D. Hoyaux, A. Boom, L. Van Den Bosch, N. Belot, Jean-Jacques Martin, C. Heizmann, R. Kiss, R. Pochet
Astrogliosis is one of the earliest pathological changes observed in neurodegenerative diseases in general and in amyotrophic lateral sclerosis (ALS) in particular. ALS is characterized by selective degeneration of motoneurons. There are 2 forms of the disease: sporadic ALS (SALS), comprising 90%–95% of cases, and familial ALS (FALS), comprising 5%–10% of cases. FALS is an age-dependent autosomal dominant disorder in which mutations in the homodimeric enzyme Cu/Zn superoxide dismutase 1 (SOD1) is linked to the disease. The animal model for this disease is a transgenic mouse expressing the mutated human SOD1G93A gene. Here we show by immunohistochemistry and double immunofluorescence that astrocytes located near impaired axons of motoneurons that were selectively programmed to die overexpressed S100A6, a Ca2+/Zn2+ binding protein able to translocate into the nucleus. Transgenic mice overexpressing the mutated human SOD1 gene and patients suffering from SALS showed this selective astrocytic S100A6 expression. For instance, the pyramidal tract could be macroscopically detected on S100A6-labeled spinal cord and brainstem sections from SALS patients. Transgenic mice overexpressing the non-mutated SOD1 gene did not overexpress S100A6, although glial fibrillary associated protein astrogliosis was seen. Although these results do not give any clue about the beneficial or detrimental role played by S100A6, its induction may be assumed to appropriately serve some function(s).
{"title":"S100A6 Overexpression within Astrocytes Associated with Impaired Axons from Both ALS Mouse Model and Human Patients","authors":"D. Hoyaux, A. Boom, L. Van Den Bosch, N. Belot, Jean-Jacques Martin, C. Heizmann, R. Kiss, R. Pochet","doi":"10.1093/JNEN/61.8.736","DOIUrl":"https://doi.org/10.1093/JNEN/61.8.736","url":null,"abstract":"Astrogliosis is one of the earliest pathological changes observed in neurodegenerative diseases in general and in amyotrophic lateral sclerosis (ALS) in particular. ALS is characterized by selective degeneration of motoneurons. There are 2 forms of the disease: sporadic ALS (SALS), comprising 90%–95% of cases, and familial ALS (FALS), comprising 5%–10% of cases. FALS is an age-dependent autosomal dominant disorder in which mutations in the homodimeric enzyme Cu/Zn superoxide dismutase 1 (SOD1) is linked to the disease. The animal model for this disease is a transgenic mouse expressing the mutated human SOD1G93A gene. Here we show by immunohistochemistry and double immunofluorescence that astrocytes located near impaired axons of motoneurons that were selectively programmed to die overexpressed S100A6, a Ca2+/Zn2+ binding protein able to translocate into the nucleus. Transgenic mice overexpressing the mutated human SOD1 gene and patients suffering from SALS showed this selective astrocytic S100A6 expression. For instance, the pyramidal tract could be macroscopically detected on S100A6-labeled spinal cord and brainstem sections from SALS patients. Transgenic mice overexpressing the non-mutated SOD1 gene did not overexpress S100A6, although glial fibrillary associated protein astrogliosis was seen. Although these results do not give any clue about the beneficial or detrimental role played by S100A6, its induction may be assumed to appropriately serve some function(s).","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"17 1","pages":"736–744"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78735554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Goldstine, D. Seligson, P. Beizai, H. Miyata, H. Vinters
Tissue microarrays (TMAs), also known as “tissue chips,” are a recently developed method that allows small cores or discs of tissue from dozens or hundreds of (usually paraffin-embedded) specimens to be re-embedded in a tissue block, which can then be further sectioned. The tissue cores can subsequently be studied using any combination of techniques, including immunohistochemistry, in situ hybridization (ISH), fluorescence ISH, and in situ polymerase chain reaction (PCR). To date, the technique has found greatest use in the analysis of neoplasms, including gliomas. We describe, and provide examples of, how TMAs might be utilized in investigation of autopsy (or biopsy) tissues from individuals with non-neoplastic disease, especially to address questions that require systematic review of multiple (nearly) identical brain regions across dozens or hundreds of cases. Specific questions related to patterns of protein expression (e.g. tau, Aβ, α-synuclein) in multiple regions of large numbers of brain specimens (from patients with neurodegenerative diseases) can be efficiently examined using TMA technology. One possible use of TMAs in the area of infectious disease might be to examine patterns of HIV-related brain injury or AIDS-related opportunistic CNS infections in the epochs before and after highly active antiretroviral therapy came into widespread use.
{"title":"Tissue Microarrays in the Study of Non‐Neoplastic Disease of the Nervous System","authors":"J. Goldstine, D. Seligson, P. Beizai, H. Miyata, H. Vinters","doi":"10.1093/JNEN/61.8.653","DOIUrl":"https://doi.org/10.1093/JNEN/61.8.653","url":null,"abstract":"Tissue microarrays (TMAs), also known as “tissue chips,” are a recently developed method that allows small cores or discs of tissue from dozens or hundreds of (usually paraffin-embedded) specimens to be re-embedded in a tissue block, which can then be further sectioned. The tissue cores can subsequently be studied using any combination of techniques, including immunohistochemistry, in situ hybridization (ISH), fluorescence ISH, and in situ polymerase chain reaction (PCR). To date, the technique has found greatest use in the analysis of neoplasms, including gliomas. We describe, and provide examples of, how TMAs might be utilized in investigation of autopsy (or biopsy) tissues from individuals with non-neoplastic disease, especially to address questions that require systematic review of multiple (nearly) identical brain regions across dozens or hundreds of cases. Specific questions related to patterns of protein expression (e.g. tau, Aβ, α-synuclein) in multiple regions of large numbers of brain specimens (from patients with neurodegenerative diseases) can be efficiently examined using TMA technology. One possible use of TMAs in the area of infectious disease might be to examine patterns of HIV-related brain injury or AIDS-related opportunistic CNS infections in the epochs before and after highly active antiretroviral therapy came into widespread use.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"50 1","pages":"653–662"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79161643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Perry, S. Kunz, C. Fuller, Ruma Banerjee, E. Marley, H. Liapis, M. Watson, D. Gutmann
Malignant peripheral nerve sheath tumors (MPNSTs) are diagnostically challenging neoplasms for which sensitive and specific immunohistochemical markers are lacking. Although limited to date, previous studies have suggested that NF1 (17q), NF2 (22q), p16 (9p), and EGFR (7p) alterations may be involved in MPNST tumorigenesis. To determine whether specific genetic changes differentiate between MPNST and morphologically similar neoplasms, we assessed these chromosomal regions in 22 MPNSTs (9 NF1-associated, 13 sporadic), 13 plexiform neurofibromas, 5 cellular schwannomas, 8 synovial sarcomas, 6 fibrosarcomas, and 13 hemangiopericytomas by 2-color FISH. NF1 deletions, often in the form of monosomy 17, were found in MPNSTs (76%), neurofibromas (31%), hemangiopericytomas (17%), and fibrosarcomas (17%), but not in synovial sarcomas or cellular schwannomas. NF1 losses were encountered more frequently in MPNSTs versus other sarcomas (p < 0.001), as were p16 homozygous deletions (45% vs 0%; p < 0.001), EGFR amplifications (26% vs 0%; p = 0.006), and polysomies for either chromosomes 7 (53% vs 12%; p = 0.003) or 22 (50% vs 4%; p < 0.001). Hemizygous or homozygous p16 deletions were detected in 75% of MPNSTs, but not in benign nerve sheath tumors (p < 0.001). Thus, FISH analysis identifies relatively specific genetic patterns that may be useful in selected cases, for which the differential diagnosis includes low- or high-grade MPNST.
恶性周围神经鞘肿瘤(MPNSTs)是诊断上具有挑战性的肿瘤，缺乏敏感和特异性的免疫组织化学标志物。尽管迄今为止的研究有限，但先前的研究表明NF1 (17q)、NF2 (22q)、p16 (9p)和EGFR (7p)的改变可能参与了MPNST的肿瘤发生。为了确定MPNST和形态相似的肿瘤之间是否存在特定的遗传变化，我们通过双色FISH评估了22例MPNST(9例nf1相关，13例散发性)、13例网状神经纤维瘤、5例细胞神经鞘瘤、8例滑膜肉瘤、6例纤维肉瘤和13例血管外皮细胞瘤的染色体区域。NF1缺失常以单体17的形式出现在mpnst(76%)、神经纤维瘤(31%)、血管外皮细胞瘤(17%)和纤维肉瘤(17%)中，但在滑膜肉瘤或细胞神经鞘瘤中未见。与其他肉瘤相比，NF1缺失在mpnst中更常见(p < 0.001)， p16纯合子缺失也是如此(45%对0%;p < 0.001)， EGFR扩增(26% vs 0%;P = 0.006)， 7号染色体多体(53% vs 12%;P = 0.003)或22 (50% vs 4%;P < 0.001)。在75%的mpnst中检测到半合子或纯合子p16缺失，但在良性神经鞘肿瘤中未检测到p16缺失(p < 0.001)。因此，FISH分析确定了相对特定的遗传模式，这可能对选定的病例有用，其中鉴别诊断包括低或高级别MPNST。
{"title":"Differential NF1, p16, and EGFR Patterns by Interphase Cytogenetics (FISH) in Malignant Peripheral Nerve Sheath Tumor (MPNST) and Morphologically Similar Spindle Cell Neoplasms","authors":"A. Perry, S. Kunz, C. Fuller, Ruma Banerjee, E. Marley, H. Liapis, M. Watson, D. Gutmann","doi":"10.1093/JNEN/61.8.702","DOIUrl":"https://doi.org/10.1093/JNEN/61.8.702","url":null,"abstract":"Malignant peripheral nerve sheath tumors (MPNSTs) are diagnostically challenging neoplasms for which sensitive and specific immunohistochemical markers are lacking. Although limited to date, previous studies have suggested that NF1 (17q), NF2 (22q), p16 (9p), and EGFR (7p) alterations may be involved in MPNST tumorigenesis. To determine whether specific genetic changes differentiate between MPNST and morphologically similar neoplasms, we assessed these chromosomal regions in 22 MPNSTs (9 NF1-associated, 13 sporadic), 13 plexiform neurofibromas, 5 cellular schwannomas, 8 synovial sarcomas, 6 fibrosarcomas, and 13 hemangiopericytomas by 2-color FISH. NF1 deletions, often in the form of monosomy 17, were found in MPNSTs (76%), neurofibromas (31%), hemangiopericytomas (17%), and fibrosarcomas (17%), but not in synovial sarcomas or cellular schwannomas. NF1 losses were encountered more frequently in MPNSTs versus other sarcomas (p < 0.001), as were p16 homozygous deletions (45% vs 0%; p < 0.001), EGFR amplifications (26% vs 0%; p = 0.006), and polysomies for either chromosomes 7 (53% vs 12%; p = 0.003) or 22 (50% vs 4%; p < 0.001). Hemizygous or homozygous p16 deletions were detected in 75% of MPNSTs, but not in benign nerve sheath tumors (p < 0.001). Thus, FISH analysis identifies relatively specific genetic patterns that may be useful in selected cases, for which the differential diagnosis includes low- or high-grade MPNST.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"105 1","pages":"702–709"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75638854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bradykinin and leukotriene C4 (LTC4) have been shown to increase molecular transport across the blood-tumor barrier (BTB). The aim of this study was to quantitatively assess whether an increase in vesicular transport or opening of tight junctions was responsible for this increase in permeability. Wistar rats bearing RG2 or C6 gliomas were infused with bradykinin or LTC4 through the right carotid artery for 15 min and then perfused to achieve fixation. Prepared specimens were observed using transmission electron microscopy. Infusion of either bradykinin or LTC4 resulted in significantly increased vesicular density in capillary endothelial cells of the BTB but not in normal brain capillaries. The opening of tight junctions, assessed by determining a cleft index, was found to be greater in tumor capillaries compared to normal controls. However, neither bradykinin nor LTC4 produce variations in the cleft index. A significant accumulation of horseradish peroxidase was seen in the intercellular peri-capillary spaces and in endothelial transport vesicles after infusion of bradykinin, demonstrating that the formation of vesicles was associated with macromolecular transcytosis. These findings suggest that pinocytotic vesicular transport is the primary means by which luminal to abluminal transport occurs in response to vasomodulation with bradykinin or LTC4.
{"title":"Increased Endothelial Vesicular Transport Correlates with Increased Blood‐Tumor Barrier Permeability Induced by Bradykinin and Leukotriene C4","authors":"K. Hashizume, K. Black","doi":"10.1093/JNEN/61.8.725","DOIUrl":"https://doi.org/10.1093/JNEN/61.8.725","url":null,"abstract":"Bradykinin and leukotriene C4 (LTC4) have been shown to increase molecular transport across the blood-tumor barrier (BTB). The aim of this study was to quantitatively assess whether an increase in vesicular transport or opening of tight junctions was responsible for this increase in permeability. Wistar rats bearing RG2 or C6 gliomas were infused with bradykinin or LTC4 through the right carotid artery for 15 min and then perfused to achieve fixation. Prepared specimens were observed using transmission electron microscopy. Infusion of either bradykinin or LTC4 resulted in significantly increased vesicular density in capillary endothelial cells of the BTB but not in normal brain capillaries. The opening of tight junctions, assessed by determining a cleft index, was found to be greater in tumor capillaries compared to normal controls. However, neither bradykinin nor LTC4 produce variations in the cleft index. A significant accumulation of horseradish peroxidase was seen in the intercellular peri-capillary spaces and in endothelial transport vesicles after infusion of bradykinin, demonstrating that the formation of vesicles was associated with macromolecular transcytosis. These findings suggest that pinocytotic vesicular transport is the primary means by which luminal to abluminal transport occurs in response to vasomodulation with bradykinin or LTC4.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"71 1","pages":"725–735"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89835513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Hoozemans, M. Brückner, A. Rozemuller, R. Veerhuis, P. Eikelenboom, T. Arendt
Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) seems to reduce the progression of several diseases, including colon cancer, lung cancer, breast cancer and Alzheimer disease (AD). Several studies have shown that NSAIDs can modulate cell cycle progression, especially in the G0/G1 phase. The main target of most NSAIDs is the enzyme cyclo-oxygenase (COX), which occurs in 2 isoforms, COX-1 and COX-2. In AD and non-demented control brain, COX-2 is expressed in neuronal cells. In this study the expression of COX-2, cyclin D1, and cyclin E was investigated at the immunohistochemical level in AD and non-demented control temporal cortex. COX-2, cyclin D1, and cyclin E expression was detected in pyramidal neurons in both AD and control patients. The number of COX-2-immunoreactive neurons positively correlated with the number of cyclin E- and cyclin D1-immunoreactive neurons. Moreover, immunostaining of sequential tissue sections and double immunofluorescence labeling revealed co-expression of COX-2 and cyclin D1 and E in neuronal cells. In addition, an inverse correlation was observed between the neuronal expression of COX-2 and cyclin E and the Braak score for amyloid β deposits. Our findings suggest a relationship between the neuronal expression of COX-2 and cell cycle markers, which may be involved early in AD pathology.
{"title":"Cyclin D1 and Cyclin E Are Co‐Localized with Cyclo‐Oxygenase 2 (COX‐2) in Pyramidal Neurons in Alzheimer Disease Temporal Cortex","authors":"J. Hoozemans, M. Brückner, A. Rozemuller, R. Veerhuis, P. Eikelenboom, T. Arendt","doi":"10.1093/JNEN/61.8.678","DOIUrl":"https://doi.org/10.1093/JNEN/61.8.678","url":null,"abstract":"Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) seems to reduce the progression of several diseases, including colon cancer, lung cancer, breast cancer and Alzheimer disease (AD). Several studies have shown that NSAIDs can modulate cell cycle progression, especially in the G0/G1 phase. The main target of most NSAIDs is the enzyme cyclo-oxygenase (COX), which occurs in 2 isoforms, COX-1 and COX-2. In AD and non-demented control brain, COX-2 is expressed in neuronal cells. In this study the expression of COX-2, cyclin D1, and cyclin E was investigated at the immunohistochemical level in AD and non-demented control temporal cortex. COX-2, cyclin D1, and cyclin E expression was detected in pyramidal neurons in both AD and control patients. The number of COX-2-immunoreactive neurons positively correlated with the number of cyclin E- and cyclin D1-immunoreactive neurons. Moreover, immunostaining of sequential tissue sections and double immunofluorescence labeling revealed co-expression of COX-2 and cyclin D1 and E in neuronal cells. In addition, an inverse correlation was observed between the neuronal expression of COX-2 and cyclin E and the Braak score for amyloid β deposits. Our findings suggest a relationship between the neuronal expression of COX-2 and cell cycle markers, which may be involved early in AD pathology.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"84 1","pages":"678–688"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72647414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A variety of techniques have been developed to evaluate cell proliferation. Many of these methods provide a more accurate means of assessing the true proliferation rate of a given neoplasm, as compared with the simple assessment of mitotic activity. Similar to the evaluation of mitotic activity, these methods are also subject to limitations associated with tumor heterogeneity and interobserver variability. This paper reviews a variety of methodologies including radiolabeling, flow cytometric, and immunohistochemical that have been used in recent years to evaluate cell proliferation in brain neoplasms. Factors that affect these methodologies and their practical application to routine practice of diagnostic neuropathology will be explored.
{"title":"Cell Proliferation and Tumors of the Central Nervous System, Part II: Radiolabeling, Cytometric, and Immunohistochemical Techniques","authors":"R. Prayson","doi":"10.1093/JNEN/61.8.663","DOIUrl":"https://doi.org/10.1093/JNEN/61.8.663","url":null,"abstract":"A variety of techniques have been developed to evaluate cell proliferation. Many of these methods provide a more accurate means of assessing the true proliferation rate of a given neoplasm, as compared with the simple assessment of mitotic activity. Similar to the evaluation of mitotic activity, these methods are also subject to limitations associated with tumor heterogeneity and interobserver variability. This paper reviews a variety of methodologies including radiolabeling, flow cytometric, and immunohistochemical that have been used in recent years to evaluate cell proliferation in brain neoplasms. Factors that affect these methodologies and their practical application to routine practice of diagnostic neuropathology will be explored.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"124 1","pages":"663–672"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87819113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Superficial siderosis of the human central nervous system is caused by small continuous or recurrent subarachnoid hemorrhages that lead to the destructive deposition of hemosiderin. The excessive tissue iron derives from heme that is oxidized in a rate-limiting step by the enzyme heme oxygenase (HO), and especially the inducible form, HO-1. We postulated that competitive inhibition of HO by tin-protoporphyrin IX (SnPP) could prevent experimental superficial siderosis. Since synthetic metalloporphyrins do not cross the blood-brain barrier, SnPP was delivered directly into the cisterna magna. Rabbits received weekly intracisternal injections of washed autologous red blood cells (RBC) over a period of 1 to 16 wk. In companion experiments, SnPP was added to the suspension of RBC, or SnPP was injected without RBC. All injections caused increased HO-1 immunoreactivity in the Bergmann glia of the cerebellar cortex and in superficial astrocytes of the piriform cortex. The injections of RBC or RBC with added SnPP also generated a vigorous microglial response. The metalloporphyrin entered the tissue in inhibitory amounts and greatly reduced the accumulation of histochemically detectable iron. It did not alter the microglial response. The observations allowed the conclusion that SnPP suppressed heme oxidation but did not affect other steps in the pathogenesis of superficial siderosis.
{"title":"Tin‐Protoporphyrin Prevents Experimental Superficial Siderosis in Rabbits","authors":"A. Koeppen, A. Dickson","doi":"10.1093/JNEN/61.8.689","DOIUrl":"https://doi.org/10.1093/JNEN/61.8.689","url":null,"abstract":"Superficial siderosis of the human central nervous system is caused by small continuous or recurrent subarachnoid hemorrhages that lead to the destructive deposition of hemosiderin. The excessive tissue iron derives from heme that is oxidized in a rate-limiting step by the enzyme heme oxygenase (HO), and especially the inducible form, HO-1. We postulated that competitive inhibition of HO by tin-protoporphyrin IX (SnPP) could prevent experimental superficial siderosis. Since synthetic metalloporphyrins do not cross the blood-brain barrier, SnPP was delivered directly into the cisterna magna. Rabbits received weekly intracisternal injections of washed autologous red blood cells (RBC) over a period of 1 to 16 wk. In companion experiments, SnPP was added to the suspension of RBC, or SnPP was injected without RBC. All injections caused increased HO-1 immunoreactivity in the Bergmann glia of the cerebellar cortex and in superficial astrocytes of the piriform cortex. The injections of RBC or RBC with added SnPP also generated a vigorous microglial response. The metalloporphyrin entered the tissue in inhibitory amounts and greatly reduced the accumulation of histochemically detectable iron. It did not alter the microglial response. The observations allowed the conclusion that SnPP suppressed heme oxidation but did not affect other steps in the pathogenesis of superficial siderosis.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"16 1","pages":"689–701"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75375906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Protein deposition is a common event in age-related neurological diseases that are characterized by neuronal dysfunction and eventual cell death. Here, cultured hippocampal slices were infused with the lysosomal disrupter chloroquine to examine the link between abnormal protein processing/deposition and early synaptopathogenesis. Tau species of 55 to 69 kDa increased over several days of treatment with chloroquine, while the protein and message levels of synaptic markers were selectively reduced. Neurons of subfields CA1, CA3, and dentate gyrus accumulated protein deposits recognized by antibodies against paired helical filaments and ubiquitin, and this was accompanied by tubulin fragmentation and deacetylation. The deposition filled the basal pole of pyramidal neurons, encompassing the area of the axon hillock and initial dendritic branching but without causing overt neuronal atrophy. Neurons containing the polar aggregates exhibited severely impaired transport along basal dendrites. Transport capability was also lost along apical dendrites, the opposite direction of deposited material in the basal pole; thus, perpetuating the problem beyond physical blockage must be the associated loss of microtubule integrity. These data indicate that transport failure forms a link between tau deposition and synaptic decline, thus shedding light on how protein aggregation events disrupt synaptic and cognitive functions before the ensuing cellular destruction.
{"title":"Intracellular Deposition, Microtubule Destabilization, and Transport Failure: An “Early” Pathogenic Cascade Leading to Synaptic Decline","authors":"J. Bendiske, E. Caba, Queenie B. Brown, B. Bahr","doi":"10.1093/JNEN/61.7.640","DOIUrl":"https://doi.org/10.1093/JNEN/61.7.640","url":null,"abstract":"Protein deposition is a common event in age-related neurological diseases that are characterized by neuronal dysfunction and eventual cell death. Here, cultured hippocampal slices were infused with the lysosomal disrupter chloroquine to examine the link between abnormal protein processing/deposition and early synaptopathogenesis. Tau species of 55 to 69 kDa increased over several days of treatment with chloroquine, while the protein and message levels of synaptic markers were selectively reduced. Neurons of subfields CA1, CA3, and dentate gyrus accumulated protein deposits recognized by antibodies against paired helical filaments and ubiquitin, and this was accompanied by tubulin fragmentation and deacetylation. The deposition filled the basal pole of pyramidal neurons, encompassing the area of the axon hillock and initial dendritic branching but without causing overt neuronal atrophy. Neurons containing the polar aggregates exhibited severely impaired transport along basal dendrites. Transport capability was also lost along apical dendrites, the opposite direction of deposited material in the basal pole; thus, perpetuating the problem beyond physical blockage must be the associated loss of microtubule integrity. These data indicate that transport failure forms a link between tau deposition and synaptic decline, thus shedding light on how protein aggregation events disrupt synaptic and cognitive functions before the ensuing cellular destruction.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"1 1","pages":"640–650"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75676553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shuo Yu, Zhiguo Chen, E. Mix, Shunwei Zhu, B. Winblad, H. Ljunggren, Jie Zhu
Experimental autoimmune neuritis (EAN) is a demyelinating disease of the peripheral nervous system (PNS). This acute inflammatory disease is mediated by CD4+ T cells and bears significant similarities to the Guillain-Barré syndrome of humans. In the present study, we investigated the function of IL-18 in T cell-mediated autoimmunity of EAN in mice induced by P0 peptide 180–199 and Freund's complete adjuvant. Our data indicate that in 2 different therapeutic regimens, anti-IL-18 monoclonal antibody (mAb) effectively ameliorates the clinical and pathological signs of EAN. The suppression is associated with reduced inflammatory cell infiltration into the PNS and an insufficiency of autoreactive Th1 cells, as reflected by a reduced mononuclear cell proliferation and IFN-γ-secretion in the spleen. Increased numbers of IL-4 expressing cells and decreased numbers of IFN-γ and TNF-α expressing cells were found in the PNS. Our results suggest that shifting the Th1/Th2 balance towards Th2 cells may be one mechanism underlying EAN suppression by anti-IL-18 mAb. In addition, anti-IL-18 mAb treatment reduced anti-P0 peptide 180–199 autoantibody responses, which may also contribute to EAN suppression. We conclude that endogenous IL-18 plays a critical role in the pathogenesis of autoimmune demyelinating disease of the PNS and that IL-18 antagonists may provide a new therapy for these diseases.
{"title":"Neutralizing Antibodies to IL‐18 Ameliorate Experimental Autoimmune Neuritis by Counter‐Regulation of Autoreactive Th1 Responses to Peripheral Myelin Antigen","authors":"Shuo Yu, Zhiguo Chen, E. Mix, Shunwei Zhu, B. Winblad, H. Ljunggren, Jie Zhu","doi":"10.1093/JNEN/61.7.614","DOIUrl":"https://doi.org/10.1093/JNEN/61.7.614","url":null,"abstract":"Experimental autoimmune neuritis (EAN) is a demyelinating disease of the peripheral nervous system (PNS). This acute inflammatory disease is mediated by CD4+ T cells and bears significant similarities to the Guillain-Barré syndrome of humans. In the present study, we investigated the function of IL-18 in T cell-mediated autoimmunity of EAN in mice induced by P0 peptide 180–199 and Freund's complete adjuvant. Our data indicate that in 2 different therapeutic regimens, anti-IL-18 monoclonal antibody (mAb) effectively ameliorates the clinical and pathological signs of EAN. The suppression is associated with reduced inflammatory cell infiltration into the PNS and an insufficiency of autoreactive Th1 cells, as reflected by a reduced mononuclear cell proliferation and IFN-γ-secretion in the spleen. Increased numbers of IL-4 expressing cells and decreased numbers of IFN-γ and TNF-α expressing cells were found in the PNS. Our results suggest that shifting the Th1/Th2 balance towards Th2 cells may be one mechanism underlying EAN suppression by anti-IL-18 mAb. In addition, anti-IL-18 mAb treatment reduced anti-P0 peptide 180–199 autoantibody responses, which may also contribute to EAN suppression. We conclude that endogenous IL-18 plays a critical role in the pathogenesis of autoimmune demyelinating disease of the PNS and that IL-18 antagonists may provide a new therapy for these diseases.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"2015 1","pages":"614–622"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87949114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
I. Camby, N. Belot, F. Lefranc, N. Sadeghi, Y. Launoit, H. Kaltner, S. Musette, F. Darro, A. Danguy, I. Salmon, H. Gabius, R. Kiss
We show that high-grade astrocytic tumors with high levels of galectin-1 expression are associated with dismal prognoses. The immunohistochemical analysis of galectin-1 expression of human U87 and U373 glioblastoma xenografts from the brains of nude mice revealed a higher level of galectin-1 expression in invasive areas rather than non-invasive areas of the xenografts. Nude mice intracranially grafted with U87 or U373 cells constitutively expressing low levels of galectin-1 (by stable transfection of an expression vector containing the antisense mRNA of galectin-1) had longer survival periods than those grafted with U87 or U373 cells expressing normal levels of galectin-1. Galectin-1 added to the culture media markedly and specifically increased cell motility levels in human neoplastic astrocytes. These effects are related to marked modifications in the organization of the actin cytoskeleton and the increase in small GTPase RhoA expression. All the data obtained indicate that galectin-1 enhances the migratory capabilities of tumor astrocytes and, therefore, their biological aggressiveness.
{"title":"Galectin‐1 Modulates Human Glioblastoma Cell Migration into the Brain Through Modifications to the Actin Cytoskeleton and Levels of Expression of Small GTPases","authors":"I. Camby, N. Belot, F. Lefranc, N. Sadeghi, Y. Launoit, H. Kaltner, S. Musette, F. Darro, A. Danguy, I. Salmon, H. Gabius, R. Kiss","doi":"10.1093/JNEN/61.7.585","DOIUrl":"https://doi.org/10.1093/JNEN/61.7.585","url":null,"abstract":"We show that high-grade astrocytic tumors with high levels of galectin-1 expression are associated with dismal prognoses. The immunohistochemical analysis of galectin-1 expression of human U87 and U373 glioblastoma xenografts from the brains of nude mice revealed a higher level of galectin-1 expression in invasive areas rather than non-invasive areas of the xenografts. Nude mice intracranially grafted with U87 or U373 cells constitutively expressing low levels of galectin-1 (by stable transfection of an expression vector containing the antisense mRNA of galectin-1) had longer survival periods than those grafted with U87 or U373 cells expressing normal levels of galectin-1. Galectin-1 added to the culture media markedly and specifically increased cell motility levels in human neoplastic astrocytes. These effects are related to marked modifications in the organization of the actin cytoskeleton and the increase in small GTPase RhoA expression. All the data obtained indicate that galectin-1 enhances the migratory capabilities of tumor astrocytes and, therefore, their biological aggressiveness.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"10 1","pages":"585–596"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86553048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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