bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of Synaptopodin, an Actin‐associated Protein, in the Rat Hippocampus after Limbic Epilepsy
Authors: Roth Stephanie U. , Sommer Clemens , Mundel Peter , Kiessling Marika
Published: July 2010

Synaptopodin, a 100 kD protein, associated with the actin cytoskeleton of the postsynaptic density and dendritic spines, is thought to play a role in modulating actin‐based shape and motility of dendritic spines during formation or elimination of synaptic contacts. Temporal lobe epilepsy in humans and in rats shows neuronal damage, aberrant sprouting of hippocampal mossy fibers and subsequent synaptic remodeling processes. Using kainic acid (KA) induced epilepsy in rats, the postictal hippocampal expression of synaptopodin was analyzed by in situ hybridization (ISH) and immunohistochemistry. Sprouting of mossy fibers was visualized by a modified Timm's staining. ISH showed elevated levels of Synaptopodin mRNA in perikarya of CA3 principal neurons, dentate granule cells and in surviving hilar neurons these levels persisted up to 8 weeks after seizure induction. Synaptopodin immunoreactivity in the dendritic layers of CA3, in the hilus and in the inner molecular layer of the dentate gyrus (DG) was initially reduced. Eight weeks after KA treatment Synaptopodin protein expression returned to control levels in dendritic layers of CA3 and in the entire molecular layer of the DG. The recovery of protein expression was accompanied by simultaneous supra‐ and infragranular mossy fiber sprouting. Postictal upregulation of Synaptopodin mRNA levels in target cell populations of limbic epilepsy‐elicited damage and subsequent Synaptopodin protein expression largely co‐localized with remodeling processes as demonstrated by mossy fiber sprouting. It may thus represent a novel postsynaptic molecular correlate of hippocampal neuroplasticity.
Non‐sarcolemmal Muscular Dystrophies
Authors: Brown Susan C. , Muntoni Francesco , Sewry Caroline A.
Published: July 2010

The muscular dystrophies are characterised by progressive muscle weakness and wasting. Pathologically the hallmarks are muscle fibre degeneration and fibrosis. Several recessive forms of muscular dystrophy are caused by defects in proteins localised to the sarcolemma. However, it is now apparent that others are due to defects in a wide range of proteins including those which are either nuclear‐related (Emery‐Dreifuss type muscular dystrophies, oculopharyngeal muscular dystrophy), enzymatic (limb‐girdle muscular dystrophy 2A, myotonic dystrophy) or sarcomeric (limb‐girdle muscular dystrophies 1A and 2G). Although the clinical and molecular basis of these disorders is heterogeneous all display myopathic morphological features. These include variation in fibre size, an increase in internal nuclei, and some myofibrillar distortion. Degeneration and fibrosis occur, but usually not to the same extent as in muscular dystrophies associated with sarcolemmal protein defects. This review outlines the genetic basis of these “non‐sarcolemmal” forms of dystrophy and discusses current ideas on their pathogenesis.
Sarcolemmopathy: Muscular Dystrophies with Cell Membrane Defects
Authors: Ozawa Eijiro , Nishino Ichizo , Nonaka Ikuya
Published: July 2010

In this article, we review the molecular pathology of muscular dystrophies caused by defects of proteins located within or near cell membranes. These disorders include Bethlem myopathy, merosinopathy, dystrophinopathy, sarcoglycanopathies, integrinopathy, dysferlinopathy and caveolinopathy. We refer to these diseases collectively as sarcolemmopathy. Here, we describe the biological functions of these proteins in the context of muscular contractions and their roles in the infrastructure of muscle; defects of muscle infrastructures cause those diseases.

As an example, in dystrophinopathy, cell membranes have mechanical defects due to the absence of dystrophin. Cracks of the cell membrane induced by muscle contraction may allow the influx and efflux of substances that trigger muscle cell degeneration. However, such cracks may be resealed on relaxation. In addition, dystrophinopathy causes secondary defects of various dystrophin‐associated proteins suggesting that defects in cell signaling participate in the pathologic process. With regard to other sarcolemmopathies, we discuss pathological mechanisms based on available data.
Spinal Muscular Atrophy: Present State
Authors: Schmalbruch Henning , Haase Georg
Published: July 2010

Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease caused by homozygous deletions or mutations in the SMN1 gene on Chr.5q13. SMA spans from severe Werdnig‐Hoffmann disease (SMA 1) to relatively benign Kugelberg‐Welander disease (SMA 3). Onset before birth possibly aggravates the clinical course, because immature motoneurons do not show compensatory sprouting and collateral reinnervation, and motor units in SMA 1, in contrast to those in SMA 3, are not enlarged. Genetic evidence indicates that SMN2, a gene 99% identical to SMN1, can attenuate SMA severity: in patients, more SMN2 copies and higher SMN protein levels are correlated with milder SMA. There is evidence that SMN plays a role in motoneuron RNA metabolism, but it has also been linked to apoptosis.

Several mouse models with motoneuron disease have been successfully treated with neurotrophic factors. None of these models is, however, homologous to SMA. Recently, genetic mouse models of SMA have been created by introducing human SMN2 transgenes into Smn knockout mice or by targeting the Smn gene knockout to neurons. These mice not only provide important insights into the pathogenesis of SMA but are also crucial for testing new therapeutic strategies. These include SMN gene transfer, molecules capable to up‐regulate SMN expression and trophic or antiapoptotic factors.
p73 is not Mutated in Meningiomas as Determined with a Functional Yeast Assay but p73 Expression Increases with Tumor Grade
Authors: Nozaki Michimasa , Tada Mitsuhiro , Kashiwazaki Haruhiko , Hamou Marie‐France , Diserens Annie‐Claire , Shinohe Yumiko , Sawamura Yutaka , Iwasaki Yoshinobu , de Tribolet Nicolas , Hegi Monika E.
Published: July 2010

The p53 gene is normally wild type in meningiomas. Since all three members of the p53 gene family recognize the same DNA sequence, tumors containing wild type p53 could decrease transactivation of p53 target genes by mutating either p63 or p73. In meningiomas the most likely target is p73, because loss of heterozygosity of the chromosomal band containing p73 is the commonest genetic lesion in these tumors. To screen p73 for mutations we have developed a functional assay which tests the ability of p73 to activate transcription from a p53‐responsive promoter in yeast. The assay correctly identified p73 mutants with mutations equivalent to hotspot mutations in p53, demonstrating that the assay can detect transcriptionally inactive p73. No mutations in p73 were identified in meningiomas. p73 RNA level was higher in more advanced tumors, but there was no correlation between the expression level of p73 and p21, a known p53 target gene. The yeast assay was also used to measure the intrinsic sensitivity of the p73 protein to mutagenesis. Like p53, p73 is exceptionally easy to inactivate as a transcription factor by point mutation. Taken together, these results indicate that p53 and p73 serve very different functions in tumors.
Transgenic and Knockout Mouse Models Clarify Pituitary Development, Function and Disease
Authors: Asa Sylvia L.
Published: July 2010

Mouse models have been used to study various aspects of pituitary development, function and disease. Transgenic or knockout technology has been applied to examine the regulation of hormone gene expression and the pathophysiology of its alterations, to ascertain the factors that determine cell differentiation, and to manipulate oncogenesis. Transgenic mice have elucidated the necessary elements required for the tissue‐ and cell‐specific expression of pituitary hormones. Transgenic and knockout technologies have derived mice with hormone overexpression or abrogation of hormone action, and have identified novel hormones. The role of precursor cells in cell differentiation has been confirmed by genetic ablation of cell lineages. Inactivation of transcription factors implicated in pituitary organogenesis and cytogenesis has proven their critical roles in pituitary development. Pituitary oncogenesis has been studied by promoter‐directed oncogene expression or tumor suppressor gene ablation, by adenohypophysiotropic hormone overexpression, or by growth factor or receptor overexpression. The tumors have provided a number of cell lines for use in the continuing study of pituitary physiology and pathology. These models may also be used in the future to examine novel therapeutic strategies for the management of patients with pituitary disorders.
An Animal Model of Varicella Virus Infection
Authors: White Tiffany M. , Gilden Donald H. , Mahalingam Ravi
Published: July 2010

Varicella‐zoster virus (VZV) causes chickenpox in children; establishes latency in cranial nerve, dorsal root, and autonomic ganglia; and reactivates decades later to produce zoster. VZV produces disease only in humans. Although attempts to produce disease and study VZV latency in experimentally infected animals have resulted in virus in trigeminal or dorsal root ganglia, no clinical signs of infection or reactivation developed. In contrast, simian varicella virus (SVV) produces a naturally occurring exanthematous disease in non‐human primates that mimics human varicella. Experimental inoculation of non‐human primates causes similar, if not identical, clinical and pathological changes observed in monkeys naturally infected with SVV. Like VZV, SVV becomes latent in ganglia and reactivates, often with entire body rash. SVV and VZV encode antigenically related polypeptides. Both virus genomes have been sequenced and shown to be colinear, sharing up to 75% DNA homology. During latency, an SVV homolog of one of the five VZV genes transcribed in latently infected human ganglia has been detected in monkey ganglia. Preliminary studies in which monkeys were inoculated intratracheally with SVV revealed the presence of viral DNA and RNA in multiple tissues, including blood mononuclear cells, months after experimental infection. These findings differed from the expected restricted localization of the virus DNA to ganglia only and the expected limited viral gene expression, and probably reflect the high virus load delivered intratracheally compared to natural SVV infection in monkeys. Nevertheless, clinical, pathological, and molecular similarities between SVV and VZV indicate that SVV infection in non‐human primates has considerable potential as an animal model for human varicella.
Fluorescence In Situ Hybridization (FISH) in Diagnostic and Investigative Neuropathology
Authors: Fuller Christine E. , Perry Arie
Published: July 2010

Over the last decade, fluorescence in situ hybridization (FISH) has emerged as a powerful clinical and research tool for the assessment of target DNA dosages within interphase nuclei. Detectable alterations include aneusomies, deletions, gene amplifications, and translocations, with primary advantages to the pathologist including its basis in morphology, its applicability to archival, formalin‐fixed paraffin‐embedded (FFPE) material, and its similarities to immunohistochemistry. Recent technical advances such as improved hybridization protocols, markedly expanded probe availability resulting from the human genome sequencing initiative, and the advent of high‐throughput assays such as gene chip and tissue microarrays have greatly enhanced the applicability of FISH. In our lab, we currently utilize only a limited battery of DNA probes for routine diagnostic purposes, with determination of chromosome 1p and 19q dosage in oligodendroglial neoplasms representing the most common application. However, research applications are numerous and will likely translate into a growing list of clinically useful markers in the near future. In this review, we highlight the advantages and disadvantages of FISH and familiarize the reader with current applications in diagnostic and investigative neuropathology.
Allelic Gain and Amplification on the Long Arm of Chromosome 17 in Anaplastic Meningiomas
Authors: Büschges Rainer , Ichimura Koichi , Weber Ruthild G. , Reifenberger Guido , Collins V. Peter
Published: July 2010

Using comparative genomic hybridization (CGH) we have previously identified amplification at 17q21‐qter as a common aberration in anaplastic meningiomas but not in atypical or benign meningiomas (19). To define the amplified genomic region, we analyzed 44 meningeal tumors, including 7 benign meningiomas of World Health Organization (WHO) grade I, 19 atypical meningiomas (WHO grade II) and 18 anaplastic meningiomas (WHO grade III) at 46 chromosome 17 loci (including 42 17q loci). In line with the CGH data we found evidence of increased numbers of alleles on 17q. The incidence rose with malignancy grade, culminating at 61% (11 of 18 cases) in the anaplastic meningioma group. The majority of cases showing increased allele numbers had, on average, low‐level allelic gains (relative increase in allele dosage of 2‐ to 5‐fold). Amplification of alleles (defined here as an average relative increase in allele dosage of more than 5 times) was detected in 2 anaplastic meningiomas. The amplification patterns in these tumors defined a number of common regions of amplification/increased allele copy number, the best defined include one between D17S790 and D17S1607 and one between D17S1160 and PS6K. Real‐time PCR analysis of the PS6K candidate gene revealed no high‐level amplification despite this affecting adjacent loci. Our findings are fundamental for the identification of the gene(s) in 17q22‐q23 that is (are) the target(s) for increased copy number in anaplastic meningiomas and possibly other tumor types.
What is an Oligodendroglioma?
Authors: Burger Peter C.
Published: July 2010

Editor's Note:

With this issue, we begin a new series of articles entitled “Controversies in neuropathology.” These will represent brief position papers on controversial topics in our specialty. They are not intended to be review articles, rather will represent “position papers” on topical issues, with a relatively circumscribed and selective bibliography. Authors of these papers are encouraged to present and defend their own views on the subject in question. Most of these papers will be by invitation, but authors who would like to submit an article for this series are encouraged to contact the Brain Pathology editorial office. HVV
Intraneuronal APP/Aβ Trafficking and Plaque Formation in β‐Amyloid Precursor Protein and Presenilin‐1 Transgenic Mice
Authors: Wirths Oliver , Multhaup Gerd , Czech Christian , Feldmann Nicole , Blanchard Véronique , Tremp Günter , Beyreuther Konrad , Pradier Laurent , Bayer Thomas A.
Published: July 2010

Neuropil deposition of β‐amyloid peptides Aβ40 and Aβ42 is believed to be the key event in the neurodegenerative processes of Alzheimer's disease (AD). Since Aβ seems to carry a transport signal that is required for axonal sorting of its precursor β‐amyloid precursor protein (APP), we studied the intraneuronal staining profile of Aβ peptides in a transgenic mouse model expressing human mutant APP751 (KM670/671NL and V717I) and human mutant presenilin‐1 (PS‐1 M146L) in neurons. Using surface plasmon resonance we analyzed the Aβ antibodies and defined their binding profile to APP, Aβ40 and Aβ42. Immunohistochemical staining revealed that intraneuronal Aβ40 and Aβ42 staining preceded plaque deposition, which started at 3 months of age. Aβ was observed in the somatodendritic and axonal compartments of many neurons. Interestingly, the striatum, which lacks transgenic APP expression harbored many plaques at 10 months of age. This is most likely due to an APP/Aβ transport problem and may be a model region to study APP/Aβ trafficking as an early pathological event.
Human Brain Parenchymal Microglia Express CD14 and CD45 and are Productively Infected by HIV‐1 in HIV‐1 Encephalitis
Authors: Cosenza; Melissa A. , Zhao; Meng‐Liang , Si; Qiusheng , Lee Sunhee C.
Published: July 2010

Microglia are endogenous brain macrophages that show distinct phenotypes such as expression of myeloid antigens, ramified morphology, and presence within the neural parenchyma. They play significant roles in a number of human CNS diseases including AIDS dementia. Together with monocytederived (perivascular) macrophages, microglia represent a major target of HIV‐1 infection. However, a recent report challenged this notion based on findings in SIV encephalitis. This study concluded that perivascular macrophages can be distinguished from parenchymal microglial cells by their expression of CD14 and CD45, and that macrophages, but not microglia, are productively infected in SIV and HIV encephalitis. To address whether parenchymal microglia are productively infected in HIV encephalitis, we analyzed expression of CD14, CD45 and HIV‐1 p24 in human brain. Microglia were identified based on their characteristic ramified morphology and location in the neural parenchyma. We found that parenchymal microglia are CD14+ (activated), CD45+ (resting and activated), and constitute approximately two thirds of the p24+ cells in HIV encephalitis cases. These results demonstrate that microglia are major targets of infection by HIV‐1, and delineate possible differences between HIVE and SIVE. Because productively infected tissue macrophages serve as the major viral reservoir, these findings have important implications for AIDS.
Oligodendrocyte Progenitor Cells in the Adult Rat CNS Express Myelin Oligodendrocyte Glyco‐protein (MOG)
Authors: Li; Guilin , Crang; A. John , Rundle; Jon L. , Blakemore William F.
Published: July 2010

While the effects of high dose X‐irradiation on mitotically active progenitor cells and remyelination are well‐documented, its effects on myelinating oligodendrocytes are less clear, due in part to divergent views on their mitotic capacity. To examine the effect of X‐irradiation on oligodendrocytes, the spinal cord of rats was exposed to 40 Gy of X‐irradiation and the number of oligodendrocytes and oligodendrocyte progenitors in the dorsal funiculi at T12 and L1 was determined by in situ hybridization using cRNA‐probes for platelet derived growth factor alpha receptor (PDGFRα) (to identify oligodendrocyte progenitors), exon 3b of proteolipid protein (PLP) (to identify mature oligodendrocytes) and myelin oligodendrocyte glycoprotein (MOG). X‐irradiation resulted in no change in the number of PLP positive cells and no loss of myelin internodes, but caused an almost complete loss of PDGFRα‐expressing cells, and a reduction in the number of MOG positive cells to a number similar to that found using the PLP exon 3b probe. Importantly, the number of radiation‐sensitive MOG‐expressing cells was similar to the number of PDGFRα positive cells. To determine if the radiation‐sensitive MOG positive cells were the same population as the radiation sensitive PDGFRα‐expressing cells, MOG and PDGFRα‐expressing cells were isolated from the adult CNS using antibody coated magnetic beads. Twelve to thirteen percent of MOG positive cells were PDGFRα positive and nearly all the PDGFRa isolated cells were MOG and galactocerebroside positive. Double immunofluorescence revealed colocalization of NG2 and MOG on cells in the normal adult rat spinal cord. These results show that in situ in the adult rat spinal cord white matter oligodendrocyte progenitors are MOG positive and indicates that expression of MOG cannot be regarded a marker that only identifies mature myelin‐supporting oligodendrocytes in tissue.
Upregulation of Group 1 CD1 Antigen Presenting Molecules in Guinea Pigs with Experimental Autoimmune Encephalomyelitis: An Immunohistochemical Study
Authors: Cipriani Barbara , Chen Lanfen , Hiromatsu Kenji , Knowles Heather , Raine Cedric S. , Battistini Luca , Porcelli Steven A. , Brosnan Celia F.
Published: July 2010

In humans, group 1 CD1 glycoproteins present foreign and self lipid and glycolipid antigens to Tcells. Homologues of these molecules are not found in mice or rats but are present in guinea pigs (GPs). We examined CD1 and MHC class II expression in the central nervous system (CNS) of GPs sensitized for experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. In normal GPs and the uninflamed CNS, low‐level MHC class II (MHC II) immunoreactivity occurred on vascular elements, meningeal macrophages and parenchymal microglial cells, whereas immunoreactivity for CD1 was absent. In the inflamed CNS, the majority of infiltrating cells were MHC II+ and microglia showed increased expression. CD1 immunoreactivity was detected on astrocytes and subsets of inflammatory cells including B cells and macrophages. Minimal CD1 and MHC II co‐expression was noted on inflammatory cells or glia. We conclude that group 1 CD1 molecules are strongly upregulated in the inflamed CNS on subsets of cells distinct from the majority of MHC II bearing cells. The expression of CD1 proteins in such lesions broadens the potential repertoire of antigens recognized at these sites and highlights the value of the GP as a model for studies of the relevance of CD1 molecules in host defense and autoimmune diseases.
Targeted Molecular Therapy of GBM
Authors: Mischel Paul S. , Cloughesy Timothy F.
Published: July 2010

Major advances in molecular biology, cellular biology and genomics have substantially improved our understanding of cancer. Now, these advances are being translated into therapy. Targeted therapy directed at specific molecular alterations is already creating a shift in the treatment of cancer patients. Glioblastoma (GBM), the most common brain cancer of adults, is highly suited for this new approach. GBMs commonly overexpress the oncogenes EGFR and PDGFR, and contain mutations and deletions of tumor suppressor genes PTEN and TP53. Some of these alterations lead to activation of the PI3K/Akt and Ras/MAPK pathways, which provide targets for therapy. In this paper, we review the ways in which molecular therapies are being applied to GBM patients, and describe the tools of these approaches: pathway inhibitors, monoclonal antibodies and oncolytic viruses. We describe strategies to: i) target EGFR, its ligand‐independent variant EGFRvIII, and PDGFR on the cell surface, ii) inhibit constitutively activate RAS/MAPK and PI3K/Akt signaling pathways, iii) target TP53 mutant tumors, and iv) block GBM angiogenesis and invasion. These new approaches are likely to revolutionize the treatment of GBM patients. They will also present new challenges and opportunities for neuropathology.
HIV‐1 Persistence, Viral Reservoir, and the Central Nervous System in the HAART Era
Authors: Lambotte Olivier , Deiva Kumaran , Tardieu Marc
Published: July 2010

HAART therapy has led to a significant reduction of general and neurological morbidity, and mortality among HIV‐1 infected patients. It can also decrease HIV‐1 RNA titres in plasma and CSF towards undetectable level. However, the initial hope of achieving total eradication of the virus from the body has vanished. Even in patients who do not develop viral resistance or treatment intolerance, two kinds of viral persistence have been demonstrated both in lymphoid and central nervous system. The first one is a smoldering infection that persists, despite prolonged and apparently efficient HAART, in monocytes, tissue macrophages and most probably microglia. The second one is an integration of proviral DNA in the genome of subpopulations of CD4 lymphocytes of patients receiving efficient HAART. A similar viral integration in astrocytes and less likely in resting microglia is suggested by several studies, although it has yet to be demonstrated conclusively
Granular Cell Astrocytomas Show a High Frequency of Allelic Loss but are not a Genetically Defined Subset
Authors: Castellano‐Sanchez Amilcar A. , Ohgaki Hiroko , Yokoo Hideako , Scheithauer Bernd W. , Burger Peter C. , Hamilton Ronald L. , Finkelstein Sydney D. , Brat Daniel J.
Published: July 2010

Granular cell astrocytomas (GCA) are an uncommon morphologic variant of infiltrative glioma that contains a prominent population of atypical granular cells. As a rule, they are biologically aggressive compared to similar tumors without granular features. We sought to determine whether GCAs possess distinct genotypic alterations that might reflect their unique morphology or clinical behavior. Eleven GCAs occurring in 7 men and 4 women ranging in age from 46 to 75 years were investigated for genetic alterations of known significance in glial tumorigenesis, including LOH at 1p, 9p, 10q, 17p, and 19q, point mutations of TP53, deletions of p16(CDKN2A) and p14ARF, as well as EGFR amplifications. Tumors included had an infiltrative growth pattern and consisted of large, round cells packed with eosinophilic, PAS‐positive granules that varied in quantity, ranging from 30 to 100% of tumor cells. Three tumors were of WHO grade II, one was grade III, and 7 were grade IV lesions. Overall, the tumors showed higher frequencies of LOH at 1p, 9p, 10q, 17p, and 19q than typical infiltrating astrocytomas of similar grades. Losses on 9p and 10q occurred in nearly all cases, including low grade lesions. TP53 mutations were identified in 2 grade IV GCAs, while combined p14ARF and p16(CDKN2A) homozygous deletions were noted in only one grade IV lesion. None showed EGFR amplification. We found no genetic alterations specific for GCA. Instead, it appears that granular cell change occurs across genetic subsets. The high frequency of allelic loss, especially on 9p and 10q, may confer aggressive growth potential and be related to their rapid clinical progression.
Iatrogenic Creutzfeldt‐Jakob Disease with Florid Plaques
Authors: Kretzschmar Hans A. , Sethi Shneh , Földvári Zsuzsanna , Windl Otto , Querner Veronika , Zerr Inga , Poser Sigrid
Published: July 2010

Florid plaques indistinguishable from those found in vCJD were identified at a postmortem examination in the brain of a 58‐year‐old clinical suspect case of Creutzfeldt‐Jakob disease (CJD). Western blotting of brain tissue revealed an unusual prion protein type. Since the patient had received a dura mater graft 20 years prior to death and florid plaques are not only found in new variant CJD, the findings argue in favor of an iatrogenic origin of the disease with the longest incubation time following a dura mater graft reported to date even though he may have been exposed to BSE. The peculiar pathological, clinical and biochemical features may define a new type of human prion disease.
Increase in Cholesterol and Cholesterol Oxidation Products, and Role of Cholesterol Oxidation Products in Kainate‐induced Neuronal Injury
Authors: Ong Wei‐Yi , Goh Eugene Wee‐Sing , Lu Xin‐Rong , Farooqui Akhlaq A. , Patel Shutish C. , Halliwell Barry
Published: July 2010

Little is known about changes in sterols, in particular cholesterol, and cholesterol oxidation products (COPs) in oxidative injury in neural tissues. We have therefore examined changes in cholesterol and COPs using a model of excitotoxic injury. Intracerebroventricular injections of kainate in rats resulted in an increase in immunoreactivity to cholesterol in the affected CA fields of the hippocampus. The increase was confirmed by increased filipin staining of cholesterol in adjacent sections from the same animals, and in hippocampal slice or neuronal cultures after kainate treatment. In neuronal cultures, addition of lovastatin, an inhibitor of cholesterol synthesis, attenuated the increased filipin staining after kainate treatment, indicating that the increase in cholesterol could involve increased cholesterol synthesis. Furthermore, gas chromatographic mass spectrometric (GC/MS) analysis of cholesterol and COPs in kainate‐injected rat brain showed a marked increase in cholesterol and COPs including 7‐ketocholesterol, 3 days after kainate treatment. The addition of some COPs, including 7‐ketocholesterol and cholesterol epoxides to hippocampal slices resulted in neuronal injury as reflected by decreased staining of a neuronal marker in the affected CA fields. The ability of these COPs to produce neuronal injury was attenuated by glutathione, suggesting that oxidative mechanisms are involved in neuronal injury induced by these products. These results, together with GC/MS results that showed significant increase in 7‐ketocholesterol at 3 days post‐kainate injury suggest that 7‐ketocholesterol may be a factor in aggravating oxidative damage to neurons, after the initial stages of kainate‐induced neuronal injury.
Endogenous Ciliary Neurotrophic Factor Protects GABAergic, But Not Cholinergic, Septohippocam pal Neurons Following Fimbria‐fornix Transection
Authors: Naumann Thomas , Schnell Oliver , Zhi Qixia , Kirsch Matthias , Schubert Klaus Oliver , Sendtner Michael , Hofmann Hans‐Dieter
Published: July 2010

Application of neurotrophic proteins including ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF), members of the family of gp130‐associated cytokines, can rescue CNS neurons from injury‐induced degeneration. However, it is not clear so far if these effects reflect a physiological function of the endogenous cytokines. Using fimbria‐fornix transection as a model, we examined whether responses of GABAergic and cholinergic septohippocampal neurons to axotomy are altered in mice lacking CNTF. In addition, we studied the cellular expression of CNTF, LIF and related cytokine receptor components in the septal complex following lesion.

Degeneration of septohippocampal GABAergic neurons in the medial septum as indicated by the loss of parvalbumin‐immunoreactive neurons was accelerated and permanently enhanced in CNTF' mice as compared to wild‐type animals. Unexpectedly, the number of axotomized cholinergic MS neurons was significantly higher in CNTF‐deficient mice during the first 2 weeks postlesion. Both in wild‐type and in CNTF‐/‐ mutants, expression of mRNAfor the CNTF‐specific α‐subunit of the cytokine receptor complex was specifically upregulated in axotomized GABAergic septal neurons, whereas enhanced expression of the LIF‐binding β‐subunit was specifically observed in axotomized cholinergic neurons. Following lesion, CNTF expression in wild‐type mice was induced in activated astrocytes surrounding the axotomized neurons and at the lesion site. Expression of LIF mRNA was localized in the GABAergic and cholinergic septohippocampal neurons.

These results strongly indicate that endogenous CNTF, supplied by reactive glia cells, acts as a neuroprotective factor for axotomized CNS neurons. In the septum, endogenous CNTF specifically supports lesioned GABAergic projection neurons, whereas LIF may play a similar role for the cholinergic counterparts.
Neural Stem Cells: A Potential Source for Remyelination in Neuroinflammatory Disease
Authors: Brundin Lou , Brismar Hjalmar , Danilov Alexandre I. , Olsson Tomas , Johansson Clas B.
Published: July 2010

In multiple sclerosis, the central nervous system is lesioned through invasion of plaque‐forming inflammatory cells, primarily contributing to immune attack of myelin and oligodendrocytes. In this report we address the possible activation and differentiation of central nervous system stem cells following such immunological insults in a well‐characterized rat model of multiple sclerosis characterised by spinal cord pathology. Dye‐labeled central nervous system stem cells, residing within the ependymal layer of the central canal responded to the multiple sclerosis‐like conditions by proliferation, while some of the migrating stem cell‐derived cells expressed markers typical for oligodendrocytes (O4) and astrocytes (glial fibrillary acidic protein, GFAP) in the demyelinated area. Our results indicate that regenerative stem cell activation following immunoactivity is different from that after trauma, exemplified by the slower time course of stem cell proliferation and migration of progeny, in addition to the ability of the stem cell‐derived cells to express oligodendrocyte markers. Finally, deleterious effects of macrophages on the stem cell population were evident and may contribute to the depletion of the stem cell population in neuroinflammatory disorders.
Anaplasia and Grading in Medulloblastomas
Authors: Eberhart; Charles G. , Burger Peter C.
Published: July 2010

The variable clinical outcomes of medulloblastoma patients have prompted a search for markers with which to tailor therapies to individuals. In this review, we discuss clinical, histological and molecular features that can be used in such treatment customization, focusing on how histopathological grading can impact both patient care and research on the molecular basis of CNS embryonal tumors. Medulloblastomas span a histological spectrum ending in overtly malignant large cell/anaplastic lesions characterized by increased nuclear size, marked cytological anaplasia, and increased mitotic and apoptotic rates. These “high‐grade” lesions make up approximately one quarter of medulloblastomas, and recur and metastasize more frequently than tumors lacking anaplasia. We believe anaplastic change represents a type of malignant progression common to many medulloblastoma subtypes and to other CNS embryonal lesions as well. Correlation of these histological changes with the accumulation of genetic events suggests a model for the histological and molecular progression of medulloblastoma.
Minor Contribution of Bone Marrow‐Derived Endothelial Progenitors to the Vascularization of Murine Gliomas
Authors: Machein Márcia Regina , Renninger Sabine , De Lima‐Hahn Elisete , Plate Karl H.
Published: July 2010

Until recently, it was generally accepted that the vascularization of solid tumors occurred exclusively through the sprouting and co‐option from preexisting blood vessels. Growing evidence now suggests that bone marrow‐derived endothelial progenitor cells (EP) circulate in the blood and may play an important role in the formation of new blood vessels in certain tumors. Whether endothelial progenitors participate in the vascularization of brain tumors has not yet been evaluated. In this study, we examined the contribution of EP to tumor angiogenesis in a murine glioma tumor model. Donor bone marrow cells obtained from transgenic mice constitutively expressing β‐galactosidase or GFP either ubiquitously or transcriptionally regulated by an endothelial specific promotor Tie‐2 were injected into lethally irradiated adult mice. After bone marrow reconstitution by donor cells, mice were implanted with syngeneic GL261 murine glioma cells. Morphological and confocal 3‐dimensional analysis showed that the majority of the engrafted donor marrow cells were expressing hematopoietic and/or microglia markers, but did not appreciably contribute to the tumor vasculature. Implantation of glioma cells genetically engineered to overexpress VEGF produced highly vascularized tumors. However, the number of endothelial progenitors incorporated in the tumor vasculature did not increase. These data strongly suggest that neovascularization in the brain might fundamentally be regulated by the sprouting of pre‐existing vessels and implicate that circulating endothelial progenitors do not play a significant role in this process.
Human Monoclonal IgM Antibody Promotes CNS Myelin Repair Independent of Fc Function
Authors: Ciric Bogoljub , Howe Charles L. , Soldan Mateo Paz , Warrington Arthur E. , Bieber Allan J. , Van Keulen Virginia , Rodriguez Moses , Pease Larry R.
Published: July 2010

The human monoclonal IgM antibody sHIgM22 and mouse IgM monoclonal antibody 94.03 bind to oligodendrocytes, induce calcium signals in cultured glial cells, and promote remyelination in mouse models of multiple sclerosis. In order to address the mechanisms employed by these antibodies to promote CNS repair, bivalent monomers, F(ab′)2 fragments, and monovalent forms of these antibodies were investigated to determine whether they exhibit the same remyelinating potential as the intact IgMs. The two antibodies displayed different structural requirements for retention of function. Antibody sHIgM22 remained functional even when reduced to a bivalent F(ab′)2 fragment, while disruption of the pentameric structure of antibody 94.03 destroyed its functional properties. Competition studies demonstrated that the two antibodies recognize different entities on the surface of glial cells. These results indicate that the constant region and pentameric structure of IgM is not always necessary for the stimulation of myelin repair, eliminating the requirement for IgM immune effector functions in this process. The ability of the antibodies to crosslink cell surface determinants on oligodendrocytes appears to be an essential aspect of the mechanism of cellular activation. The finding that two antibodies, which induce similar in vivo effects, bind to different structures, and have different cross‐linking requirements suggests that activation of glial cells involves the rearrangement of a complex membrane compartment.
Oligodendroglial Tumors: Refinement of Candidate Regions on Chromosome Arm 1p and Correlation of 1p/19q Status with Survival
Authors: Felsberg Jörg , Erkwoh Angelika , Sabel Michael C. , Kirsch Lutz , Fimmers Rolf , Blaschke Britta , Schlegel Uwe , Schramm Johannes , Wiestler Otmar D. , Reifenberger Guido
Published: July 2010

Loss of heterozygosity (LOH) on the chromosome arms 1p and 19q is frequent in oligodendroglial tumors and has been correlated with chemosensitivity and good prognosis in anaplastic oligodendrogliomas. The oligodendroglioma‐associated tumor suppressor genes on 1p and 19q are as yet unknown. To narrow down candidate regions on 1p, we investigated oligodendroglial tumors from 89 patients for LOH at up to 30 polymorphic loci on 1p. In addition, all tumors were studied for LOH at 7 loci on 19q. Combined LOH on 1p and 19q was detected in 20 (83%) of 24 oligodendrogliomas, 15 (63%) of 24 anaplastic oligodendrogliomas, 10 (56%) of 18 oligoastrocytomas, and 12 (52%) of 23 anaplastic oligoastrocytomas. Five tumors demonstrated partial deletions on 1p, which allowed to define 3 distinct candidate regions at 1 p36.31 ‐pter distal to D1S2633, 1p36.22‐p36.31 between D1S489 and D1S2642, and 1p34.2‐p36.1 between D1S2743 and D1S482, respectively. No partial deletions were detected on 19q. Combined LOH on 1p and 19q was associated with prolonged time to progression (TTP), longer overall survival (OS), and a higher 5‐year survival rate. Depending on the presence or absence of combined LOH on 1p and 19q, patients with anaplastic oligodendroglial tumors treated with adjuvant radio‐ and/or chemotherapy showed a median TTP of 86 months versus 39 months, a median OS of 91 months versus 46 months, and a 5‐year survival rate of 80% versus 36%, respectively. Similarly, LOH on 1p and 19q was associated with longer survival in patients with low‐grade oligodendroglial tumors (TTP: 57 months versus 47 months; OS: 172 months versus 105 months; 5‐year survival rate: 92% versus 70%). Thus, our results refine the location of putative oligodendroglioma suppressor genes on 1p and support the significance of LOH on 1p and 19q as a favorable prognostic marker.
Mechanisms and Time Course of Neuronal Degeneration in Experimental Autoimmune Encephalomyelitis
Authors: Hobom Muriel , Storch Maria K. , Weissert Robert , Maier Katharina , Radhakrishnan Anand , Kramer Birgit , Bähr Mathias , Diem Ricarda
Published: July 2010

Neuronal and axonal damage is considered to be the main cause for long‐term disability in multiple sclerosis. We analyzed the mechanisms and kinetics of neuronal cell death in experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) by combining an electrophysiological in vivo assessment of the optic pathway with the investigation of retinal ganglion cell (RGC) counts. In accordance with our previous findings in this animal model, neuritis of the optic nerve (ON) leads to apoptotic RGC death. By further investigating the time course of RGC apoptosls in the present study, we found that neuronal cell death together with decreased visual acuity values occurred before the onset of clinical symptoms. Simultaneously with the time course of RGC apoptosis, we found a down‐regulation of phospho‐Akt as well as a shift in the relation of 2 proteins of the Bcl‐2 family, Bax and Bcl‐2, towards a more proapoptotic ratio in these cells. Comparing the kinetics and mechanisms of RGC death during MOG‐EAE with those following complete surgical transection of the ON, we found significant agreement. We hypothesize that the main reason for RGC loss in MOG‐EAE is the inflammatory attack but RGC death also occurs independently of histopathological ON changes.
Direct Stimulation of Adult Neural Stem Cells In Vitro and Neurogenesis In Vivo by Vascular Endothelial Growth Factor
Authors: Schänzer Anne , Wachs Frank‐Peter , Wilhelm Daniel , Acker Till , Cooper‐Kuhn Christiana , Beck Heike , Winkler Jürgen , Aigner Ludwig , Plate Karl H. , Kuhn H. Georg
Published: July 2010

Hypoxia as well as global and focal ischemia are strong activators of neurogenesis in the adult mammalian central nervous system. Here we show that the hypoxia‐inducible vascular endothelial growth factor (VEGF) and its receptor VEGFR‐2/Flk‐1 are expressed in clonally‐derived adult rat neural stem cells in vitro. VEGF stimulated the expansion of neural stem cells whereas blockade of VEGFR‐2/Flk‐1‐kinase activity reduced neural stem cell expansion. VEGF was also infused into the lateral ventricle to study changes in neurogenesis in the ventricle wall, olfactory bulb and hippocampus. Using a low dose (2.4 ng/d) to avoid endothelial proliferation and changes in vascular permeability, VEGF stimulated adult neurogenesis in vivo. After VEGF infusion, we observed reduced apoptosis but unaltered proliferation suggesting a survival promoting effect of VEGF in neural progenitor cells. Strong expression of VEGFR‐2/Flk‐1 was detected in the ventricle wall adjacent to the choroid plexus, a site of significant VEGF production, which suggests a paracrine function of endogenous VEGF on neural stem cells in vivo. We propose that VEGF acts as a trophic factor for neural stem cells in vitro and for sustained neurogenesis in the adult nervous system. These findings may have implications for the pathogenesis and therapy of neurodegenerative diseases.
A Pathogenic Peripherin Gene Mutation in a Patient with Amyotrophic Lateral Sclerosis
Authors: Leung Conrad L. , He Cui Zhen , Kaufmann Petra , Chin Steven S. , Naini Ali , Liem Ronald K. H. , Mitsumoto Hiroshi , Hays Arthur P.
Published: July 2010

Peripherin is a neuronal intermediate filament protein that is expressed chiefly in motor neurons and other nerve cells that project into the peripheral nervous system. Transgenic mice that over‐express peripherin develop motor neuron degeneration, suggesting that mutations in peripherin could contribute to the development of motor neuron disease. In this paper, we report the identification of a homozygous mutation in the peripherin gene (PRPH) in a patient with amyotrophic lateral sclerosis (ALS). The mutation resulted in a substitution of aspartate with tyrosine at amino acid position 141, which is located within the first linker region of the rod domain. Immunocytochemical analysis of the spinal cord of the patient upon autopsy revealed distinctive large aggregates within the cell bodies of residual spinal motor neurons that contained peripherin and was also immunoreactive with antibodies to the neurofilament proteins. In order to study the effect of the mutation on peripherin assembly, we performed transient transfections. Unlike wild‐type peripherin, which self‐assembles to form a filamentous network, the mutant peripherin was prone to form aggregates in transfected cells, indicating that the mutation adversely affects peripherin assembly. Moreover, the neurofilament light (NF‐L) protein was not able to rescue the mutant protein from forming aggregates. These data imply that mutation of PRPH is a contributing factor for ALS.
Endothelins Negatively Regulate Glial Glutamate Transporter Expression
Authors: Rozyczka Joanna , Figiel Maciej , Engele Jürgen
Published: July 2010

Glutamate is the main excitatory neurotransmitter in the mammalian central nervous system which at high extracellular levels leads to neuronal over‐stimulation and subsequent excitotoxic neuronal cell death. Both the termination of glutamatergic neurotransmission and the prevention of neurotoxic extracellular glutamate concentrations are predominantly achieved by the uptake of extracellular glutamate into astroglia through the high‐affinity glutamate transporters, excitatory amino acid transporter‐2/glutamatetransporter‐1 (EAAT‐2/GLT‐1) and EAAT‐1/glutamate aspartate transporter (GLAST). Although several injury‐induced growth factors such as epidermal growth factor (EGF) and transforming growth factor a (TGFa) potently stimulate the expression of glutamate transporters in cultured astroglia, GLT‐1 and/or GLAST expression temporarily decreases during acute brain injuries eventually contributing to secondary neuronal cell death. We now demonstrate that the stimulatory influences of these injury‐regulated growth factors are overridden by endothelins (ETs), a family of peptides also up‐regulated in the injured brain. Exposure of cultured cortical astroglia to ET‐1, ET‐2, and ET‐3 resulted in a major loss of basal glutamate transporter expression after 72 hours and the complete prevention of the known stimulatory influences of dibutyryl cyclic (dbc)AMP, pituitary adenylate cyclase‐activating polypeptide (PACAP), EGF, and TGFa on both GLT‐1 and GLAST expression. With all ET isoforms, the inhibitory effects were detectable with similar low nanomolar concentrations and persisted in endothelin B‐receptor deficient astroglia, suggesting that the inhibitory action is equally induced by endothelin A and B receptors. In astroglial cultures maintained with endothelins alone or in combination with PACAP, the inhibitory action was remarkably long‐lasting and was still detectable after 7 days. In apparent contrast, glutamate transporter expression partially recovered between days 5 and 7 in cultures maintained with a combination of ETs and the injury‐regulated growth factors EGF or TGFa. These findings point to ETs as major mediators of injury‐dependent down‐regulation of glial glutamate transporters and subsequent glutamate‐induced brain damage.
APRIL 2004: WOMAN IN HER EARLY FIFTIES WITH A CERVICAL INTRASPINAL AND EXTRASPINAL MASSLESION
Authors: Hamilton Ronald L. , Kuchelmeister Klaus , Lotz Claudia , Schönmayr Robert , Schachenmayr Walter
Published: July 2010

CASE OF THE MONTH: ABSTRACT

April 2004: A 53‐year‐old woman presented with a large club‐shaped intra‐ and extraspinal tumor of the C6 nerve root which had intradurally grown through the enlarged C5–6 neural foramen and focally infiltrated the dura mater. Microscopy revealed a melanin‐pigmented tumor with spindle‐shaped and epithelioid cells and scattered psammoma bodies, a so‐called psammomatous melanotic schwannoma (PMS). More than half of the patients with PMS have Carney complex, a genetically heterogeneous multiple neoplasia syndrome of autosomal‐dominant inheritance, which in our patient, however, could not be detected unequivocally. Prognosis of all melanotic schwannomas (MSs) is not good with local recurrences or metastases in over 40% of cases. In our case, frequent versicular nuclei with distinct nucleoli, occasional mitoses and apoptoses and increased focal MIB‐1 labeling indices prompted us to diagnose a malignant PMS. However, histologic criteria for malignancy in MSs are not clearly defined and there is no reliable histopathological indicator of malignant clinical behavior in MSs. Therefore, designation of “PMS with malignant histologic features” may be more appropriate. Since tumor recurrences and metastases im MSs may occur after more than 5 years, long‐term follow‐up of affected patients is required. One year after operation our patient showed no signs of tumor recurrence or metastases.