Normal Human Central Nervous System Research Articles

DNA Damage Response in Human Stem Cells and Neural Descendants.

Glial cells are crucial for the normal function of neurons and are intricately involved in the pathogenesis of neurodegenerative diseases as well as neurologic malignancies. A deeper understanding of the mechanisms by which glial cells influence the development of such pathologies will undoubtedly lead to new and improved therapeutic approaches. Commercially available human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), both of which can be differentiated into neural progenitors (NPs) and various neural cell lineages, have become widely used as sources for producing normal human central nervous system (CNS) cells. A better understanding of the DNA damage response (DDR) that occurs in these cells after therapeutic ionizing radiation (IR) and chemotherapy is essential for assessing the effects on healthy human brain.Neurodegenerative features associated with conditions such as ataxia telangiectasia and Nijmegen breakage syndrome highlight the importance of DNA double strand break (DSB) repair pathways in maintaining genomic integrity in cells of the CNS. Similarly, the development of brain tumors is also intricately linked to DNA repair. The importance of ATM and the other phosphatidylinositol 3-kinase-related kinase (PIKK) family members, ATR and DNA-PKcs, is not fully defined in either CNS developmental or pathological states. While their roles are relatively well established in the DDR of proliferating cells, our recent work has demonstrated that these processes exhibit spatiotemporal evolution during cell differentiation. This chapter discusses and explores various laboratory techniques for investigating the role of ATM in hESCs and differentiated neural cells.

Tumour necrosis factor receptor superfamily member 9 (TNFRSF9) is up‐regulated in reactive astrocytes in human gliomas

The prognosis of patients with malignant gliomas is still dismal despite maximum treatment. Novel therapeutic alternatives targeting tumorigenic pathways are, therefore, demanded. In murine glioma models, targeting of tumour necrosis factor receptor superfamily (TNFRSF) 9 led to complete tumour eradication. Thus, TNFRSF9 might also constitute a promising target in human diffuse gliomas. As there is a lack of data, we aimed to define the expression pattern and cellular source of TNFRSF9 in human gliomas. We investigated TNFRSF9 expression in normal human central nervous system (CNS) tissue and glioma specimens using immunohistochemistry, immunofluorescence and Western blotting techniques. Our results show that TNFRSF9 is considerably up-regulated in human gliomas when compared with normal brain tissue. In addition, our data provides evidence for an immune cell-independent de novo expression pattern of TNFRSF9 in mainly non-neoplastic reactive astrocytes and excludes classic immunological cell types, namely lymphocytes and microglia as the source of TNFRSF9. Moreover, TNFRSF9 is predominantly expressed in a perivascular and peritumoural distribution with significantly higher expression in IDH-1 mutant gliomas. Our findings provide a novel, TNFRSF9-positive, reactive astrocytic phenotype and challenge the therapeutic suitability of TNFRSF9 as a promising target for human gliomas.

Classical dynamin DNM1 and DNM3 genes attain maximum expression in the normal human central nervous system

Dynamin is a super-family of large GTPase proteins that polymerise during their biological activity. Dynamin polymers form around lipid tubes and contribute to the membrane fission and scission of nascent vesicles from parent membranes. Here we used the NCBI Gene Expression Omnibus (GEO) database and the BioGPS gene expression portal to study differential dynamin gene expression in normal human organs or tissues. From the GDS1096 and GDS596 dataset, we downloaded the relative expression levels of dynamin-related genes (presented as percentages), with respect to all of the other genes on the array (platform Affymetrix GPL96), which includes the best characterised human genes. The expression profiles of dynamin in the central nervous system (CNS) are clearly distinct from the expression profiles in the other organs or tissues studied. We found that the classical dynamin DNM1 and DNM3 genes reach their maximum expression levels (100% of maximal expression) in all normal human CNS tissues studied. This is in contrast to the expression profile in the other normal human organs or tissues studied, in which both dynamin DNM1 and DNM3 genes showed approximately 50% maximal expression. This data mining analysis supports the concept that there is a relationship between the synapse and the molecular function of dynamin, suggesting a new field of work in the study of neurodegenerative diseases.

Self-renewal induced efficiently, safely, and effective therapeutically with one regulatable gene in a human somatic progenitor cell

In the field of induced potency and fate reprogramming, it remains unclear what the best starting cell might be and to what extent a cell need be transported back to a more primitive state for translational purposes. Reprogramming a committed cell back to pluripotence to then instruct it toward a particular specialized cell type is demanding and may increase risks of neoplasia and undesired cell types. Precursor/progenitor cells from the organ of therapeutic concern typically lack only one critical attribute--the capacity for sustained self-renewal. We speculated that this could be induced in a regulatable manner such that cells proliferate only in vitro and differentiate in vivo without the need for promoting pluripotence or specifying lineage identity. As proof-of-concept, we generated and tested the efficiency, safety, engraftability, and therapeutic utility of "induced conditional self-renewing progenitor (ICSP) cells" derived from the human central nervous system (CNS); we conditionally induced self-renewal efficiently within neural progenitors solely by introducing v-myc tightly regulated by a tetracycline (Tet)-on gene expression system. Tet in the culture medium activated myc transcription and translation, allowing efficient expansion of homogeneous, clonal, karyotypically normal human CNS precursors ex vivo; in vivo, where Tet was absent, myc was not expressed, and self-renewal was entirely inactivated (as was tumorigenic potential). Cell proliferation ceased, and differentiation into electrophysiologically active neurons and other CNS cell types in vivo ensued upon transplantation into rats, both during development and after adult injury--with functional improvement and without neoplasia, overgrowth, deformation, emergence of non-neural cell types, phenotypic or genomic instability, or need for immunosuppression. This strategy of inducing self-renewal might be applied to progenitors from other organs and may prove to be a safe, effective, efficient, and practical method for optimizing insights gained from the ability to reprogram cells.

Tissue Type-Specific Expression of the dsRNA-Binding Protein 76 and Genome-Wide Elucidation of Its Target mRNAs

BackgroundRNA-binding proteins accompany all steps in the life of mRNAs and provide dynamic gene regulatory functions for rapid adjustment to changing extra- or intracellular conditions. The association of RNA-binding proteins with their targets is regulated through changing subcellular distribution, post-translational modification or association with other proteins.MethodologyWe demonstrate that the dsRNA binding protein 76 (DRBP76), synonymous with nuclear factor 90, displays inherently distinct tissue type-specific subcellular distribution in the normal human central nervous system and in malignant brain tumors of glial origin. Altered subcellular localization and isoform distribution in malignant glioma indicate that tumor-specific changes in DRBP76-related gene products and their regulatory functions may contribute to the formation and/or maintenance of these tumors. To identify endogenous mRNA targets of DRBP76, we performed RNA-immunoprecipitation and genome-wide microarray analyses in HEK293 cells, and identified specific classes of transcripts encoding critical functions in cellular metabolism.SignificanceOur data suggest that physiologic DRBP76 expression, isoform distribution and subcellular localization are profoundly altered upon malignant transformation. Thus, the functional role of DRBP76 in co- or post-transcriptional gene regulation may contribute to the neoplastic phenotype.

Quantification of oligodendrocyte progenitor cells in human and cat optic nerve: Implications for endogenous repair in multiple sclerosis

In multiple sclerosis (MS), one strategy to reduce disability is enhancement of endogenous repair by remyelinating oligodendrocytes derived from oligodendrocyte progenitor cells (OP). An important prerequisite is determining the abundance of OP relative to oligodendrocytes in normal human central nervous system (CNS), which, in turn, requires reliable OP identification. To achieve this, cat and human optic nerves (ON) were subjected to varied preparation protocols, and the resultant neuroglial staining profiles correlated to generate an antigenic phenotype for OP applicable to human autopsy specimens. OP, interchangeably called NG2cells due to universal NG2 expression, were shown to comprise a separate class of neuroglial cells, related to oligodendrocytes by expression of the oligodendrocyte lineage transcription factors, Olig1 and Olig2. Despite their morphological complexity, including contact with axons and other neuroglia, NG2cells all appear capable of responding as OP to counter local oligodendrocyte loss. However, quantification revealed that NG2cells comprised less than 5% of the neuroglia and had a ratio to oligodendrocytes of about 1:10, not only in human and cat ON but also in white and gray-matter regions of cat spinal cord. The finding that NG2cells are not abundant, particularly relative to oligodendrocytes, may have implications for efforts to enhance endogenous repair in MS.

GATA4 is a regulator of astrocyte cell proliferation and apoptosis in the human and murine central nervous system

The GATA transcription factors consist of six family members, which bind to the consensus DNA-binding element, W-GATA-R, and are poorly characterized in the central nervous system (CNS). Using retroviral gene trapping on transgenic mouse glioma models, we identified GATA6 to be a novel tumor suppressor gene in glioblastoma multiforme. We now show GATA4, a family member of GATA6, to be expressed in the neurons and glia of normal murine and human embryonic and adult CNS. Silencing GATA4 in normal astrocytes did not alter their growth properties. In contrast, knockdown of Gata4 in p53 null non-transformed murine astrocytes induced transformation, with increased proliferation and resistance to chemotherapy or radiation-induced apoptosis. Furthermore, GATA4 expression was lost in a panel of human malignant astrocytoma cell lines. GATA4 overexpression in normal human and murine astrocytes resulted in a cell cycle block in G1 phase, with increased apoptosis. Mechanistically, GATA4 was a transcriptional inducer of the cyclin-dependent kinase inhibitor, p15INK4B, leading to the attenuation of cyclin D1. GATA4 expression was also induced by transforming growth factor-beta, leading to the inhibition of astrocyte proliferation. Collectively, we show that GATA4 is expressed in the embryonic and adult CNS and acts as a negative regulator of astrocyte proliferation and growth.

Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain

Microglia are involved in neurodegeneration, are prime targets for anti-inflammatory therapy and are potential biomarkers of disease progression. For example, positron emission tomography imaging employing radioligands for the mitochondrial translocator protein of 18 kDa (TSPO, formerly known as the peripheral benzodiazepine receptor) is being scrutinized to detect neuroinflammation in various diseases. TSPO is presumably present in activated microglia, but may be present in other neural cells. We sought to elucidate the protein expression in normal human central nervous system, several neurological diseases (HIV encephalitis, Alzheimer's disease, multiple sclerosis and stroke) and simian immunodeficiency virus encephalitis by performing immunohistochemistry with two anti-TSPO antibodies. Although the overall parenchymal staining was minimal in normal brain, endothelial and smooth muscle cells, subpial glia, intravascular monocytes and ependymal cells were TSPO-positive. In disease states, elevated TSPO was present in parenchymal microglia, macrophages and some hypertrophic astrocytes, but the distribution of TSPO varied depending on the disease, disease stage and proximity to the lesion or relation to infection. Staining with the two antibodies correlated well in white matter, but one antibody also stained cortical neurones. Quantitative analysis demonstrated a significant increase in TSPO in the white matter of HIV encephalitis compared with brains without encephalitis. TSPO expression was also increased in simian immunodeficiency virus encephalitis. This report provides the first comprehensive immunohistochemical analysis of the expression of TSPO. The results are useful for informing the usage of positron emission tomography as an imaging modality and have an impact on the potential use of TSPO as an anti-inflammatory pharmacological target.

Differentiation of blood monocytes to dendritic cells following reverse transmigration across the blood-brain barrier (94.6)

Abstract Dendritic cells (DC) are absent in the normal human central nervous system (CNS) but their presence has been documented in neuroinflammation. The origin of CNS DC is still controversial. The objective of this study was to determine whether monocytes that cross the blood-brain barrier (BBB) differentiate into DC. Primary human brain microvessel endothelial cells (HBMEC) were cultured on collagen gels. Purified human CD14+ monocytes were incubated with confluent HBMEC for 48h and the reverse transmigrated (RT) cells were characterized by FACS analysis. Approximately 50% of the monocytes reverse transmigrated across HBMEC monolayers and 70% of the RT cells expressed DC-SIGN. Monocytes incubated on gels in the absence of HBMEC retained their phenotype. The percentage of RT cells expressing CD83 increased from 25% to 70% when human CNS myelin was incorporated into the gels, and there was significant increase in CCR7 expression. Analysis of culture supernatants showed high levels of IL-6, TNF-α, PGE2 and IL-1β when HBMEC were cultured on myelin gels suggesting that these cytokines may contribute to the differentiation of monocytes to mature DC. There was an associated increase of MIP-3β, MCP-1, MIP-1α, and MIP-1β in the supernatants. Mixed lymphocyte reactions by co-culturing CFSE-labeled T cells and RT cells showed that RT cells were capable of stimulating allogeneic T cell proliferation. In conclusion, the results suggest that monocytes which reverse-transmigrate across HBMEC differentiate into mostly mature DC capable of inducing T cell proliferative responses. (Supported by MSS, Canada)

Novel autoantigens recognized by CSF IgG from Hashimoto's encephalitis revealed by a proteomic approach

To identify the target of IgG autoimmune response in Hashimoto's encephalopathy (HE), we studied the binding of IgG present in serum and cerebro-spinal fluid (CSF) from six patients with HE and 15 controls to human central nervous system (CNS) white matter antigens by 2D-PAGE and immunoblotting and by immunohistochemistry. We found that CSF IgG from HE patients specifically recognized 3 spots, which were identified as dimethylargininase-I (DDAHI) and aldehyde reductase-I (AKRIAI). DDAHI was present in two isoforms recognized respectively by five and four HE patients; immunohistochemistry with anti-DDAHI antiserum depicted endothelial cells in normal human CNS. AKRIAI was recognized by three HE CSF and this enzyme was widely distributed on neurons and endothelia by immunohistochemistry. IgG from HE CSF immunostained both neuronal and endothelial cells in mouse CNS. The presence of these autoantibodies selectively in the CSF of HE patients may have important diagnostic and pathogenetic implications, since the autoimmune response to these enzymes may lead to vascular and/or neuronal damage, two major mechanisms involved in the pathogenesis of HE.

Immune surveillance of the human central nervous system (CNS): Different migration pathways of immune cells through theblood–brain barrier and blood–cerebrospinal fluid barrier in healthy persons

Since for immune surveillance, only lymphocytes in the activated state are able to enter normal human central nervous system (CNS), available data are briefly reviewed to reveal lymphocyte transfer through blood-brain barrier (bbb) and blood-cerebrospinal fluid barrier (bCSFb). With immuno-histochemical and -cytochemical methods, bbb was studied on brain microvessels and bCSFb on choroid plexus epithelium and microvessels. Lymphocyte transfer capacity on the barriers was determined with blood/CSF cell ratios revealed by quantified multicolour flow-cytometry of CSF and blood sample pairs. Four paths attenuated the restricted transfer of lymphocyte and NK cell subsets (none for B cells) through bbb and bCSFb, preferring memory cells in normal human brain, using different cell adhesion molecules (CAM). CAM pattern changed in choroid plexus where indication of lymphocyte recirculating from CSF into blood may exist in animal brains. Since efficiency of migration of blood-borne lymphocytes into CSF across bbb or bCSFb of normal human brain is not fully revealed, further data are needed to understand the transfer of immune cells across the barriers in health and disease.

Expression of GATA6 in the human and mouse central nervous system

The mammalian GATA family of transcription factors comprises of 6 members that are involved in diverse roles. The expression profile of GATA6 has been poorly defined in the central nervous system (CNS). In this report, we identify GATA6 expression in the normal mouse and human CNS, using Northern blot analyses, immunohistochemistry (IHC), and immunofluorescence (IF). GATA6 is expressed as a 2.2 kb transcript in the adult mouse brain and several regions of the adult human brain. Furthermore, cellular characterization demonstrates GATA6 nuclear expression in neurons, astrocytes, choroids plexus epithelium, and endothelial cells.

CD163‐positive perivascular macrophages in the human CNS express molecules for antigen recognition and presentation

Perivascular macrophages (PVM) constitute a subpopulation of resident macrophages in the central nervous system (CNS) that by virtue of their strategic location at the blood-brain barrier potentially lend themselves to a variety of important functions in both health and disease. Functional evidence suggests that PVM play a supportive role during experimental autoimmune encephalomyelitis in rodents. However, the function of PVM in the human CNS remains poorly characterized. We first set out to investigate the validity of the antibody EDhu1, which recognizes human CD163, to specifically identify human PVM. Second, we wanted to gain insight into the function of PVM in antigen recognition and presentation and therefore we studied the expression of DC-SIGN, mannose receptor, MHC class II, and several costimulatory molecules by PVM in the normal and inflamed human CNS (multiple sclerosis (MS) brain lesions). Conventional immunohistochemistry and double-labeled immunofluorescence techniques were used. We show that CD163 specifically reveals PVM in the normal human CNS. In MS lesions, CD163 staining reveals expression on foamy macrophages and microglia, besides an upregulation of the amount of PVM stained. In contrast, mannose receptor expression is restricted to PVM in both normal and inflamed brain tissue. Furthermore, we show that a subpopulation of PVM in the human brain express several molecules involved in antigen recognition, presentation, and costimulation. Therefore PVM, which occupy a strategic location at the BBB, are equipped to recognize antigen and present it to T cells, supporting a role in the regulation of perivascular inflammation in the human CNS.

Tissue plasminogen activator and neuroserpin are widely expressed in the human central nervous system.

Tissue plasminogen activator (tPA) is increasingly recognized to play important roles in various physiological and pathological processes in the central nervous system (CNS). Much of the data on the involvement of plasminogen activators in neurophysiology and -pathology have been derived from studies on experimental animals. We have now performed a systematic characterization of the expression of tPA and its inhibitor, neuroserpin, in normal human CNS. Brain and spinal cord samples from 30-36 anatomic locations covering all major brain regions were collected at 9 autopsies of donors with no neurological disease. Tissues were embedded in paraffin and tissue arrays were constructed. In two cases parallel samples were snap-frozen for biochemical analysis. Expression and activity profiling of tPA and neuroserpin were performed by immunohistochemistry, in situ hybridization, immunocapture and zymography assays. In the adult CNS, tPA was expressed at the mRNA and protein levels in many types of neurons, in particular in thalamus, cortex of cerebellum, pontine nuclei, neocortex, limbic system, and medulla oblongata. Interestingly, tPA was often co-expressed with its CNS inhibitor, neuroserpin. Despite overlapping expression of tPA and neuroserpin, zymography and immunocapture assays demonstrated that human neural tissue is a rich source of active tPA. Our analysis documents a detailed map of expression of tPA and its inhibitor in the human CNS and is compatible with the view that tPA is a key player in CNS physiology and pathology.

Zinc- or cadmium-pre-induced metallothionein protects human central nervous system cells and astrocytes from radiation-induced apoptosis

We have shown the protection of human central nervous system (CNS) cultures by zinc (Zn) or cadmium (Cd)-pre-induced metallothionein (MT) synthesis from radiation-induced cytotoxicity (lactate dehydrogenase (LDH) release and neuronal dendritic injury). The present study is to further define the types of cell death induced by different dose levels of radiation and investigate the effect of MT induction (by Zn or Cd) on radiation-induced apoptosis in primary human CNS and astrocyte cultures. Apoptosis was detected by fragmented DNA electrophoresis, TUNEL technique, and propidium iodide staining. Expression of MT protein was examined by immunofluorescent staining. Results showed that exposure of primary human CNS cultures to 15 and 30 Gy γ-radiation predominantly induced apoptotic cell death, while exposure to 60 Gy γ-radiation predominantly induced necrotic cell death. Normal primary human CNS cultures showed weak MT staining, while primary human CNS cultures exposed to Zn or Cd showed intense MT staining. The induced apoptotic cell death by exposure to 30 Gy γ-radiation increased to a maximum level at 12 and 24 h, and was reduced significantly by Zn or Cd pre-induced MT. Using primary human astrocytes, the induction of MT protein by Zn or Cd was further confirmed. The enhanced MT expression also afforded a significant protection from 30 Gy γ-ray-induced apoptosis in the primary human astrocytes. These results suggest that MT protected human CNS cells from apoptosis following ionizing radiation, probably through its antioxidant property.

Microglia in diseases of the central nervous system

Microglia (MG) are enigmatic cells of the central nervous system (CNS). MG are morphologically, antigenically and functionally flexible, and have the potential for mobility and proliferation. MG are professional antigen-presenting cells and constitute part of the local CNS innate immune system, communicating with other immune cells via chemokines, cytokines and growth factors. MG contain several antigenic and functional markers similar to macrophages and dendritic cells (DCs), but also present several differences from DCs. The exact role(s) played by MG in the normal human CNS is the topic of lively debate. MG participate in many reactive processes in the CNS and are therefore an integral part of lesions in a variety of pathologic conditions. It is thought that MG may exacerbate diverse neurological conditions, including viral encephalitis, AIDS, Multiple Sclerosis (MS) and Alzheimer's disease. A recurrent theme is the perpetuation by MG of pathological cycles of monocyte recruitment, activation and cytopathic secretions, and/or auto antigen presentation.

Identification of the Motif in Versican G3 Domain That Plays a Dominant-negative Effect on Astrocytoma Cell Proliferation through Inhibiting Versican Secretion and Binding

This study was designed to investigate the mechanisms by which mutant versican constructs play a dominant-negative effect on astrocytoma cell proliferation. Although a mini-versican or a versican G3 construct promoted growth of U87 astrocytoma cells, a mini-versican lacking epidermal growth factor (EGF) motifs (versicanDeltaEGF) and a G3 mutant (G3DeltaEGF) exerted a dominant-negative effect on cell proliferation. G3DeltaEGF-transfected cells formed smaller colonies, arrested cell cycle at G(1) phase, inhibited expression of cell cycle proteins cdk4 and cyclin D1, and contained multiple nucleoli. In cell surface binding assays, G3 products expressed in COS-7 cells and bacteria bound to U87 cell surface. G3DeltaEGF products exhibited decreased binding activity, but higher levels of G3DeltaEGF products were able to inhibit the binding of G3 to the cell surface. G3DeltaEGF expression inhibited secretion of endogenous versican in astrocytoma cells and also inhibited the secretion of mini-versican in COS-7 cells co-transfected with the mini-versican and G3DeltaEGF constructs. The effect seems to depend on the expression efficiency of G3DeltaEGF, and it occurred via the carbohydrate recognition domain.

MSP, a trypsin‐like serine protease, is abundantly expressed in the human nervous system

The goal of the present investigation was to determine the regional and cellular specific expression patterns of the newly identified serine protease, myelencephalon-specific protease (MSP), in the adult human brain (Scarisbrick et al. [1997b] J. Neurosci. 17:8156–8168). To assess the potential scope of MSP activity, Northern blot techniques were used to determine the relative abundance of MSP mRNA in 16 different adult human brain regions, and in the brain and peripheral tissues of the midgestation human fetus. The regional and temporal specific expression patterns of MSP mRNA were directly compared with those of tissue plasminogen activator (tPA), a serine protease strongly implicated in the development, ongoing plasticity, and response of the nervous system to injury and disease. mRNA encoding each protease was distributed widely throughout the normal adult human central nervous system (CNS), but the expression of each was only partially overlapping. Additionally, compared with tPA, MSP exhibited a more restricted distribution and delayed developmental onset. By immunohistochemical localization, MSP was present at moderate to high levels in neurons and oligodendroglia of the adult human brain, at a level closely resembling the relative abundance indicated by Northern blot. MSP was most abundantly expressed in the spinal cord, hippocampus, substantia nigra, and basal ganglia. The robust expression of MSP in clinically significant regions of the adult human CNS indicates that further study of this protease in terms of both normal brain physiology and neurodegenerative disorders is warranted. J. Comp. Neurol. 431:347–361, 2001. © 2001 Wiley-Liss, Inc.

Local distribution of microglia in the normal adult human central nervous system differs by up to one order of magnitude.

Although microglia are considered to be a sensitive sensor for pathological processes in the central nervous system, there are only a few studies about the distribution and density of microglia in the normal human brain. Therefore, a study of local density of microglial cells was conducted by investigating 20 normal human brains with no clinical neurological symptoms or diseases and no neuropathological alterations. Microglial cells were visualized by immunolabeling of proteins which are known to be expressed either constitutively or facultatively, such as CD68, major histocompatibility complex class II (MHC-II), leukocyte common antigen (LCA), leukocyte chemotactic factor (LCF), macrophage inhibitory factor-related protein (MRP) 8, MRP14, CD4 and allograft-inflammatory factor-1 (AIF-1). CD68, MHC-II and AIF-1 showed the highest densities with significant regional differences ranging from 0.5% to 16.6% of all cells in the brain parenchyma with significantly more microglia in white than in gray matter. LCF and LCA showed a similar pattern of distribution as the proteins described above, but with lower percentages of microglial cells. CD4 was not found in the brain parenchyma. We conclude that CD68, MHC-II and AIF-1 define the main microglial cell population, whereas LCF and LCA are expressed by a subpopulation of microglial cells. The brains showed no or a negligible vascular expression of MRP8 and MRP14. Information about the local microglia density in the normal human brain can serve as a reference for the evaluation of pathological microglial responses.

Neuregulin: An Oligodendrocyte Growth Factor Absent in Active Multiple Sclerosis Lesions

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) which results in demyelination and axonal injury. Conventional therapy for MS is immune suppression in the absence of agents that promote neural and glial survival or remyelination. Neuregulins are a family of ligands that exert trophic effects on both neurons and glia. Using mice bearing a null mutation in the neuregulin gene, here we demonstrate that neuregulins are necessary for the normal development of oligodendrocytes. In addition, neuregulins are produced in the normal human CNS by astrocytes as well as neurons. Astrocyte-derived neuregulin is functionally active in bioassays and exists in secreted and membrane-associated β-isoforms. In active and chronic active MS lesions, however, the expression of astrocyte neuregulin is dramatically reduced. The absence of neuregulin in active MS lesions may contribute to the paucity of remyelination in MS.