C. Katsetos, L. Del Valle, J. Geddes, K. Aldape, J. Boyd, A. Legido, K. Khalili, E. Perentes, S. Mörk
The class III β-tubulin isotype (βIII) is widely regarded as a neuronal marker in development and neoplasia. Whereas the expression of βIII in neuronal/neuroblastic tumors is differentiation-dependent, the aberrant expression of this cytoskeletal protein in astrocytomas is associated with an ascending gradient of malignancy. To test the generality of this observation we have compared the immunoreactivity (IR) profiles of the βIII isotype with the Ki-67 nuclear antigen proliferative index in 41 archival, surgically excised oligodendrogliomas (32 classical [WHO grade II] and 9 anaplastic [WHO grade III]). Seventeen of 41 tumors were examined by quantitative microsatellite analysis for loss of 1p and/or 19q. Minimal deletion regions were defined on 1p (D1S468, D1S214) and 19q (D19S408, D19S867). Three of 10 classical oligodendrogliomas had combined 1p/19q loss, while 2 exhibited loss of either 1p or 19q. Three of 7 anaplastic tumors had combined 1p/19q loss. βIII IR was present in all tumors, but was significantly greater in the anaplastic (median labeling index [MLI] 61%, interquartile range [IQR] 55%–64%) as compared with the classical variants (MLI, 19%, IQR, 11–36%) (p < 0.0001). A highly significant relationship was found to exist between βIII and Ki-67 LIs (βIII, p < 0.0001 and Ki-67, p < 0.0001, r = 0.809). βIII localization delineated hitherto understated unipolar or bipolar tumor phenotypes with growth cones and leading cell processes resembling migrating oligodendrocyte progenitor cells. Codistribution of βIII and GFAP IR was present in “gliofibrillary” tumor areas. Synaptophysin IR was detected in rare tumor cells (mean LI, 0.7%), and only in 4/41 samples (10%), denoting a lack of relationship between βIII and synaptophysin expression. No significant differences in βIII LIs were observed in tumors with 1p and/or 19q loss as compared to those with 1p/19q intact status. Increased βIII IR in oligodendrogliomas is associated with an ascending degree of malignancy and thus is a potentially useful tumor marker. However, the significance of high βIII LIs in low-grade oligodendrogliomas with respect to prognostic and predictive value requires further evaluation. Class III β-tubulin expression in oligodendrogliomas should not be construed as a priori evidence of divergent neuronal differentiation.
{"title":"Localization of the Neuronal Class III β‐Tubulin in Oligodendrogliomas: Comparison with Ki‐67 Proliferative Index and 1p/19q Status","authors":"C. Katsetos, L. Del Valle, J. Geddes, K. Aldape, J. Boyd, A. Legido, K. Khalili, E. Perentes, S. Mörk","doi":"10.1093/JNEN/61.4.307","DOIUrl":"https://doi.org/10.1093/JNEN/61.4.307","url":null,"abstract":"The class III β-tubulin isotype (βIII) is widely regarded as a neuronal marker in development and neoplasia. Whereas the expression of βIII in neuronal/neuroblastic tumors is differentiation-dependent, the aberrant expression of this cytoskeletal protein in astrocytomas is associated with an ascending gradient of malignancy. To test the generality of this observation we have compared the immunoreactivity (IR) profiles of the βIII isotype with the Ki-67 nuclear antigen proliferative index in 41 archival, surgically excised oligodendrogliomas (32 classical [WHO grade II] and 9 anaplastic [WHO grade III]). Seventeen of 41 tumors were examined by quantitative microsatellite analysis for loss of 1p and/or 19q. Minimal deletion regions were defined on 1p (D1S468, D1S214) and 19q (D19S408, D19S867). Three of 10 classical oligodendrogliomas had combined 1p/19q loss, while 2 exhibited loss of either 1p or 19q. Three of 7 anaplastic tumors had combined 1p/19q loss. βIII IR was present in all tumors, but was significantly greater in the anaplastic (median labeling index [MLI] 61%, interquartile range [IQR] 55%–64%) as compared with the classical variants (MLI, 19%, IQR, 11–36%) (p < 0.0001). A highly significant relationship was found to exist between βIII and Ki-67 LIs (βIII, p < 0.0001 and Ki-67, p < 0.0001, r = 0.809). βIII localization delineated hitherto understated unipolar or bipolar tumor phenotypes with growth cones and leading cell processes resembling migrating oligodendrocyte progenitor cells. Codistribution of βIII and GFAP IR was present in “gliofibrillary” tumor areas. Synaptophysin IR was detected in rare tumor cells (mean LI, 0.7%), and only in 4/41 samples (10%), denoting a lack of relationship between βIII and synaptophysin expression. No significant differences in βIII LIs were observed in tumors with 1p and/or 19q loss as compared to those with 1p/19q intact status. Increased βIII IR in oligodendrogliomas is associated with an ascending degree of malignancy and thus is a potentially useful tumor marker. However, the significance of high βIII LIs in low-grade oligodendrogliomas with respect to prognostic and predictive value requires further evaluation. Class III β-tubulin expression in oligodendrogliomas should not be construed as a priori evidence of divergent neuronal differentiation.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"67 1","pages":"307–320"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89306934","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}
B. Popko, D. Pearl, D. M. Walker, T. Comas, Kristine D. Baerwald, P. Burger, B. Scheithauer, A. Yates
The classification of human gliomas is currently based solely on neuropathological criteria. Prognostic and therapeutic parameters are dependent upon whether the tumors are deemed to be of astrocytic or oligodendroglial in origin. We sought to identify molecular reagents that might provide a more objective parameter to assist in the classification of these tumors. In order to identify mRNA transcripts for genes normally transcribed exclusively by oligodendrocytes, Northern blot analysis was carried out on RNA samples from 138 human gliomas. Transcripts encoding the myelin basic protein (MBP) were found in an equally high percentage of tumors that by neuropathological criteria were either astrocytic or oligodendroglial. In contrast, proteolipid protein (PLP) and cyclic nucleotide phosphodiesterase (CNP) mRNA molecules were found significantly more often in oligodendrogliomas than in astrocytomas. The strongest association with histological typing was found with the transcript for the myelin galactolipid biosynthetic enzyme UDP-galactose: ceramide galactosytransferase (CGT), which was about twice as frequently detected in tumors of oligodendroglial type. Results of glycolipid analyses were previously reported on a subset of the tumors studied herein. Statistical analyses of both molecular and biochemical data on this subset of astrocytomas, oligoastrocytomas, and oligodendrogliomas were performed to determine if a panel of markers could be used to separate astrocytic and oligodendroglial tumors. The presence of asialo GM1 (GA1) and the absence of paragloboside occurred most frequently in oligodendrogliomas. Ceramide monohexoside (CMH) levels correlated highly with the expression of mRNA for 4 myelin proteins: CGT, MBP, CNP, and PLP. The best combination of 2 markers of oligodendroglial tumors was CGT and GA1; the best combination of 3 markers was the presence of CGT, GA1, and the absence of paragloboside. We conclude that this combination of markers could be useful in distinguishing between astrocytic and oligodendroglial tumors.
{"title":"Molecular Markers that Identify Human Astrocytomas and Oligodendrogliomas","authors":"B. Popko, D. Pearl, D. M. Walker, T. Comas, Kristine D. Baerwald, P. Burger, B. Scheithauer, A. Yates","doi":"10.1093/JNEN/61.4.329","DOIUrl":"https://doi.org/10.1093/JNEN/61.4.329","url":null,"abstract":"The classification of human gliomas is currently based solely on neuropathological criteria. Prognostic and therapeutic parameters are dependent upon whether the tumors are deemed to be of astrocytic or oligodendroglial in origin. We sought to identify molecular reagents that might provide a more objective parameter to assist in the classification of these tumors. In order to identify mRNA transcripts for genes normally transcribed exclusively by oligodendrocytes, Northern blot analysis was carried out on RNA samples from 138 human gliomas. Transcripts encoding the myelin basic protein (MBP) were found in an equally high percentage of tumors that by neuropathological criteria were either astrocytic or oligodendroglial. In contrast, proteolipid protein (PLP) and cyclic nucleotide phosphodiesterase (CNP) mRNA molecules were found significantly more often in oligodendrogliomas than in astrocytomas. The strongest association with histological typing was found with the transcript for the myelin galactolipid biosynthetic enzyme UDP-galactose: ceramide galactosytransferase (CGT), which was about twice as frequently detected in tumors of oligodendroglial type. Results of glycolipid analyses were previously reported on a subset of the tumors studied herein. Statistical analyses of both molecular and biochemical data on this subset of astrocytomas, oligoastrocytomas, and oligodendrogliomas were performed to determine if a panel of markers could be used to separate astrocytic and oligodendroglial tumors. The presence of asialo GM1 (GA1) and the absence of paragloboside occurred most frequently in oligodendrogliomas. Ceramide monohexoside (CMH) levels correlated highly with the expression of mRNA for 4 myelin proteins: CGT, MBP, CNP, and PLP. The best combination of 2 markers of oligodendroglial tumors was CGT and GA1; the best combination of 3 markers was the presence of CGT, GA1, and the absence of paragloboside. We conclude that this combination of markers could be useful in distinguishing between astrocytic and oligodendroglial tumors.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"112 1","pages":"329–338"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85360925","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}
Glial lipopigment appears in the globus pallidus without accumulating in neurons (except for late adolescence) in multiple chronic childhood diseases. In this observational study, we compared the age-related development of glial pigmentation in children with the chronic illness (cystic fibrosis) and children dying acutely. A secondary goal was to search for pallidal neuronal lipopigment in childhood. We recorded pigmentation in the brains of 37 consecutive cystic fibrosis children ranging in age from 0–23 yr and in 17 controls ranging in age from 0–18 yr. We characterized the lipofuscin histochemically and used several regression models to describe the mode of deposition. We observed that in the controls, intraglial pallidal pigment accumulated in 2 forms (relatively large globules and, separately, as clusters of fine granules) at a slow rate during childhood. In cystic fibrosis, both forms of pallidal glial pigment started accumulating at a younger age and were deposited far more rapidly. There was a further increase in the rate of accumulation between 8 and 10 yr of age. We did not encounter pallidal neuronal lipofuscin at any age. These observations are consistent with 2 propositions: 1) that globus pallidus glial cells are unique in their ability to accumulate lipofuscin before it accumulates in nearby neurons; and 2) that they are particularly susceptible to some systemic effect of this chronic illness.
{"title":"Globus Pallidus Glial Pigment and Its Changes with Age and Chronic Illness in Childhood","authors":"F. Gilles, C. Tavaré","doi":"10.1093/JNEN/61.4.351","DOIUrl":"https://doi.org/10.1093/JNEN/61.4.351","url":null,"abstract":"Glial lipopigment appears in the globus pallidus without accumulating in neurons (except for late adolescence) in multiple chronic childhood diseases. In this observational study, we compared the age-related development of glial pigmentation in children with the chronic illness (cystic fibrosis) and children dying acutely. A secondary goal was to search for pallidal neuronal lipopigment in childhood. We recorded pigmentation in the brains of 37 consecutive cystic fibrosis children ranging in age from 0–23 yr and in 17 controls ranging in age from 0–18 yr. We characterized the lipofuscin histochemically and used several regression models to describe the mode of deposition. We observed that in the controls, intraglial pallidal pigment accumulated in 2 forms (relatively large globules and, separately, as clusters of fine granules) at a slow rate during childhood. In cystic fibrosis, both forms of pallidal glial pigment started accumulating at a younger age and were deposited far more rapidly. There was a further increase in the rate of accumulation between 8 and 10 yr of age. We did not encounter pallidal neuronal lipofuscin at any age. These observations are consistent with 2 propositions: 1) that globus pallidus glial cells are unique in their ability to accumulate lipofuscin before it accumulates in nearby neurons; and 2) that they are particularly susceptible to some systemic effect of this chronic illness.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"22 1","pages":"351–357"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79257778","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}
M. Baes, P. Gressens, S. Huyghe, K. D. Nys, C. Qi, Y. Jia, G. Mannaerts, P. Evrard, P. Veldhoven, Peter Declercq, J. Reddy
The purpose of this study was to investigate whether deficient peroxisomal β-oxidation is causally involved in the neuronal migration defect observed in Pex5 knockout mice. These mice are models for Zellweger syndrome, a peroxisome biogenesis disorder. Neocortical development was evaluated in mice carrying a partial or complete defect of peroxisomal β-oxidation at the level of the second enzyme of the pathway, namely, the hydratase-dehydrogenase multifunctional/bifunctional enzymes MFP1/L-PBE and MFP2/D-PBE. In contrast to patients with multifunctional protein 2 deficiency who present with neocortical dysgenesis, impairment of neuronal migration was not observed in the single MFP2 or in the double MFP1/MFP2 knockout mice. At birth, the double knockout pups displayed variable growth retardation and about one half of them were severely hypotonic, whereas the single MFP2 knockout animals were all normal in the perinatal period. These results indicate that in the mouse, defective peroxisomal β-oxidation does not cause neuronal migration defects by itself. This does not exclude that the inactivity of this metabolic pathway contributes to the brain pathology in mice and patients with complete absence of functional peroxisomes.
{"title":"The Neuronal Migration Defect in Mice with Zellweger Syndrome (Pex5 Knockout) is not Caused by the Inactivity of Peroxisomal β‐Oxidation","authors":"M. Baes, P. Gressens, S. Huyghe, K. D. Nys, C. Qi, Y. Jia, G. Mannaerts, P. Evrard, P. Veldhoven, Peter Declercq, J. Reddy","doi":"10.1093/JNEN/61.4.368","DOIUrl":"https://doi.org/10.1093/JNEN/61.4.368","url":null,"abstract":"The purpose of this study was to investigate whether deficient peroxisomal β-oxidation is causally involved in the neuronal migration defect observed in Pex5 knockout mice. These mice are models for Zellweger syndrome, a peroxisome biogenesis disorder. Neocortical development was evaluated in mice carrying a partial or complete defect of peroxisomal β-oxidation at the level of the second enzyme of the pathway, namely, the hydratase-dehydrogenase multifunctional/bifunctional enzymes MFP1/L-PBE and MFP2/D-PBE. In contrast to patients with multifunctional protein 2 deficiency who present with neocortical dysgenesis, impairment of neuronal migration was not observed in the single MFP2 or in the double MFP1/MFP2 knockout mice. At birth, the double knockout pups displayed variable growth retardation and about one half of them were severely hypotonic, whereas the single MFP2 knockout animals were all normal in the perinatal period. These results indicate that in the mouse, defective peroxisomal β-oxidation does not cause neuronal migration defects by itself. This does not exclude that the inactivity of this metabolic pathway contributes to the brain pathology in mice and patients with complete absence of functional peroxisomes.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"216 1","pages":"368–374"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73274900","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}
H. Beck, T. Acker, A. Püschel, H. Fujisawa, P. Carmeliet, K. Plate
Neuropilin-1 and -2 (NP-1/NP-2) are transmembrane receptors that play a role in axonal guidance by binding of class III semaphorins, and in angiogenesis by binding of the vascular endothelial growth factor isoform VEGF165 and placenta growth factor (PLGF). We investigated the expression pattern of NP-1/NP-2, their co-receptors, vascular endothelial growth factor receptor-1 and -2 (VEGFR-1, VEGFR-2), and their ligands, class III semaphorins, VEGF and PLGF, following experimental cerebral ischemia in mice. By means of in situ hybridization and immunohistochemistry we observed loss of expression of class III semaphorins in neurons in the infarct/peri-infarct area. In contrast, we observed high expression of NP-1 in vessels, neurons, and astrocytes surrounding the infarct. VEGF and PLGF were upregulated in different cell types following stroke. Our results suggest a shift in the balance between semaphorins and VEGF/PLGF, which compete for NP-binding. Possibly, the loss of semaphorins facilitates binding of the competing ligands (VEGF/PLGF), thus inducing angiogenesis. In addition, the observed expression patterns further suggest a neurotrophic/neuroprotective role of VEGF/PLGF.
{"title":"Cell Type‐Specific Expression of Neuropilins in an MCA‐Occlusion Model in Mice Suggests a Potential Role in Post‐Ischemic Brain Remodeling","authors":"H. Beck, T. Acker, A. Püschel, H. Fujisawa, P. Carmeliet, K. Plate","doi":"10.1093/JNEN/61.4.339","DOIUrl":"https://doi.org/10.1093/JNEN/61.4.339","url":null,"abstract":"Neuropilin-1 and -2 (NP-1/NP-2) are transmembrane receptors that play a role in axonal guidance by binding of class III semaphorins, and in angiogenesis by binding of the vascular endothelial growth factor isoform VEGF165 and placenta growth factor (PLGF). We investigated the expression pattern of NP-1/NP-2, their co-receptors, vascular endothelial growth factor receptor-1 and -2 (VEGFR-1, VEGFR-2), and their ligands, class III semaphorins, VEGF and PLGF, following experimental cerebral ischemia in mice. By means of in situ hybridization and immunohistochemistry we observed loss of expression of class III semaphorins in neurons in the infarct/peri-infarct area. In contrast, we observed high expression of NP-1 in vessels, neurons, and astrocytes surrounding the infarct. VEGF and PLGF were upregulated in different cell types following stroke. Our results suggest a shift in the balance between semaphorins and VEGF/PLGF, which compete for NP-binding. Possibly, the loss of semaphorins facilitates binding of the competing ligands (VEGF/PLGF), thus inducing angiogenesis. In addition, the observed expression patterns further suggest a neurotrophic/neuroprotective role of VEGF/PLGF.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"12 1","pages":"339–350"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88447232","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}
The myelin-synthesizing oligodendrocyte is compromised in many neuropathological diseases, including demyelinating diseases (e.g. multiple sclerosis), metabolic diseases (e.g. Pelizaeus-Merzbacher), infectious diseases (e.g. progressive multifocal leukoencephalopathy), neurodegenerative diseases (e.g. multisystem degeneration), and possibly neoplasms (e.g. oligodendrogliomas). Understanding the development of the oligodendrocyte has important implications for both the pathogenesis of these diseases and also potential therapy. Over the past 20 yr, research in oligodendrocyte development has delineated a pathway from progenitors to mature oligodendrocytes. In fact, the oligodendrocyte has served as a model for lineage development in part due to the identification of specific phenotypic stages during maturation. From this has come the identification of numerous signaling molecules that instruct oligodendrocyte development. More recently, transgenic and targeted mutagenesis studies have begun to identify new factors involved in oligodendrocyte development and have questioned some of the older observations. This review will attempt to update the current state of research on the progression of the oligodendrocyte lineage. Oligodendrocytes develop from proliferating precursor cells migrating out of germinal zones in the brain and spinal cord. When the cells reach their final destination in the brain parenchyma, they become postmitotic, extend processes, and begin to synthesize the components of myelin as extensions of their plasma membranes. In most animals, this occurs relatively late in CNS development during late embryonic and early postnatal life, after neurons and astrocytes are formed. This myelin forms an insulating sheath around axons, serving dual functions in the nervous system. Historically, myelin was recognized as critical because it facilitates rapid propagation of nervous impulses through very small spaces, thus permitting axons to be of small caliber (1). More recently, myelin has been found to modulate axonal structure and support axonal integrity, as well (2). The oligodendrocyte has become a model CNS cell type for the study of lineage development due …
{"title":"Cells and Signaling in Oligodendrocyte Development","authors":"J. Grinspan","doi":"10.1093/JNEN/61.4.297","DOIUrl":"https://doi.org/10.1093/JNEN/61.4.297","url":null,"abstract":"The myelin-synthesizing oligodendrocyte is compromised in many neuropathological diseases, including demyelinating diseases (e.g. multiple sclerosis), metabolic diseases (e.g. Pelizaeus-Merzbacher), infectious diseases (e.g. progressive multifocal leukoencephalopathy), neurodegenerative diseases (e.g. multisystem degeneration), and possibly neoplasms (e.g. oligodendrogliomas). Understanding the development of the oligodendrocyte has important implications for both the pathogenesis of these diseases and also potential therapy. Over the past 20 yr, research in oligodendrocyte development has delineated a pathway from progenitors to mature oligodendrocytes. In fact, the oligodendrocyte has served as a model for lineage development in part due to the identification of specific phenotypic stages during maturation. From this has come the identification of numerous signaling molecules that instruct oligodendrocyte development. More recently, transgenic and targeted mutagenesis studies have begun to identify new factors involved in oligodendrocyte development and have questioned some of the older observations. This review will attempt to update the current state of research on the progression of the oligodendrocyte lineage.\u0000\u0000Oligodendrocytes develop from proliferating precursor cells migrating out of germinal zones in the brain and spinal cord. When the cells reach their final destination in the brain parenchyma, they become postmitotic, extend processes, and begin to synthesize the components of myelin as extensions of their plasma membranes. In most animals, this occurs relatively late in CNS development during late embryonic and early postnatal life, after neurons and astrocytes are formed. This myelin forms an insulating sheath around axons, serving dual functions in the nervous system. Historically, myelin was recognized as critical because it facilitates rapid propagation of nervous impulses through very small spaces, thus permitting axons to be of small caliber (1). More recently, myelin has been found to modulate axonal structure and support axonal integrity, as well (2).\u0000\u0000The oligodendrocyte has become a model CNS cell type for the study of lineage development due …","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"103 1","pages":"297–306"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80644089","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}
Y. Kawamoto, I. Akiguchi, Yasuyuki Honjyo, H. Shibasaki, H. Budka
Several components of Lewy bodies have been identified, but the precise mechanism responsible for the formation of Lewy bodies remains undetermined. The 14-3-3 protein family is involved in numerous signal transduction pathways and interacts with α-synuclein, which is a major constituent of Lewy bodies. To elucidate the role of 14-3-3 proteins in neurodegenerative disorders associated with Lewy bodies, we performed immunohistochemical studies on 14-3-3 in brains from 5 elderly control subjects and from 10 patients with Parkinson disease (PD) or diffuse Lewy body disease (DLBD). In the normal controls, 14-3-3-like immunoreactivity was mainly observed in the neuronal somata and processes in various cortical and subcortical regions. In the PD and DLBD cases, a similar immunostaining pattern was found and immunoreactivity was generally spared in the surviving neurons from the severely affected regions. In addition, both classical and cortical Lewy bodies were intensely immunolabeled and some dystrophic neurites were also immunoreactive for 14-3-3. Our results suggest that 14-3-3 proteins may be associated with Lewy body formation and may play an important role in the pathogenesis of PD and DLBD.
{"title":"14‐3‐3 Proteins in Lewy Bodies in Parkinson Disease and Diffuse Lewy Body Disease Brains","authors":"Y. Kawamoto, I. Akiguchi, Yasuyuki Honjyo, H. Shibasaki, H. Budka","doi":"10.1093/JNEN/61.3.245","DOIUrl":"https://doi.org/10.1093/JNEN/61.3.245","url":null,"abstract":"Several components of Lewy bodies have been identified, but the precise mechanism responsible for the formation of Lewy bodies remains undetermined. The 14-3-3 protein family is involved in numerous signal transduction pathways and interacts with α-synuclein, which is a major constituent of Lewy bodies. To elucidate the role of 14-3-3 proteins in neurodegenerative disorders associated with Lewy bodies, we performed immunohistochemical studies on 14-3-3 in brains from 5 elderly control subjects and from 10 patients with Parkinson disease (PD) or diffuse Lewy body disease (DLBD). In the normal controls, 14-3-3-like immunoreactivity was mainly observed in the neuronal somata and processes in various cortical and subcortical regions. In the PD and DLBD cases, a similar immunostaining pattern was found and immunoreactivity was generally spared in the surviving neurons from the severely affected regions. In addition, both classical and cortical Lewy bodies were intensely immunolabeled and some dystrophic neurites were also immunoreactive for 14-3-3. Our results suggest that 14-3-3 proteins may be associated with Lewy body formation and may play an important role in the pathogenesis of PD and DLBD.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"1 1","pages":"245–253"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89318076","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}
D. Thal, E. Ghebremedhin, U. Rüb, H. Yamaguchi, K. Tredici, H. Braak
Cerebral amyloid angiopathy (CAA) is a type of β-amyloidosis that occurs in leptomeningeal and cortical vessels of the elderly. In a sample of 41 CAA cases including 16 Alzheimer disease (AD) cases and 28 controls, we show that 2 types of sporadic CAA exist: The first type is characterized by immunohistochemically detectable amyloid β-protein (Aβ) in cortical capillaries, leptomeningeal and cortical arteries, arterioles, veins, and venules. It is referred to here as CAA-Type 1. The second type of CAA also exhibits immunohistochemically detectable Aβ deposits in leptomeningeal and cortical vessels, with the exception of cortical capillaries. This type is termed CAA-Type 2. In cases with CAA-Type 1, the frequency of the apolipoprotein E (ApoE) ϵ4 allele is more than 4 times greater than in CAA-Type 2 cases and in controls. CAA-Type 2 cases have a higher ϵ2 allele frequency than CAA-Type 1 cases and controls. The ratio of CAA-Type 2 to CAA-Type 1 cases does not shift significantly with respect to the severity of AD-related β-amyloidosis, with respect to degrees of CAA-severity, or with increasing age. Therefore, CAA-Type 1 is unlikely to be the late stage of CAA-Type 2; rather, they represent 2 different entities. Since both the ApoE ϵ2 and the ϵ4 allele are known to be risk factors for CAA, we can assign the risk factor ApoE ϵ4 to a distinct morphological type of CAA. The ApoE ϵ4 allele constitutes a risk factor for CAA-Type 1 and, as such, for neuropil-associated dyshoric vascular Aβ deposition in capillaries, whereas the ϵ2 allele does not. CAA-Type 2 is not associated with the ϵ4 allele as a risk factor but shows a higher ϵ2 allele frequency than CAA-Type 1 cases and controls in our sample.
{"title":"Two Types of Sporadic Cerebral Amyloid Angiopathy","authors":"D. Thal, E. Ghebremedhin, U. Rüb, H. Yamaguchi, K. Tredici, H. Braak","doi":"10.1093/JNEN/61.3.282","DOIUrl":"https://doi.org/10.1093/JNEN/61.3.282","url":null,"abstract":"Cerebral amyloid angiopathy (CAA) is a type of β-amyloidosis that occurs in leptomeningeal and cortical vessels of the elderly. In a sample of 41 CAA cases including 16 Alzheimer disease (AD) cases and 28 controls, we show that 2 types of sporadic CAA exist: The first type is characterized by immunohistochemically detectable amyloid β-protein (Aβ) in cortical capillaries, leptomeningeal and cortical arteries, arterioles, veins, and venules. It is referred to here as CAA-Type 1. The second type of CAA also exhibits immunohistochemically detectable Aβ deposits in leptomeningeal and cortical vessels, with the exception of cortical capillaries. This type is termed CAA-Type 2. In cases with CAA-Type 1, the frequency of the apolipoprotein E (ApoE) ϵ4 allele is more than 4 times greater than in CAA-Type 2 cases and in controls. CAA-Type 2 cases have a higher ϵ2 allele frequency than CAA-Type 1 cases and controls. The ratio of CAA-Type 2 to CAA-Type 1 cases does not shift significantly with respect to the severity of AD-related β-amyloidosis, with respect to degrees of CAA-severity, or with increasing age. Therefore, CAA-Type 1 is unlikely to be the late stage of CAA-Type 2; rather, they represent 2 different entities. Since both the ApoE ϵ2 and the ϵ4 allele are known to be risk factors for CAA, we can assign the risk factor ApoE ϵ4 to a distinct morphological type of CAA. The ApoE ϵ4 allele constitutes a risk factor for CAA-Type 1 and, as such, for neuropil-associated dyshoric vascular Aβ deposition in capillaries, whereas the ϵ2 allele does not. CAA-Type 2 is not associated with the ϵ4 allele as a risk factor but shows a higher ϵ2 allele frequency than CAA-Type 1 cases and controls in our sample.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"26 1","pages":"282–293"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84837362","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}
S. Hunter, A. Young, J. Olson, D. Brat, G. Bowers, J. Wilcox, D. Jaye, Savvas E Mendrinos, A. Neish
Fibrillary astrocytoma, the most common primary central nervous system neoplasm, is infiltrating, rapidly proliferating, and almost invariably fatal. This contrasts with the biologically distinct pilocytic astrocytoma, which is circumscribed, often cystic, slowly proliferating, and associated with a favorable long-term outcome. Diagnostic markers for distinguishing pilocytic astrocytomas from infiltrating anaplastic astrocytomas are currently not available. To identify genes that might either serve as markers or explain these distinct biologic behaviors, cDNA microarray analysis was used to compare the expression of 7,073 genes (nearly one quarter of the human genome) between these 2 types of astrocytoma. Messenger RNAs pooled from 3 pilocytic astrocytomas and from 4 infiltrating anaplastic astrocytomas were compared. Apolipoprotein D (apoD), which expressed 8.5-fold higher in pilocytic astrocytomas, showed the greatest level of differential expression and emerged as a potential marker for pilocytic tumors. By immunohistochemistry, 10 of 13 pilocytic astrocytomas stained positively for apoD, while none of 21 infiltrating astrocytomas showed similar staining. ApoD immunostaining was also seen in 9 of 14 of gangliogliomas, 4 of 5 subependymal giant cell astrocytomas (SEGAs), and a single pleomorphic xanthoastrocytomas (PXAs). By in situ hybridization, pilocytic astrocytomas, in contrast with infiltrating astrocytomas, showed widespread increased apoD expression. SAGE analysis using the NCBI database showed a higher level of expression of apoD RNA in pilocytic astrocytoma than in any of the other 94 neoplastic and non-neoplastic tissues in the database. ApoD is associated with decreased proliferation in some cell lines, and is the protein found in highest concentration in cyst fluid from benign cystic disease of the breast. ApoD might play a role in either decreased proliferation or cyst formation in pilocytic astrocytomas, gangliogliomas, SEGAs, and PXAs.
{"title":"Differential Expression between Pilocytic and Anaplastic Astrocytomas: Identification of Apolipoprotein D as a Marker for Low‐Grade, Non‐Infiltrating Primary CNS Neoplasms","authors":"S. Hunter, A. Young, J. Olson, D. Brat, G. Bowers, J. Wilcox, D. Jaye, Savvas E Mendrinos, A. Neish","doi":"10.1093/JNEN/61.3.275","DOIUrl":"https://doi.org/10.1093/JNEN/61.3.275","url":null,"abstract":"Fibrillary astrocytoma, the most common primary central nervous system neoplasm, is infiltrating, rapidly proliferating, and almost invariably fatal. This contrasts with the biologically distinct pilocytic astrocytoma, which is circumscribed, often cystic, slowly proliferating, and associated with a favorable long-term outcome. Diagnostic markers for distinguishing pilocytic astrocytomas from infiltrating anaplastic astrocytomas are currently not available. To identify genes that might either serve as markers or explain these distinct biologic behaviors, cDNA microarray analysis was used to compare the expression of 7,073 genes (nearly one quarter of the human genome) between these 2 types of astrocytoma. Messenger RNAs pooled from 3 pilocytic astrocytomas and from 4 infiltrating anaplastic astrocytomas were compared. Apolipoprotein D (apoD), which expressed 8.5-fold higher in pilocytic astrocytomas, showed the greatest level of differential expression and emerged as a potential marker for pilocytic tumors. By immunohistochemistry, 10 of 13 pilocytic astrocytomas stained positively for apoD, while none of 21 infiltrating astrocytomas showed similar staining. ApoD immunostaining was also seen in 9 of 14 of gangliogliomas, 4 of 5 subependymal giant cell astrocytomas (SEGAs), and a single pleomorphic xanthoastrocytomas (PXAs). By in situ hybridization, pilocytic astrocytomas, in contrast with infiltrating astrocytomas, showed widespread increased apoD expression. SAGE analysis using the NCBI database showed a higher level of expression of apoD RNA in pilocytic astrocytoma than in any of the other 94 neoplastic and non-neoplastic tissues in the database. ApoD is associated with decreased proliferation in some cell lines, and is the protein found in highest concentration in cyst fluid from benign cystic disease of the breast. ApoD might play a role in either decreased proliferation or cyst formation in pilocytic astrocytomas, gangliogliomas, SEGAs, and PXAs.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"10 1","pages":"275–281"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81669386","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}
Cytonectin is a novel 35,000 molecular weight protein that displays remarkable ion-independent adherence properties. This consigns it to a family of well-known adherence molecules essential for cell communication and the development of 3-dimensional tissue structures. Cytonectin is expressed in a variety of organs and tissues, being evolutionarily conserved from human to avian species. It is hypothesized to serve as a key structural component of the body, and as a “do not attack” signal molecule that prevents tissue destruction by cells of monocyte lineage. This paper describes the properties of cytonectin and its proposed role in normal and disease states. The protein is overexpressed in Alzheimer disease entorhinal cortex as compared to normal age-matched controls. It is also detected in tissues from patients with Down syndrome and leukemia. Its presence in all 3 of these related conditions may prove important to their etiopathogenesis.
{"title":"Cytonectin Expression in Alzheimer Disease","authors":"S. J. Anderson, P. Barker, M. Hadfield","doi":"10.1093/JNEN/61.3.230","DOIUrl":"https://doi.org/10.1093/JNEN/61.3.230","url":null,"abstract":"Cytonectin is a novel 35,000 molecular weight protein that displays remarkable ion-independent adherence properties. This consigns it to a family of well-known adherence molecules essential for cell communication and the development of 3-dimensional tissue structures. Cytonectin is expressed in a variety of organs and tissues, being evolutionarily conserved from human to avian species. It is hypothesized to serve as a key structural component of the body, and as a “do not attack” signal molecule that prevents tissue destruction by cells of monocyte lineage. This paper describes the properties of cytonectin and its proposed role in normal and disease states. The protein is overexpressed in Alzheimer disease entorhinal cortex as compared to normal age-matched controls. It is also detected in tissues from patients with Down syndrome and leukemia. Its presence in all 3 of these related conditions may prove important to their etiopathogenesis.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"3 1","pages":"230–236"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78080509","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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