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1.
J Neurosci ; 21(23): 9214-23, 2001 Dec 01.
Article in English | MEDLINE | ID: mdl-11717355

ABSTRACT

Previous results from this laboratory revealed the presence of high-affinity saturable binding sites for monocyte chemoattractant protein-1 (MCP-1) along human brain microvessels (Andjelkovic et al., 1999; Andjelkovic and Pachter, 2000), which suggested that CC chemokine receptor 2 (CCR2), the recognized receptor for this chemokine, was expressed by the brain microvascular endothelium. To test the role of CCR2 directly in mediating MCP-1 interactions with the brain microvasculature, we assessed MCP-1 binding activity in murine brain microvessels isolated from wild-type mice and from CCR2 (-/-) mice engineered to lack this receptor. Results demonstrate that MCP-1 binding is greatly attenuated in microvessels prepared from CCR2 (-/-) mice compared with wild-type controls. Moreover, microvessels from wild-type mice exhibited MCP-1-induced downmodulation in MCP-1 binding and a recovery of binding activity that was not dependent on de novo protein synthesis. Furthermore, MCP-1 was shown to be internalized within wild-type microvessels, but not within microvessels obtained from CCR2 (-/-) mice, additionally demonstrating that CCR2 is obligatory for MCP-1 endocytosis. Last, internalization of MCP-1, but not transferrin, was observed to be inhibited by disruption of caveolae. Internalized MCP-1 also colocalized at some sites with caveolin-1, a major protein of caveolae, implying that this chemokine is endocytosed, in part, via nonclathrin-coated vesicles. These results prompt consideration that MCP-1 signals may be relayed across the blood-brain barrier by highly specialized interactions of this chemokine with its cognate receptor, CCR2, along brain microvascular endothelial cells.


Subject(s)
Brain/blood supply , Chemokine CCL2/metabolism , Endothelium, Vascular/metabolism , Microcirculation/metabolism , Receptors, Chemokine/metabolism , Animals , Binding, Competitive/physiology , Caveolae/drug effects , Caveolae/metabolism , Caveolin 1 , Caveolins/metabolism , Chemokines/metabolism , Crosses, Genetic , Down-Regulation , Endocytosis/drug effects , Endocytosis/physiology , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Filipin/pharmacology , In Vitro Techniques , Ligands , Mice , Mice, Inbred Strains , Mice, Knockout , Microcirculation/drug effects , Protein Binding/physiology , Receptors, CCR2 , Receptors, Chemokine/deficiency , Receptors, Chemokine/genetics , Temperature , Transferrin/metabolism
2.
Exp Neurol ; 161(1): 96-101, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10683276

ABSTRACT

Experiments were performed to determine if scavenger receptors (SRs) play a role in amyloid beta (Abeta) stimulation of peripheral blood monocyte (PBM) neurotoxicity. Results indicate that Abeta does not block binding of the SR ligand DiI-acetylated low density lipoprotein to PBM, nor does another SR ligand, fucoidin, inhibit Abeta-PBM binding. Moreover, neither of three SR ligands alone stimulates neurotoxicity in PBM, nor antagonizes the ability of Abeta to activate PBM to a neurocytopathic state. Such findings suggest that Abeta's action is not dependent upon engagement of the SR ligand binding domain and raise doubts about the role of SR in Abeta neurotoxicity.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/toxicity , Membrane Proteins , Monocytes/pathology , Peptide Fragments/toxicity , Receptors, Immunologic/metabolism , Receptors, Lipoprotein , Alzheimer Disease/immunology , Alzheimer Disease/pathology , Animals , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Binding Sites/physiology , Carbocyanines , Cells, Cultured , Cholesterol, LDL/metabolism , Cholesterol, LDL/pharmacology , Fluorescent Dyes , Humans , Monocytes/drug effects , Monocytes/immunology , Neurons/chemistry , Neurons/metabolism , Neurons/pathology , Phagocytosis/immunology , Polysaccharides/metabolism , Polysaccharides/pharmacology , Rats , Receptors, Immunologic/chemistry , Receptors, Scavenger , Scavenger Receptors, Class B , Signal Transduction/physiology
3.
J Biol Chem ; 273(28): 17660-4, 1998 Jul 10.
Article in English | MEDLINE | ID: mdl-9651362

ABSTRACT

Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system results in neuronal apoptosis. Activated HIV-1-infected monocytes secrete high levels of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and the phospholipid mediator platelet-activating factor (PAF). TNF-alpha and PAF are elevated in the central nervous system of patients with HIV-1-associated dementia. We now demonstrate that conditioned media from activated HIV-1-infected monocytes induces neuronal apoptosis, which can be prevented by co-incubation with PAF acetylhydrolase, the enzyme that catabolizes PAF in the central nervous system. Preceding apoptosis is a TNF-alpha-induced increase in neuronal ceramide levels. TNF-alpha-mediated neuronal apoptosis can also be blocked by co-incubation with PAF acetylhydrolase, or a PAF receptor antagonist. Blocking pathologic activation of PAF receptors may therefore be a pivotal step in the treatment of HIV-1-associated dementia.


Subject(s)
Central Nervous System/virology , HIV Infections/metabolism , HIV-1/pathogenicity , Platelet Activating Factor/metabolism , Platelet Membrane Glycoproteins/metabolism , Receptors, Cell Surface , Receptors, G-Protein-Coupled , 1-Alkyl-2-acetylglycerophosphocholine Esterase , Apoptosis/drug effects , Central Nervous System/pathology , Ceramides/metabolism , Culture Media, Conditioned , HIV Infections/pathology , Humans , Monocytes/drug effects , Monocytes/virology , Neurons/drug effects , Neurons/virology , Phospholipases A/metabolism , Platelet Activating Factor/antagonists & inhibitors , Tumor Cells, Cultured , Tumor Necrosis Factor-alpha/pharmacology
4.
J Neuroimmunol ; 80(1-2): 6-12, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9413254

ABSTRACT

Previous work from this laboratory has demonstrated that prior exposure of peripheral blood monocytes (PBM) to aggregated beta-amyloid peptide (A beta), the major protein comprising the amyloid plaques characteristically present in the brain of Alzheimer disease (AD)-afflicted individuals, activates these cells to a neurotoxic state when co-cultured with brain tissue. In this report we extend these findings to further show that such A beta-induced PBM neurotoxicity can be inhibited by three differentially-acting antiinflammatory drugs, indomethacin, dexamethasone, and colchicine, which are typically used clinically to treat peripheral inflammatory disease. In addition, evidence is presented that these toxic effects are initiated, in large part, by soluble factors released from A beta-stimulated PBM. Our results suggest a rationale for antiinflammatory therapy in the treatment of AD.


Subject(s)
Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/pharmacology , Anti-Inflammatory Agents/pharmacology , Immunosuppressive Agents/pharmacology , Monocytes/drug effects , Neurotoxins/immunology , Animals , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Cerebral Cortex/immunology , Coculture Techniques , Colchicine/pharmacology , Dexamethasone/pharmacology , Humans , Indomethacin/pharmacology , Monocytes/immunology , Monocytes/metabolism , Neurotoxins/metabolism , Organ Culture Techniques , Rats , Rats, Inbred Strains , Solubility
5.
J Virol ; 68(7): 4628-35, 1994 Jul.
Article in English | MEDLINE | ID: mdl-8207837

ABSTRACT

The pathogenesis of central nervous system disease during human immunodeficiency virus type 1 (HIV-1) infection revolves around productive viral infection of brain macrophages and microglia. Neuronal losses in the cortex and subcortical gray matter accompany macrophage infection. The question of how viral infection of brain macrophages ultimately leads to central nervous system (CNS) pathology remains unanswered. Our previous work demonstrated high-level production of tumor necrosis factor alpha, interleukin 1 beta, arachidonic acid metabolites, and platelet-activating factor (PAF) from HIV-infected monocytes and astroglia (H. E. Gendelman, P. Genis, M. Jett, and H. S. L. M. Nottet, in E. Major, ed., Technical Advances in AIDS Research in the Nervous System, in press; P. Genis, M. Jett, E. W. Bernton, H. A. Gelbard, K. Dzenko, R. Keane, L. Resnick, D. J. Volsky, L. G. Epstein, and H. E. Gendelman, J. Exp. Med. 176:1703-1718, 1992). These factors, together, were neurotoxic. The relative role(s) of each of these candidate neurotoxins in HIV-1-related CNS dysfunction was not unraveled by these initial experiments. We now report that PAF is produced during HIV-1-infected monocyte-astroglia interactions. PAF was detected at high levels in CSF of HIV-1-infected patients with immunosuppression and signs of CNS dysfunction. The biologic significance of the results for neurological disease was determined by addition of PAF to cultures of primary human fetal cortical or rat postnatal retinal ganglion neurons. Here, PAF at concentrations of > or = 300 pg/ml produced neuronal death. The N-methyl-D-aspartate receptor antagonist MK-801 or memantine partially blocked the neurotoxic effects of PAF. The identification of PAF as an HIV-1-induced neurotoxin provides new insights into how HIV-1 causes neurological impairment and how it may ultimately be ameliorated.


Subject(s)
HIV-1/pathogenicity , Platelet Activating Factor/biosynthesis , AIDS Dementia Complex/microbiology , AIDS Dementia Complex/physiopathology , Acquired Immunodeficiency Syndrome/microbiology , Acquired Immunodeficiency Syndrome/physiopathology , Adult , Animals , Astrocytes/metabolism , Cell Survival , Cells, Cultured , Child , Child, Preschool , Fetus/cytology , Humans , Infant , Middle Aged , Monocytes/microbiology , Neurons/cytology , Neurons/microbiology , Platelet Activating Factor/cerebrospinal fluid , Platelet Activating Factor/physiology , Rats
6.
Dev Neurosci ; 15(6): 417-22, 1993.
Article in English | MEDLINE | ID: mdl-7835247

ABSTRACT

Human immunodeficiency virus type 1 (HIV) infection of the central nervous system is characterized by neuronal loss in discrete areas of the central nervous system. We have previously demonstrated that HIV-infected monocytes in culture with astroglial cells produce high levels (> or = 200 pg/ml) of the cytokine tumor necrosis factor-alpha (TNF alpha). We now demonstrate that TNF alpha (> or = 200 pg/ml) is neurotoxic to cultured primary human fetal cortical neurons at both light and electron microscopic levels. Subtoxic doses of TNF alpha (50 pg/ml) are neurotoxic in combination with the glutamate (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) subtype receptor agonist AMPA (100 microM). The neurotoxic effects of TNF alpha (200 pg/ml) are blocked in part by the AMPA receptor antagonist, 6-cyano-7-nitroquinoxaline-2, 3-dione (10 microM). This suggests that TNF alpha may exert neurotoxic effects on human neurons by indirect activation of AMPA receptors, which may be important in the pathogenesis and treatment of HIV-mediated encephalopathy.


Subject(s)
AIDS Dementia Complex/pathology , Neurons/drug effects , Receptors, AMPA/agonists , Tumor Necrosis Factor-alpha/toxicity , 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology , Cell Survival/drug effects , Cells, Cultured , Dizocilpine Maleate/pharmacology , Humans , Microscopy, Electron , Neurons/ultrastructure , Receptors, AMPA/antagonists & inhibitors
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