{"title":"Microglia contribute to polyG-dependent neurodegeneration in neuronal intranuclear inclusion disease","authors":"Shaoping Zhong, Yangye Lian, Binbin Zhou, Ruiqing Ren, Lewei Duan, Yuyin Pan, Yuchen Gong, Xiaoling Wu, Dengfeng Cheng, Puming Zhang, Boxun Lu, Xin Wang, Jing Ding","doi":"10.1007/s00401-024-02776-0","DOIUrl":"10.1007/s00401-024-02776-0","url":null,"abstract":"<div><p>Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder caused by the expansion of GGC trinucleotide repeats in <i>NOTCH2NLC</i> gene. Despite identifying uN2CpolyG, a toxic polyglycine (polyG) protein translated by expanded GGC repeats, the exact pathogenic mechanisms of NIID remain unclear. In this study, we investigated the role of polyG by expressing various forms of <i>NOTCH2NLC</i> in mice: the wild-type, the expanded form with 100 GGC repeats (either translating or not translating into uN2CpolyG), and the mutated form that encodes a pure polyG without GGC-repeat RNA and the C-terminal stretch (uN2CpolyG-dCT). Both uN2CpolyG and uN2CpolyG-dCT induced the formation of inclusions composed by filamentous materials and resulted in neurodegenerative phenotypes in mice, including impaired motor and cognitive performance, shortened lifespan, and pathologic lesions such as white-matter lesions, microgliosis, and astrogliosis. In contrast, expressing GGC-repeat RNA alone was non-pathogenic. Through bulk and single-nuclei RNA sequencing, we identified common molecular signatures linked to the expression of uN2CpolyG and uN2CpolyG-dCT, particularly the upregulation of inflammation and microglia markers, and the downregulation of immediate early genes and splicing factors. Importantly, microglia-mediated inflammation was visualized in NIID patients using positron emission tomography, correlating with levels of white-matter atrophy. Furthermore, microglia ablation ameliorated neurodegenerative phenotypes and transcriptional alterations in uN2CpolyG-expressing mice but did not affect polyG inclusions. Together, these results demonstrate that polyG is crucial for the pathogenesis of NIID and highlight the significant role of microglia in polyG-induced neurodegeneration.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02776-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987141","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}
Anat O. Stemmer-Rachamimov, Liana Kozanno, Scott R. Plotkin, Justin T. Jordan, Joseph F. Rizzo 3rd
{"title":"Reply to L. Lucchino et al. on commentary on “Histologic correlates of “Choroidal Abnormalities” in Neurofibromatosis type 1”","authors":"Anat O. Stemmer-Rachamimov, Liana Kozanno, Scott R. Plotkin, Justin T. Jordan, Joseph F. Rizzo 3rd","doi":"10.1007/s00401-024-02782-2","DOIUrl":"10.1007/s00401-024-02782-2","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02782-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987142","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}
Luca Lucchino, Fabiana Mallone, Magda Gharbiya, Ludovico Alisi
{"title":"Key features of choroidal abnormalities in neurofibromatosis type 1, a commentary on “Histologic correlates of “choroidal abnormalities” in neurofibromatosis type 1 (NF1)”","authors":"Luca Lucchino, Fabiana Mallone, Magda Gharbiya, Ludovico Alisi","doi":"10.1007/s00401-024-02783-1","DOIUrl":"10.1007/s00401-024-02783-1","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02783-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987180","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}
Md Rejaul Hoq, Anllely Fernandez, Frank S. Vago, Grace I. Hallinan, Sakshibeedu R. Bharath, Daoyi Li, Kadir A. Ozcan, Holly J. Garringer, Wen Jiang, Ruben Vidal, Bernardino Ghetti
{"title":"Cryo-EM structures of cotton wool plaques’ amyloid β and of tau filaments in dominantly inherited Alzheimer disease","authors":"Md Rejaul Hoq, Anllely Fernandez, Frank S. Vago, Grace I. Hallinan, Sakshibeedu R. Bharath, Daoyi Li, Kadir A. Ozcan, Holly J. Garringer, Wen Jiang, Ruben Vidal, Bernardino Ghetti","doi":"10.1007/s00401-024-02786-y","DOIUrl":"10.1007/s00401-024-02786-y","url":null,"abstract":"<div><p>Cotton wool plaques (CWPs) have been described as features of the neuropathologic phenotype of dominantly inherited Alzheimer disease (DIAD) caused by some missense and deletion mutations in the presenilin 1 (<i>PSEN1</i>) gene. CWPs are round, eosinophilic amyloid-β (Aβ) plaques that lack an amyloid core and are recognizable, but not fluorescent, in Thioflavin S (ThS) preparations. Amino-terminally truncated and post-translationally modified Aβ peptide species are the main component of CWPs. Tau immunopositive neurites may be present in CWPs. In addition, neurofibrillary tangles coexist with CWPs. Herein, we report the structure of Aβ and tau filaments isolated from brain tissue of individuals affected by DIAD caused by the <i>PSEN1 V261I</i> and <i>A431E</i> mutations, with the CWP neuropathologic phenotype. CWPs are predominantly composed of type I Aβ filaments present in two novel arrangements, type Ic and type Id; additionally, CWPs contain type I and type Ib Aβ filaments. Tau filaments have the AD fold, which has been previously reported in sporadic AD and DIAD. The formation of type Ic and type Id Aβ filaments may be the basis for the phenotype of CWPs. Our data are relevant for the development of PET imaging methodologies to best detect CWPs in DIAD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11327195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987179","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}
Rehana K. Leak, Rachel N. Clark, Muslim Abbas, Fei Xu, Jeffrey L. Brodsky, Jun Chen, Xiaoming Hu, Kelvin C. Luk
{"title":"Current insights and assumptions on α-synuclein in Lewy body disease","authors":"Rehana K. Leak, Rachel N. Clark, Muslim Abbas, Fei Xu, Jeffrey L. Brodsky, Jun Chen, Xiaoming Hu, Kelvin C. Luk","doi":"10.1007/s00401-024-02781-3","DOIUrl":"10.1007/s00401-024-02781-3","url":null,"abstract":"<div><p>Lewy body disorders are heterogeneous neurological conditions defined by intracellular inclusions composed of misshapen α-synuclein protein aggregates. Although α-synuclein aggregates are only one component of inclusions and not strictly coupled to neurodegeneration, evidence suggests they seed the propagation of Lewy pathology within and across cells. Genetic mutations, genomic multiplications, and sequence polymorphisms of the gene encoding α-synuclein are also causally linked to Lewy body disease. In nonfamilial cases of Lewy body disease, the disease trigger remains unidentified but may range from industrial/agricultural toxicants and natural sources of poisons to microbial pathogens. Perhaps due to these peripheral exposures, Lewy inclusions appear at early disease stages in brain regions connected with cranial nerves I and X, which interface with inhaled and ingested environmental elements in the nasal or gastrointestinal cavities. Irrespective of its identity, a stealthy disease trigger most likely shifts soluble α-synuclein (directly or indirectly) into insoluble, cross-β-sheet aggregates. Indeed, β-sheet-rich self-replicating α-synuclein multimers reside in patient plasma, cerebrospinal fluid, and other tissues, and can be subjected to α-synuclein seed amplification assays. Thus, clinicians should be able to capitalize on α-synuclein seed amplification assays to stratify patients into potential responders <i>versus</i> non-responders in future clinical trials of α-synuclein targeted therapies. Here, we briefly review the current understanding of α-synuclein in Lewy body disease and speculate on pathophysiological processes underlying the potential transmission of α-synucleinopathy across the neuraxis.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974781","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}
Kevin Y. Zhang, Megan Parker, Carly Weber-Levine, Anita Kalluri, Ignacio Gonzalez-Gomez, Eric Raabe, Jonathan C. Dudley, Christopher Gocke, Ming-Tseh Lin, Ying Zou, Mohamed Sherief, David O. Kamson, Matthias Holdhoff, Debraj Mukherjee, Victoria Croog, Karisa C. Schreck, Jordina Rincon-Torroella, Chetan Bettegowda, Charles G. Eberhart, Tejus Bale, Calixto-Hope G. Lucas
{"title":"ASXL1 inactivation and reduced H3K27me3 across central nervous system tumors","authors":"Kevin Y. Zhang, Megan Parker, Carly Weber-Levine, Anita Kalluri, Ignacio Gonzalez-Gomez, Eric Raabe, Jonathan C. Dudley, Christopher Gocke, Ming-Tseh Lin, Ying Zou, Mohamed Sherief, David O. Kamson, Matthias Holdhoff, Debraj Mukherjee, Victoria Croog, Karisa C. Schreck, Jordina Rincon-Torroella, Chetan Bettegowda, Charles G. Eberhart, Tejus Bale, Calixto-Hope G. Lucas","doi":"10.1007/s00401-024-02785-z","DOIUrl":"10.1007/s00401-024-02785-z","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11324662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974780","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}
Sybren L. N. Maas, Thomas Hielscher, Philipp Sievers, Volker Hovestadt, Abigail K. Suwala, Till Acker, Michael Weller, Matthias Preusser, Christel Herold-Mende, Wolfgang Wick, Andreas von Deimling, Natalie Berghaus, Felix Sahm
{"title":"Loss over 5% of chromosome 1p is a clinically relevant and applicable cut-off for increased risk of recurrence in meningioma","authors":"Sybren L. N. Maas, Thomas Hielscher, Philipp Sievers, Volker Hovestadt, Abigail K. Suwala, Till Acker, Michael Weller, Matthias Preusser, Christel Herold-Mende, Wolfgang Wick, Andreas von Deimling, Natalie Berghaus, Felix Sahm","doi":"10.1007/s00401-024-02777-z","DOIUrl":"10.1007/s00401-024-02777-z","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11310275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900585","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}
Melissa J. Alldred, Harshitha Pidikiti, Kyrillos W. Ibrahim, Sang Han Lee, Adriana Heguy, Gabriel E. Hoffman, Panos Roussos, Thomas Wisniewski, Jerzy Wegiel, Grace E. Stutzmann, Elliott J. Mufson, Stephen D. Ginsberg
{"title":"Analysis of microisolated frontal cortex excitatory layer III and V pyramidal neurons reveals a neurodegenerative phenotype in individuals with Down syndrome","authors":"Melissa J. Alldred, Harshitha Pidikiti, Kyrillos W. Ibrahim, Sang Han Lee, Adriana Heguy, Gabriel E. Hoffman, Panos Roussos, Thomas Wisniewski, Jerzy Wegiel, Grace E. Stutzmann, Elliott J. Mufson, Stephen D. Ginsberg","doi":"10.1007/s00401-024-02768-0","DOIUrl":"10.1007/s00401-024-02768-0","url":null,"abstract":"<div><p>We elucidated the molecular fingerprint of vulnerable excitatory neurons within select cortical lamina of individuals with Down syndrome (DS) for mechanistic understanding and therapeutic potential that also informs Alzheimer’s disease (AD) pathophysiology. Frontal cortex (BA9) layer III (L3) and layer V (L5) pyramidal neurons were microisolated from postmortem human DS and age- and sex-matched controls (CTR) to interrogate differentially expressed genes (DEGs) and key biological pathways relevant to neurodegenerative programs. We identified > 2300 DEGs exhibiting convergent dysregulation of gene expression in both L3 and L5 pyramidal neurons in individuals with DS versus CTR subjects. DEGs included over 100 triplicated human chromosome 21 genes in L3 and L5 neurons, demonstrating a trisomic neuronal karyotype in both laminae. In addition, thousands of other DEGs were identified, indicating gene dysregulation is not limited to trisomic genes in the aged DS brain, which we postulate is relevant to AD pathobiology. Convergent L3 and L5 DEGs highlighted pertinent biological pathways and identified key pathway-associated targets likely underlying corticocortical neurodegeneration and related cognitive decline in individuals with DS. Select key DEGs were interrogated as potential hub genes driving dysregulation, namely the triplicated DEGs amyloid precursor protein (APP) and superoxide dismutase 1 (SOD1), along with key signaling DEGs including mitogen activated protein kinase 1 and 3 (MAPK1, MAPK3) and calcium calmodulin dependent protein kinase II alpha (CAMK2A), among others. Hub DEGs determined from multiple pathway analyses identified potential therapeutic candidates for amelioration of cortical neuron dysfunction and cognitive decline in DS with translational relevance to AD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02768-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892596","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}
Nur Jury-Garfe, Javier Redding-Ochoa, Yanwen You, Pablo Martínez, Hande Karahan, Enrique Chimal-Juárez, Travis S. Johnson, Jie Zhang, Susan Resnick, Jungsu Kim, Juan C. Troncoso, Cristian A. Lasagna-Reeves
{"title":"Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease","authors":"Nur Jury-Garfe, Javier Redding-Ochoa, Yanwen You, Pablo Martínez, Hande Karahan, Enrique Chimal-Juárez, Travis S. Johnson, Jie Zhang, Susan Resnick, Jungsu Kim, Juan C. Troncoso, Cristian A. Lasagna-Reeves","doi":"10.1007/s00401-024-02775-1","DOIUrl":"10.1007/s00401-024-02775-1","url":null,"abstract":"<div><p>Asymptomatic Alzheimer’s disease (AsymAD) describes the status of individuals with preserved cognition but identifiable Alzheimer’s disease (AD) brain pathology (i.e., beta-amyloid (Aβ) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD subjects to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit enrichment in core plaques, decreased filamentous plaque accumulation, and increased plaque-surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD brains than in AD brains, and tau seeding activity was comparable to that in healthy brains. We used spatial transcriptomics to characterize the plaque niche further and revealed autophagy, endocytosis, and phagocytosis as the pathways associated with the genes upregulated in the AsymAD plaque niche. Furthermore, the levels of ARP2 and CAP1, which are actin-based motility proteins that participate in the dynamics of actin filaments to allow cell motility, were increased in the microglia surrounding amyloid plaques in AsymAD cases. Our findings suggest that the amyloid-plaque microenvironment in AsymAD cases is characterized by the presence of microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared with that in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aβ, preserving brain health, and slowing AD pathology progression.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888139","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":"Alcohol consumers with liver pathology rarely display α-synuclein pathology","authors":"Sylwia Libard, Fredrik Tamsen, Irina Alafuzoff","doi":"10.1007/s00401-024-02772-4","DOIUrl":"10.1007/s00401-024-02772-4","url":null,"abstract":"<div><p>It has been suggested that alcohol consumption protects against Parkinson's disease (PD). Here we assessed postmortem tissue samples from the brains and livers of 100 subjects with ages at death ranging from 51 to 93. Twenty percent of these subjects were demented. We used standardized assessment strategies to assess both the brain and liver pathologies (LP). Our cohort included subjects with none, mild, moderate, and severe LP caused by alcohol consumption. We noted a significant negative correlation of categorical data between liver steatosis and α-synuclein (αS) in the brain and a significant negative correlation between the extent of liver steatosis and fibrosis and the extent of αS in the brain. There was a significant negative association between the observation of Alzheimer’s type II astrocytes and αS pathology in the brain. No association was noted between LP and hyperphosphorylated τ (HPτ). No significant correlation could be seen between the extent of LP and the extent of HPτ, amyloid β protein (Aβ) or transactive DNA binding protein 43 (TDP43) in the brain. There were significant correlations observed between the extent of HPτ, Aβ, αS, and TDP43 in the brain and between liver steatosis, inflammation, and fibrosis. Subjects with severe LP displayed a higher frequency of Alzheimer’s type II astrocytes compared to those with no, or mild, LP. The assessed protein alterations were not more prevalent or severe in subjects with Alzheimer’s type II astrocytes in the brain. In all cases, dementia was attributed to a combination of altered proteins, i.e., mixed dementia and dementia was observed in 30% of those with mild LP when compared with 13% of those with severe LP. In summary, our results are in line with the outcome obtained by the two recent meta-analyses suggesting that subjects with a history of alcohol consumption seldom develop an α-synucleinopathy.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858737","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}