsp;Douglas H. Smith","doi":"10.1007/s00401-024-02829-4","DOIUrl":"10.1007/s00401-024-02829-4","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":"142611886","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":"Compartment-specific small non-coding RNA changes and nucleolar defects in human mesial temporal lobe epilepsy","authors":"Vamshidhar R. Vangoor,&nbsp;Giuliano Giuliani,&nbsp;Marina de Wit,&nbsp;Carolina K. Rangel,&nbsp;Morten T. Venø,&nbsp;Joran T. Schulte,&nbsp;Andreia Gomes-Duarte,&nbsp;Ketharini Senthilkumar,&nbsp;Noora Puhakka,&nbsp;Jørgen Kjems,&nbsp;Pierre N. E. de Graan,&nbsp;R. Jeroen Pasterkamp","doi":"10.1007/s00401-024-02817-8","DOIUrl":"10.1007/s00401-024-02817-8","url":null,"abstract":"<div><p>Mesial temporal lobe epilepsy (mTLE) is a debilitating disease characterized by recurrent seizures originating from temporal lobe structures such as the hippocampus. The pathogenic mechanisms underlying mTLE are incompletely understood but include changes in the expression of non-coding RNAs in affected brain regions. Previous work indicates that some of these changes may be selective to specific sub-cellular compartments, but the full extent of these changes and how these sub-cellular compartments themselves are affected remains largely unknown. Here, we performed small RNA sequencing (RNA-seq) of sub-cellular fractions of hippocampal tissue from mTLE patients and controls to determine nuclear and cytoplasmic expression levels of microRNAs (miRNAs). This showed differential expression of miRNAs and isomiRs, several of which displayed enriched nuclear expression in mTLE. Subsequent analysis of <i>miR-92b</i>, the most strongly deregulated miRNA in the nucleus, showed accumulation of this miRNA in the nucleolus in mTLE and association with snoRNAs. This prompted us to further study the nucleolus in human mTLE which uncovered several defects, such as altered nucleolar size or shape, mis-localization of nucleolar proteins, and deregulation of snoRNAs, indicative of nucleolar stress. In a rat model of epilepsy, nucleolar phenotypes were detected in the latency period before the onset of spontaneous seizures, suggesting that nucleolar changes may contribute to the development of seizures and mTLE. Overall, these data for the first time implicate nucleolar defects in the pathogenesis of mTLE and provide a valuable framework for further defining the functional consequences of altered sub-cellular RNA profiles in this disease.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02817-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594914","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":"TMEM106B amyloid filaments in the Biondi bodies of ependymal cells","authors":"Bernardino Ghetti,&nbsp;Manuel Schweighauser,&nbsp;Max H. Jacobsen,&nbsp;Derrick Gray,&nbsp;Mehtap Bacioglu,&nbsp;Alexey G. Murzin,&nbsp;Bradley S. Glazier,&nbsp;Taxiarchis Katsinelos,&nbsp;Ruben Vidal,&nbsp;Kathy L. Newell,&nbsp;Sujuan Gao,&nbsp;Holly J. Garringer,&nbsp;Maria Grazia Spillantini,&nbsp;Sjors H. W. Scheres,&nbsp;Michel Goedert","doi":"10.1007/s00401-024-02807-w","DOIUrl":"10.1007/s00401-024-02807-w","url":null,"abstract":"<div><p>Biondi bodies are filamentous amyloid inclusions of unknown composition in ependymal cells of the choroid plexuses, ependymal cells lining cerebral ventricles and ependymal cells of the central canal of the spinal cord. Their formation is age-dependent and they are commonly associated with a variety of neurodegenerative conditions, including Alzheimer’s disease and Lewy body disorders. Here, we show that Biondi bodies are strongly immunoreactive with TMEM239, an antibody specific for inclusions of transmembrane protein 106B (TMEM106B). Biondi bodies were labelled by both this antibody and the amyloid dye pFTAA. Many Biondi bodies were also labelled for TMEM106B and the lysosomal markers Hexosaminidase A and Cathepsin D. By transmission immuno-electron microscopy, Biondi bodies of choroid plexuses were decorated by TMEM239 and were associated with structures that resembled residual bodies or secondary lysosomes. By electron cryo-microscopy, TMEM106B filaments from Biondi bodies of choroid plexuses were similar (Biondi variant), but not identical, to the fold I that was previously identified in filaments from brain parenchyma.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02807-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581839","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":"Comprehensive mapping of synaptic vesicle protein 2A (SV2A) in health and neurodegenerative diseases: a comparative analysis with synaptophysin and ground truth for PET-imaging interpretation","authors":"Mahsa Shanaki Bavarsad,&nbsp;Salvatore Spina,&nbsp;Abby Oehler,&nbsp;Isabel E. Allen,&nbsp;Claudia K. Suemoto,&nbsp;Renata E. P. Leite,&nbsp;William S. Seeley,&nbsp;Ari Green,&nbsp;William Jagust,&nbsp;Gil D. Rabinovici,&nbsp;Lea T. Grinberg","doi":"10.1007/s00401-024-02816-9","DOIUrl":"10.1007/s00401-024-02816-9","url":null,"abstract":"<div><p>Synaptic dysfunction and loss are central to neurodegenerative diseases and correlate with cognitive decline. Synaptic Vesicle Protein 2A (SV2A) is a promising PET-imaging target for assessing synaptic density in vivo, but comprehensive mapping in the human brain is needed to validate its biomarker potential. This study used quantitative immunohistochemistry and Western blotting to map SV2A and synaptophysin (SYP) densities across six cortical regions in healthy controls and patients with early-onset Alzheimer’s disease (EOAD), late-onset Alzheimer’s disease (LOAD), progressive supranuclear palsy (PSP), and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-GRN). We identified region in SV2A density among controls and observed disease- and region-specific reductions, with the most severe in FTLD-GRN (up to 59.5%) and EOAD. EOAD showed a 49% reduction in the middle frontal gyrus (MFG), while LOAD had over 30% declines in the inferior frontal gyrus (IFG) and hippocampus (CA1). In PSP, smaller but significant reductions were noted in the hippocampal formation, with the inferior temporal gyrus (ITG) relatively unaffected. A strong positive correlation between SV2A and SYP densities confirmed SV2A’s reliability as a synaptic integrity marker. This study supports the use of SV2A PET imaging for early diagnosis and monitoring of neurodegenerative diseases, providing essential data for interpreting in vivo PET results. Further research should explore SV2A as a therapeutic target and validate these findings in larger, longitudinal studies.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142540508","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":"Effects of brain microRNAs in cognitive trajectory and Alzheimer’s disease","authors":"Selina M. Vattathil,&nbsp;Sarah Sze Min Tan,&nbsp;Paul J. Kim,&nbsp;David A. Bennett,&nbsp;Julie A. Schneider,&nbsp;Aliza P. Wingo,&nbsp;Thomas S. Wingo","doi":"10.1007/s00401-024-02818-7","DOIUrl":"10.1007/s00401-024-02818-7","url":null,"abstract":"<div><p>microRNAs (miRNAs) have a broad influence on gene expression; however, we have limited insights into their contribution to rate of cognitive decline over time or Alzheimer’s disease (AD). Given this, we tested associations of 528 miRNAs with cognitive trajectory, AD hallmark pathologies, and AD clinical diagnosis using small RNA sequencing from the dorsolateral prefrontal cortex of 641 community-based donors. We found 311 miRNAs differentially expressed in AD or its endophenotypes after adjusting for technical and sociodemographic variables. Among these, 137 miRNAs remained differentially expressed after additionally adjusting for several co-occurring age-related cerebral pathologies, suggesting that some miRNAs are associated with the traits through co-occurring pathologies while others through mechanisms independent from pathologies. Pathway enrichment analysis of downstream targets of these differentially expressed miRNAs found enrichment in transcription, postsynaptic signalling, cellular senescence, and lipoproteins. In sex-stratified analyses, five miRNAs showed sex-biased differential expression for one or more AD endophenotypes, highlighting the role that sex has in AD. Lastly, we used Mendelian randomization to test whether the identified differentially expressed miRNAs contribute to the cause or are the consequence of the traits. Remarkably, 15 differentially expressed miRNAs had evidence consistent with a causal role, laying the groundwork for future mechanistic studies of miRNAs in AD and its endophenotypes.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02818-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542959","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":"Cryo-EM structure of a natural prion: chronic wasting disease fibrils from deer","authors":"Parvez Alam,&nbsp;Forrest Hoyt,&nbsp;Efrosini Artikis,&nbsp;Jakub Soukup,&nbsp;Andrew G. Hughson,&nbsp;Cindi L. Schwartz,&nbsp;Kent Barbian,&nbsp;Michael W. Miller,&nbsp;Brent Race,&nbsp;Byron Caughey","doi":"10.1007/s00401-024-02813-y","DOIUrl":"10.1007/s00401-024-02813-y","url":null,"abstract":"<div><p>Chronic wasting disease (CWD) is a widely distributed prion disease of cervids with implications for wildlife conservation and also for human and livestock health. The structures of infectious prions that cause CWD and other natural prion diseases of mammalian hosts have been poorly understood. Here we report a 2.8 Å resolution cryogenic electron microscopy-based structure of CWD prion fibrils from the brain of a naturally infected white-tailed deer expressing the most common wild-type PrP sequence. Like recently solved rodent-adapted scrapie prion fibrils, our atomic model of CWD fibrils contains single stacks of PrP molecules forming parallel in-register intermolecular <i>β</i>-sheets and intervening loops comprising major N- and C-terminal lobes within the fibril cross-section. However, CWD fibrils from a natural cervid host differ markedly from the rodent structures in many other features, including a ~ 180° twist in the relative orientation of the lobes. This CWD structure suggests mechanisms underlying the apparent CWD transmission barrier to humans and should facilitate more rational approaches to the development of CWD vaccines and therapeutics.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02813-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489363","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":"Autoantibodies to BACE1 promote Aβ accumulation and neurodegeneration in Alzheimer’s disease","authors":"Ye-Ran Wang,&nbsp;Xiao-Qin Zeng,&nbsp;Jun Wang,&nbsp;Christopher J. Fowler,&nbsp;Qiao-Xin Li,&nbsp;Xian-Le Bu,&nbsp;James Doecke,&nbsp;Paul Maruff,&nbsp;Ralph N. Martins,&nbsp;Christopher C. Rowe,&nbsp;Colin L. Masters,&nbsp;Yan-Jiang Wang,&nbsp;Yu-Hui Liu","doi":"10.1007/s00401-024-02814-x","DOIUrl":"10.1007/s00401-024-02814-x","url":null,"abstract":"<div><p>The profile of autoantibodies is dysregulated in patients with Alzheimer’s disease (AD). Autoantibodies to beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) are present in human blood. This study aims to investigate the clinical relevance and pathophysiological roles of autoantibodies to BACE1 in AD. Clinical investigations were conducted in two independent cohorts, the Chongqing cohort, and the Australian Imaging, Biomarkers, and Lifestyle (AIBL) cohort. The Chongqing cohort included 55 AD patients, 28 patients with non-AD dementia, and 70 cognitively normal subjects (CN). The AIBL cohort included 162 Aβ-PET⁻ CN, 169 Aβ-PET⁺ cognitively normal subjects (preclinical AD), and 31 Aβ-PET⁺ cognitively impaired subjects (Clinical AD). Plasma autoantibodies to BACE1 were determined by one-site Elisa. The associations of plasma autoantibodies to BACE1 with brain Aβ load and cognitive trajectory were investigated. The effects of autoantibodies to BACE1 on AD-type pathologies and underlying mechanisms were investigated in APP/PS1 mice and SH/APPswe/PS1wt cell lines. In the Chongqing cohort, plasma autoantibodies to BACE1 were higher in AD patients, in comparison with CN and non-AD dementia patients. In the AIBL cohort, plasma autoantibodies to BACE1 were highest in clinical AD patients, followed by preclinical AD and CN subjects. Higher autoantibodies to BACE1 were associated with an increased incidence of brain amyloid positivity conversion during follow-up. Autoantibodies to BACE1 exacerbated brain amyloid deposition and subsequent AD-type pathologies, including Tau hyperphosphorylation, neuroinflammation, and neurodegeneration in APP/PS1 mice. Autoantibodies to BACE1 increased Aβ production by promoting BACE1 expression through inhibiting PPARγ signaling. These findings suggest that autoantibodies to BACE1 are pathogenic in AD and the upregulation of these autoantibodies may promote the development of the disease. This study offers new insights into the mechanism of AD from an autoimmune perspective.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489364","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":"MYB/MYBL1-altered gliomas frequently harbor truncations and non-productive fusions in the MYB and MYBL1 genes","authors":"Hye-Jung Chung,&nbsp;Sharika Rajan,&nbsp;Zhichao Wu,&nbsp;Christina K. Ferrone,&nbsp;Mark Raffeld,&nbsp;Ina Lee,&nbsp;Jeffrey Gagan,&nbsp;Christopher Dampier,&nbsp;Zied Abdullaev,&nbsp;Manoj Tyagi,&nbsp;Patrick. J. Cimino,&nbsp;Martha Quezado,&nbsp;Kenneth Aldape","doi":"10.1007/s00401-024-02803-0","DOIUrl":"10.1007/s00401-024-02803-0","url":null,"abstract":"<div><p>Astrocytomas that harbor recurrent genomic alterations in <i>MYB</i> or <i>MYBL1</i> are a group of Pediatric-type diffuse low-grade gliomas that were newly recognized in the 2021 WHO Classification of Tumors of the Central Nervous System. These tumors are described in the WHO classification as harboring fusions in <i>MYB</i> or <i>MYBL1</i>. In this report, we examine 14 consecutive cases in which a <i>MYB</i> or <i>MYBL1</i> alteration was identified, each with diagnostic confirmation by genome-wide DNA methylation profiling (6 Angiocentric gliomas and 8 Diffuse astrocytomas, <i>MYB-</i> or <i>MYBL1</i>-altered), for their specific genomic alterations in these genes. Using RNA sequencing, we find productive in-frame fusions of the <i>MYB</i> or <i>MYBL1</i> genes in only 5/14 cases. The remaining 9 cases show genomic alterations that result in truncation of the gene, without evidence of an in-frame fusion partner. Gene expression analysis showed overexpression of the <i>MYB</i>(<i>L1</i>) genes, regardless of the presence of a productive fusion. In addition, <i>QKI,</i> a recognized fusion partner common in angiocentric glioma, was generally up-regulated in these 14 cases, compared to a cohort comprising &gt;1000 CNS tumors of various types, regardless of whether a genomic alteration in <i>QKI</i> was present. Overall, the results show that truncations, in the absence of a productive fusion, of the <i>MYB</i>(<i>L1</i>) genes can likely drive the tumors and have implications for the analysis and diagnosis of Angiocentric glioma and Diffuse astrocytoma, <i>MYB-</i> or <i>MYBL1</i>-altered, especially for cases that are tested on panels designed to focus on fusion detection.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02803-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142447317","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":"Hypothesis-based investigation of known AD risk variants reveals the genetic underpinnings of neuropathological lesions observed in Alzheimer’s-type dementia","authors":"Celeste Laureyssen,&nbsp;Fahri Küçükali,&nbsp;Jasper Van Dongen,&nbsp;Klara Gawor,&nbsp;Sandra O. Tomé,&nbsp;Alicja Ronisz,&nbsp;Markus Otto,&nbsp;Christine A. F. von Arnim,&nbsp;Philip Van Damme,&nbsp;Rik Vandenberghe,&nbsp;Dietmar Rudolf Thal,&nbsp;Kristel Sleegers","doi":"10.1007/s00401-024-02815-w","DOIUrl":"10.1007/s00401-024-02815-w","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Besides neurofibrillary tangles and amyloid beta (A<i>β</i>) plaques, a wide range of co-morbid neuropathological features can be observed in AD brains. Since AD has a very strong genetic background and displays a wide phenotypic heterogeneity, this study aims at investigating the genetic underpinnings of co-morbid and hallmark neuropathological lesions. This was realized by obtaining the genotypes for 75 AD risk variants from low-coverage whole-genome sequencing data for 325 individuals from the Leuven Brain Collection. Association testing with deeply characterized neuropathological lesions revealed a strong and likely direct effect of rs117618017, a SNP in exon 1 of <i>APH1B</i>, with tau-related pathology. Second, a relation between <i>APOE</i> and granulovacuolar degeneration, a proxy for necroptosis, was also discovered in addition to replication of the well-known association of <i>APOE</i> with AD hallmark neuropathological lesions. Additionally, several nominal associations with AD risk genes were detected for pTDP pathology, <i>α</i>-synuclein lesions and pTau-related pathology. These findings were confirmed in a meta-analysis with three independent cohorts. For example, we replicated a prior association between <i>TPCN1</i> (rs6489896) and LATE-NC risk. Furthermore, we identified new putative LATE-NC-linked SNPs, including rs7068231, located upstream of <i>ANK3</i>. We found association between <i>BIN1</i> (rs6733839) and α-synuclein pathology, and replicated a prior association between <i>USP6NL</i> (rs7912495) and Lewy body pathology. Additionally, we also found that <i>UMAD1</i> (rs6943429) was nominally associated with Lewy body pathology. Overall, these results contribute to a broader general understanding of how AD risk variants discovered in large-scale clinical genome-wide association studies are involved in the pathological mechanisms of AD and indicate the importance of downstream elimination of phenotypic heterogeneity introduced in these studies.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02815-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449474","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}