Ryo Kaimori, Haruto Nishida, Kumi Murata, Mari Tamura, Kohji Kuroki, Tsutomu Daa, Shinjiro Mori
{"title":"Ultrastructural endothelial cell alterations in methanol poisoning with bilateral putaminal hemorrhages: An autopsy case report.","authors":"Ryo Kaimori, Haruto Nishida, Kumi Murata, Mari Tamura, Kohji Kuroki, Tsutomu Daa, Shinjiro Mori","doi":"10.1093/jnen/nlae030","DOIUrl":"10.1093/jnen/nlae030","url":null,"abstract":"","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140336000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
John C Hedreen, Sabina Berretta, Charles L White Iii
Two aspects of the neuropathology of early Huntington disease (HD) are examined. Neurons of the neostriatum are counted to determine relative loss in striosomes versus matrix at early stages, including for the first time in preclinical cases. An immunohistochemical procedure is described that tentatively distinguishes early HD from HD mimic disorders in postmortem brains. Counts of striatal projection neurons (SPNs) in striosomes defined by calbindin immunohistochemistry versus counts in the surrounding matrix are reported for 8 Vonsattel grade 0 (including 5 premanifest), 8 grade 1, 2 grade 2 HD, and for 8 control postmortem brains. Mean counts of striosome and matrix SPNs were significantly lower in premanifest grade 0 versus controls, with striosome counts significantly lower than matrix. In 8 grade 1 and 2 grade 2 brains, no striosomes with higher SPN counts than in the surrounding matrix were observed. Comparing dorsal versus ventral neostriatum, SPNs in dorsal striosomes and matrix declined more than ventral, making clear the importance of the dorsoventral site of tissue selection for research studies. A characteristic pattern of expanded polyglutamine-immunopositive inclusions was seen in all HD cases. Inclusions were always present in some SPNs and some pontine nucleus neurons and were absent in Purkinje cells, which showed no obvious cell loss.
本文从两个方面研究了早期亨廷顿病(HD)的神经病理学。对新纹状体的神经元进行计数,以确定纹状体与基质在早期阶段的相对损失,包括首次对临床前病例进行计数。研究描述了一种免疫组化程序,该程序可初步区分死后大脑中的早期 HD 和 HD 拟态紊乱。报告了 8 个 Vonsattel 0 级(包括 5 个发病前)、8 个 1 级、2 个 2 级 HD 和 8 个对照组死后大脑中通过钙宾定免疫组化定义的纹状体中的纹状体投射神经元(SPNs)计数与周围基质中的计数。显现前 0 级与对照组相比,纹状体和基质 SPN 的平均计数明显较低,纹状体计数明显低于基质。在 8 个 1 级和 2 个 2 级大脑中,没有观察到纹状体的 SPN 数量高于周围基质。比较背侧和腹侧新纹状体,背侧纹状体和基质中的 SPN 下降幅度大于腹侧,这清楚地表明了背腹侧组织选择对研究的重要性。在所有 HD 病例中都可以看到特征性的多聚谷氨酰胺免疫阳性包涵体扩大模式。在一些SPN和一些桥脑核神经元中始终存在包涵体,而在没有明显细胞丢失的浦肯野细胞中则没有包涵体。
{"title":"Postmortem neuropathology in early Huntington disease.","authors":"John C Hedreen, Sabina Berretta, Charles L White Iii","doi":"10.1093/jnen/nlae022","DOIUrl":"10.1093/jnen/nlae022","url":null,"abstract":"<p><p>Two aspects of the neuropathology of early Huntington disease (HD) are examined. Neurons of the neostriatum are counted to determine relative loss in striosomes versus matrix at early stages, including for the first time in preclinical cases. An immunohistochemical procedure is described that tentatively distinguishes early HD from HD mimic disorders in postmortem brains. Counts of striatal projection neurons (SPNs) in striosomes defined by calbindin immunohistochemistry versus counts in the surrounding matrix are reported for 8 Vonsattel grade 0 (including 5 premanifest), 8 grade 1, 2 grade 2 HD, and for 8 control postmortem brains. Mean counts of striosome and matrix SPNs were significantly lower in premanifest grade 0 versus controls, with striosome counts significantly lower than matrix. In 8 grade 1 and 2 grade 2 brains, no striosomes with higher SPN counts than in the surrounding matrix were observed. Comparing dorsal versus ventral neostriatum, SPNs in dorsal striosomes and matrix declined more than ventral, making clear the importance of the dorsoventral site of tissue selection for research studies. A characteristic pattern of expanded polyglutamine-immunopositive inclusions was seen in all HD cases. Inclusions were always present in some SPNs and some pontine nucleus neurons and were absent in Purkinje cells, which showed no obvious cell loss.</p>","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11029463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140326673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kliment Donev, Vanitha Sundararajan, Derek Johnson, Jagadheshwar Balan, Meagan Chambers, Vera A Paulson, Kathryn P Scherpelz, Zied Abdullaev, Martha Quezado, Patrick J Cimino, Drew Pratt, Ediel Valerio, João Vıctor Alves de Castro, Dirce Maria Carraro, Giovana Tardin Torrezan, Beatriz Martins Wolff, Leslie Domenici Kulikowski, Felipe D'Almeida Costa, Kenneth Aldape, Cristiane M Ida
Diffuse midline glioma, H3 K27-altered (DMG-H3 K27) is an aggressive group of diffuse gliomas that predominantly occurs in pediatric patients, involves midline structures, and displays loss of H3 p.K28me3 (K27me3) expression by immunohistochemistry and characteristic genetic/epigenetic profile. Rare examples of a diffuse glioma with an H3 p.K28M (K27M) mutation and without involvement of the midline structures, so-called "diffuse hemispheric glioma with H3 p.K28M (K27M) mutation" (DHG-H3 K27), have been reported. Herein, we describe 2 additional cases of radiologically confirmed DHG-H3 K27 and summarize previously reported cases. We performed histological, immunohistochemical, molecular, and DNA methylation analysis and provided clinical follow-up in both cases. Overall, DHG-H3 K27 is an unusual group of diffuse gliomas that shows similar clinical, histopathological, genomic, and epigenetic features to DMG-H3 K27 as well as enrichment for activating alterations in MAPK pathway genes. These findings suggest that DHG-H3 K27 is closely related to DMG-H3 K27 and may represent an unusual presentation of DMG-H3 K27 without apparent midline involvement and with frequent MAPK pathway activation. Detailed reports of additional cases with clinical follow-up will be important to expand our understanding of this unusual group of diffuse gliomas and to better define the clinical outcome and how to classify DHG-H3 K27.
{"title":"Diffuse hemispheric glioma with H3 p.K28M (K27M) mutation: Unusual non-midline presentation of diffuse midline glioma, H3 K27M-altered?","authors":"Kliment Donev, Vanitha Sundararajan, Derek Johnson, Jagadheshwar Balan, Meagan Chambers, Vera A Paulson, Kathryn P Scherpelz, Zied Abdullaev, Martha Quezado, Patrick J Cimino, Drew Pratt, Ediel Valerio, João Vıctor Alves de Castro, Dirce Maria Carraro, Giovana Tardin Torrezan, Beatriz Martins Wolff, Leslie Domenici Kulikowski, Felipe D'Almeida Costa, Kenneth Aldape, Cristiane M Ida","doi":"10.1093/jnen/nlae018","DOIUrl":"10.1093/jnen/nlae018","url":null,"abstract":"<p><p>Diffuse midline glioma, H3 K27-altered (DMG-H3 K27) is an aggressive group of diffuse gliomas that predominantly occurs in pediatric patients, involves midline structures, and displays loss of H3 p.K28me3 (K27me3) expression by immunohistochemistry and characteristic genetic/epigenetic profile. Rare examples of a diffuse glioma with an H3 p.K28M (K27M) mutation and without involvement of the midline structures, so-called \"diffuse hemispheric glioma with H3 p.K28M (K27M) mutation\" (DHG-H3 K27), have been reported. Herein, we describe 2 additional cases of radiologically confirmed DHG-H3 K27 and summarize previously reported cases. We performed histological, immunohistochemical, molecular, and DNA methylation analysis and provided clinical follow-up in both cases. Overall, DHG-H3 K27 is an unusual group of diffuse gliomas that shows similar clinical, histopathological, genomic, and epigenetic features to DMG-H3 K27 as well as enrichment for activating alterations in MAPK pathway genes. These findings suggest that DHG-H3 K27 is closely related to DMG-H3 K27 and may represent an unusual presentation of DMG-H3 K27 without apparent midline involvement and with frequent MAPK pathway activation. Detailed reports of additional cases with clinical follow-up will be important to expand our understanding of this unusual group of diffuse gliomas and to better define the clinical outcome and how to classify DHG-H3 K27.</p>","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11029465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140049707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
George C Murray, Timothy J Hines, Abigail L D Tadenev, Isaac Xu, Stephan Züchner, Robert W Burgess
Charcot-Marie-Tooth disease type 1A (CMT1A) is a demyelinating peripheral neuropathy caused by the duplication of peripheral myelin protein 22 (PMP22), leading to muscle weakness and loss of sensation in the hands and feet. A recent case-only genome-wide association study of CMT1A patients conducted by the Inherited Neuropathy Consortium identified a strong association between strength of foot dorsiflexion and variants in signal induced proliferation associated 1 like 2 (SIPA1L2), indicating that it may be a genetic modifier of disease. To validate SIPA1L2 as a candidate modifier and to assess its potential as a therapeutic target, we engineered mice with deletion of exon 1 (including the start codon) of the Sipa1l2 gene and crossed them to the C3-PMP22 mouse model of CMT1A. Neuromuscular phenotyping showed that Sipa1l2 deletion in C3-PMP22 mice preserved muscular endurance assayed by inverted wire hang duration and changed femoral nerve axon morphometrics such as myelin thickness. Gene expression changes suggest involvement of Sipa1l2 in cholesterol biosynthesis, a pathway that is also implicated in C3-PMP22 mice. Although Sipa1l2 deletion did impact CMT1A-associated phenotypes, thereby validating a genetic interaction, the overall effect on neuropathy was mild.
{"title":"Testing SIPA1L2 as a modifier of CMT1A using mouse models.","authors":"George C Murray, Timothy J Hines, Abigail L D Tadenev, Isaac Xu, Stephan Züchner, Robert W Burgess","doi":"10.1093/jnen/nlae020","DOIUrl":"10.1093/jnen/nlae020","url":null,"abstract":"<p><p>Charcot-Marie-Tooth disease type 1A (CMT1A) is a demyelinating peripheral neuropathy caused by the duplication of peripheral myelin protein 22 (PMP22), leading to muscle weakness and loss of sensation in the hands and feet. A recent case-only genome-wide association study of CMT1A patients conducted by the Inherited Neuropathy Consortium identified a strong association between strength of foot dorsiflexion and variants in signal induced proliferation associated 1 like 2 (SIPA1L2), indicating that it may be a genetic modifier of disease. To validate SIPA1L2 as a candidate modifier and to assess its potential as a therapeutic target, we engineered mice with deletion of exon 1 (including the start codon) of the Sipa1l2 gene and crossed them to the C3-PMP22 mouse model of CMT1A. Neuromuscular phenotyping showed that Sipa1l2 deletion in C3-PMP22 mice preserved muscular endurance assayed by inverted wire hang duration and changed femoral nerve axon morphometrics such as myelin thickness. Gene expression changes suggest involvement of Sipa1l2 in cholesterol biosynthesis, a pathway that is also implicated in C3-PMP22 mice. Although Sipa1l2 deletion did impact CMT1A-associated phenotypes, thereby validating a genetic interaction, the overall effect on neuropathy was mild.</p>","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11029467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140110448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Identification of central nervous system injury is a critical part of perinatal autopsies; however, injury is not always easily identifiable due to autolysis and immaturity of the developing brain. Here, the role of immunohistochemical stains in the identification of perinatal brain injury was investigated. Blinded semiquantitative scoring of injury was performed on sections of frontal lobe from 76 cases (51 liveborn and 25 stillborn) using H&E, GFAP, Iba-1, and β-APP stains. Digital image analysis was used to quantify GFAP and Iba-1 staining. Commonly observed pathologies included diffuse white matter gliosis (DWMG) and white matter necrosis (WMN). DWMG scores were very similar on H&E and GFAP stains for liveborn subjects. For stillborn subjects, DWMG scores were significantly higher on GFAP stain than H&E. β-APP was needed for identification of WMN in 71.4% of stillborn subjects compared to 15.4% of liveborn subjects. Diffuse staining for Iba-1 within cortex and white matter was positively correlated with subject age. Staining quantification on digital image analysis was highly correlated to semiquantitative scoring. Overall, GFAP and β-APP stains were most helpful in identifying white matter injury not seen on H&E in stillborn subjects. Immunostains may therefore be warranted as an integral part of stillborn brain autopsies.
{"title":"A role for immunohistochemical stains in perinatal brain autopsies.","authors":"Angela N Viaene","doi":"10.1093/jnen/nlae019","DOIUrl":"10.1093/jnen/nlae019","url":null,"abstract":"<p><p>Identification of central nervous system injury is a critical part of perinatal autopsies; however, injury is not always easily identifiable due to autolysis and immaturity of the developing brain. Here, the role of immunohistochemical stains in the identification of perinatal brain injury was investigated. Blinded semiquantitative scoring of injury was performed on sections of frontal lobe from 76 cases (51 liveborn and 25 stillborn) using H&E, GFAP, Iba-1, and β-APP stains. Digital image analysis was used to quantify GFAP and Iba-1 staining. Commonly observed pathologies included diffuse white matter gliosis (DWMG) and white matter necrosis (WMN). DWMG scores were very similar on H&E and GFAP stains for liveborn subjects. For stillborn subjects, DWMG scores were significantly higher on GFAP stain than H&E. β-APP was needed for identification of WMN in 71.4% of stillborn subjects compared to 15.4% of liveborn subjects. Diffuse staining for Iba-1 within cortex and white matter was positively correlated with subject age. Staining quantification on digital image analysis was highly correlated to semiquantitative scoring. Overall, GFAP and β-APP stains were most helpful in identifying white matter injury not seen on H&E in stillborn subjects. Immunostains may therefore be warranted as an integral part of stillborn brain autopsies.</p>","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11029462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140028299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cassie B MacRae, Kristina C Grieco, Isaac H Solomon
Medical autopsies have decreased in frequency due in part to advances in radiological techniques and increased availability of molecular and other ancillary testing. However, premortem diagnosis of CNS disease remains challenging; while ∼90% of brain tumor biopsies are diagnostic, only 20%-70% of biopsies for presumed nonneoplastic disease result in a specific diagnosis. The added benefits of performing an autopsy following surgical brain biopsy are not well defined. A retrospective analysis was performed of patients who underwent brain biopsy and autopsy at Brigham and Women's Hospital from 2003 to 2022. A total of 135 cases were identified, including 95 (70%) patients with primary CNS neoplasms, 16 (12%) with metastatic tumors, and 24 (18%) with nonneoplastic neurological disease. Diagnostic concordance between biopsy and autopsy diagnosis was excellent both for primary CNS neoplasms (98%) and metastatic tumors (94%). Conversely, patients with nonneoplastic disease received definitive premortem diagnoses in 7/24 (29%) cases. Five (21%) additional patients received conclusive diagnoses following autopsy; 8 (33%) received a more specific differential diagnosis compared to the biopsy. Overall, autopsy confirmed premortem diagnoses or provided new diagnostic information in 131/135 (97%) cases, highlighting the value in performing postmortem brain examination in patients with both neoplastic and nonneoplastic diseases.
{"title":"Diagnostic yield of postmortem brain examination following premortem brain biopsy for neoplastic and nonneoplastic disease.","authors":"Cassie B MacRae, Kristina C Grieco, Isaac H Solomon","doi":"10.1093/jnen/nlae025","DOIUrl":"10.1093/jnen/nlae025","url":null,"abstract":"<p><p>Medical autopsies have decreased in frequency due in part to advances in radiological techniques and increased availability of molecular and other ancillary testing. However, premortem diagnosis of CNS disease remains challenging; while ∼90% of brain tumor biopsies are diagnostic, only 20%-70% of biopsies for presumed nonneoplastic disease result in a specific diagnosis. The added benefits of performing an autopsy following surgical brain biopsy are not well defined. A retrospective analysis was performed of patients who underwent brain biopsy and autopsy at Brigham and Women's Hospital from 2003 to 2022. A total of 135 cases were identified, including 95 (70%) patients with primary CNS neoplasms, 16 (12%) with metastatic tumors, and 24 (18%) with nonneoplastic neurological disease. Diagnostic concordance between biopsy and autopsy diagnosis was excellent both for primary CNS neoplasms (98%) and metastatic tumors (94%). Conversely, patients with nonneoplastic disease received definitive premortem diagnoses in 7/24 (29%) cases. Five (21%) additional patients received conclusive diagnoses following autopsy; 8 (33%) received a more specific differential diagnosis compared to the biopsy. Overall, autopsy confirmed premortem diagnoses or provided new diagnostic information in 131/135 (97%) cases, highlighting the value in performing postmortem brain examination in patients with both neoplastic and nonneoplastic diseases.</p>","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11029448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140158289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lorraina J Robinson, Eric Goold, Donald M Cannon, Joe S Mendez, Sarah T Menacho, Qinwen Mao, Ting Liu
{"title":"A rare case of an adult primary intracranial sarcoma associated with a DICER1 mutation.","authors":"Lorraina J Robinson, Eric Goold, Donald M Cannon, Joe S Mendez, Sarah T Menacho, Qinwen Mao, Ting Liu","doi":"10.1093/jnen/nlae024","DOIUrl":"10.1093/jnen/nlae024","url":null,"abstract":"","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140184732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Giuseppe P Cortese, Anne Marie W Bartosch, Harrison Xiao, Yelizaveta Gribkova, Tiffany G Lam, Elentina K Argyrousi, Sharanya Sivakumar, Christopher Cardona, Andrew F Teich
ZCCHC17 is a master regulator of synaptic gene expression and has recently been shown to play a role in splicing of neuronal mRNA. We previously showed that ZCCHC17 protein declines in Alzheimer’s disease (AD) brain tissue before there is significant gliosis and neuronal loss, that ZCCHC17 loss partially replicates observed splicing abnormalities in AD brain tissue, and that maintenance of ZCCHC17 levels is predicted to support cognitive resilience in AD. Here, we assessed the functional consequences of reduced ZCCHC17 expression in primary cortical neuronal cultures using siRNA knockdown. Consistent with its previously identified role in synaptic gene expression, loss of ZCCHC17 led to loss of synaptic protein expression. Patch recording of neurons shows that ZCCHC17 loss significantly disrupted the excitation/inhibition balance of neurotransmission, and favored excitatory-dominant synaptic activity as measured by an increase in spontaneous excitatory post synaptic currents and action potential firing rate, and a decrease in spontaneous inhibitory post synaptic currents. These findings are consistent with the hyperexcitable phenotype seen in AD animal models and in patients. We are the first to assess the functional consequences of ZCCHC17 knockdown in neurons and conclude that ZCCHC17 loss partially phenocopies AD-related loss of synaptic proteins and hyperexcitability.
ZCCHC17 是突触基因表达的主调节器,最近被证明在神经元 mRNA 的剪接中发挥作用。我们以前的研究表明,阿尔茨海默病(AD)脑组织中的 ZCCHC17 蛋白会在出现明显的胶质细胞增生和神经元缺失之前减少,ZCCHC17 的缺失部分复制了在 AD 脑组织中观察到的剪接异常,而 ZCCHC17 水平的维持预计会支持 AD 的认知恢复能力。在这里,我们使用 siRNA 敲除技术评估了 ZCCHC17 在原代皮质神经元培养物中表达减少的功能性后果。与之前确定的 ZCCHC17 在突触基因表达中的作用一致,ZCCHC17 的缺失导致了突触蛋白表达的缺失。神经元的贴片记录显示,ZCCHC17 的缺失极大地破坏了神经传递的兴奋/抑制平衡,并有利于兴奋主导的突触活动,具体表现为自发兴奋性突触后电流和动作电位发射率的增加,以及自发抑制性突触后电流的减少。这些发现与注意力缺失症动物模型和患者的过度兴奋表型一致。我们首次评估了神经元中敲除 ZCCHC17 的功能性后果,并得出结论:ZCCHC17 的缺失部分表征了与 AD 相关的突触蛋白缺失和过度兴奋。
{"title":"ZCCHC17 knockdown phenocopies Alzheimer’s disease-related loss of synaptic proteins and hyperexcitability","authors":"Giuseppe P Cortese, Anne Marie W Bartosch, Harrison Xiao, Yelizaveta Gribkova, Tiffany G Lam, Elentina K Argyrousi, Sharanya Sivakumar, Christopher Cardona, Andrew F Teich","doi":"10.1093/jnen/nlae033","DOIUrl":"https://doi.org/10.1093/jnen/nlae033","url":null,"abstract":"ZCCHC17 is a master regulator of synaptic gene expression and has recently been shown to play a role in splicing of neuronal mRNA. We previously showed that ZCCHC17 protein declines in Alzheimer’s disease (AD) brain tissue before there is significant gliosis and neuronal loss, that ZCCHC17 loss partially replicates observed splicing abnormalities in AD brain tissue, and that maintenance of ZCCHC17 levels is predicted to support cognitive resilience in AD. Here, we assessed the functional consequences of reduced ZCCHC17 expression in primary cortical neuronal cultures using siRNA knockdown. Consistent with its previously identified role in synaptic gene expression, loss of ZCCHC17 led to loss of synaptic protein expression. Patch recording of neurons shows that ZCCHC17 loss significantly disrupted the excitation/inhibition balance of neurotransmission, and favored excitatory-dominant synaptic activity as measured by an increase in spontaneous excitatory post synaptic currents and action potential firing rate, and a decrease in spontaneous inhibitory post synaptic currents. These findings are consistent with the hyperexcitable phenotype seen in AD animal models and in patients. We are the first to assess the functional consequences of ZCCHC17 knockdown in neurons and conclude that ZCCHC17 loss partially phenocopies AD-related loss of synaptic proteins and hyperexcitability.","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140611650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cognitive dysfunction following anesthesia with agents such as sevoflurane is a significant clinical problem, particularly in elderly patients. This study aimed to explore the protective effects of the phytochemical syringaresinol (SYR) against sevoflurane-induced cognitive deficits in aged Sprague-Dawley rats and to determine the underlying mechanisms involved. We assessed the impact of SYR on sevoflurane-induced cognitive impairment, glial activation, and neuronal apoptosis through behavioral tests (Morris water maze), immunofluorescence, Western blotting for key proteins involved in apoptosis and inflammation, and enzyme-linked immunosorbent assays for interleukin-1β, tumor necrosis factor-α, and interleukin-6. SYR treatment mitigated sevoflurane-induced cognitive decline, reduced microglial and astrocyte activation (decreased Iba-1 and GFAP expression), and countered neuronal apoptosis (reduced Bax, cleaved-caspase3, and cleaved-PARP expression). SYR also enhanced Sirtuin-1 (SIRT1) expression and reduced p-Tau phosphorylation; these effects were reversed by the SIRT1 inhibitor EX527. SYR exerts neuroprotective effects on sevoflurane-induced cognitive dysfunction by modulating glial activity, apoptotic signaling, and Tau phosphorylation through the SIRT1 pathway. These findings could inform clinical strategies to safeguard cognitive function in patients undergoing anesthesia.
使用七氟醚等药物麻醉后出现认知功能障碍是一个重要的临床问题,尤其是对老年患者而言。本研究旨在探讨植物化学物质丁香树脂醇(SYR)对七氟烷诱导的老年 Sprague-Dawley 大鼠认知功能障碍的保护作用,并确定其中的潜在机制。我们通过行为测试(莫里斯水迷宫)、免疫荧光、参与细胞凋亡和炎症的关键蛋白的 Western 印迹以及白细胞介素-1β、肿瘤坏死因子-α 和白细胞介素-6 的酶联免疫吸附试验,评估了 SYR 对七氟烷诱导的认知障碍、神经胶质活化和神经细胞凋亡的影响。SYR治疗减轻了七氟烷诱导的认知能力下降,降低了小胶质细胞和星形胶质细胞的活化(减少了Iba-1和GFAP的表达),并对抗了神经元凋亡(减少了Bax、裂解的天冬酶3和裂解的PARP的表达)。SYR还能增强Sirtuin-1(SIRT1)的表达,降低p-Tau磷酸化;SIRT1抑制剂EX527能逆转这些效应。SYR通过SIRT1途径调节神经胶质细胞活性、凋亡信号传导和Tau磷酸化,对七氟烷诱导的认知功能障碍具有神经保护作用。这些发现可为临床策略提供参考,以保护麻醉患者的认知功能。
{"title":"Syringaresinol attenuates Tau phosphorylation and ameliorates cognitive dysfunction induced by sevoflurane in aged rats","authors":"Simin Zheng, Yunpeng Teng, Hongtao Liu, Jiaxuan He, Shaobo Zhang, Hongfei Xiong","doi":"10.1093/jnen/nlae026","DOIUrl":"https://doi.org/10.1093/jnen/nlae026","url":null,"abstract":"Cognitive dysfunction following anesthesia with agents such as sevoflurane is a significant clinical problem, particularly in elderly patients. This study aimed to explore the protective effects of the phytochemical syringaresinol (SYR) against sevoflurane-induced cognitive deficits in aged Sprague-Dawley rats and to determine the underlying mechanisms involved. We assessed the impact of SYR on sevoflurane-induced cognitive impairment, glial activation, and neuronal apoptosis through behavioral tests (Morris water maze), immunofluorescence, Western blotting for key proteins involved in apoptosis and inflammation, and enzyme-linked immunosorbent assays for interleukin-1β, tumor necrosis factor-α, and interleukin-6. SYR treatment mitigated sevoflurane-induced cognitive decline, reduced microglial and astrocyte activation (decreased Iba-1 and GFAP expression), and countered neuronal apoptosis (reduced Bax, cleaved-caspase3, and cleaved-PARP expression). SYR also enhanced Sirtuin-1 (SIRT1) expression and reduced p-Tau phosphorylation; these effects were reversed by the SIRT1 inhibitor EX527. SYR exerts neuroprotective effects on sevoflurane-induced cognitive dysfunction by modulating glial activity, apoptotic signaling, and Tau phosphorylation through the SIRT1 pathway. These findings could inform clinical strategies to safeguard cognitive function in patients undergoing anesthesia.","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140611470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Golgi methods were used to study human neuropathology in the 1970s, 1980s, and 1990s of the last century. Although a relatively small number of laboratories applied these methods, their impact was crucial by increasing knowledge about: (1) the morphology, orientation, and localization of neurons in human cerebral and cerebellar malformations and ganglionic tumors, and (2) the presence of abnormal structures including large and thin spines (spine dysgenesis) in several disorders linked to mental retardation, focal enlargements of the axon hillock and dendrites (meganeurites) in neuronal storage diseases, growth cone-like appendages in Alzheimer disease, as well as abnormal structures in other dementias. Although there were initial concerns about their reliability, reduced dendritic branches and dendritic spines were identified as common alterations in mental retardation, dementia, and other pathological conditions. Similar observations in appropriate experimental models have supported many abnormalities that were first identified using Golgi methods in human material. Moreover, electron microscopy, immunohistochemistry, fluorescent tracers, and combined methods have proven the accuracy of pioneering observations uniquely visualized as 3D images of fully stained individual neurons. Although Golgi methods had their golden age many years ago, these methods may still be useful complementary tools in human neuropathology.
{"title":"Historical review: The golden age of the Golgi method in human neuropathology.","authors":"I. Ferrer","doi":"10.1093/jnen/nlae031","DOIUrl":"https://doi.org/10.1093/jnen/nlae031","url":null,"abstract":"Golgi methods were used to study human neuropathology in the 1970s, 1980s, and 1990s of the last century. Although a relatively small number of laboratories applied these methods, their impact was crucial by increasing knowledge about: (1) the morphology, orientation, and localization of neurons in human cerebral and cerebellar malformations and ganglionic tumors, and (2) the presence of abnormal structures including large and thin spines (spine dysgenesis) in several disorders linked to mental retardation, focal enlargements of the axon hillock and dendrites (meganeurites) in neuronal storage diseases, growth cone-like appendages in Alzheimer disease, as well as abnormal structures in other dementias. Although there were initial concerns about their reliability, reduced dendritic branches and dendritic spines were identified as common alterations in mental retardation, dementia, and other pathological conditions. Similar observations in appropriate experimental models have supported many abnormalities that were first identified using Golgi methods in human material. Moreover, electron microscopy, immunohistochemistry, fluorescent tracers, and combined methods have proven the accuracy of pioneering observations uniquely visualized as 3D images of fully stained individual neurons. Although Golgi methods had their golden age many years ago, these methods may still be useful complementary tools in human neuropathology.","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140703908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}