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1
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Morisaki Y, Ohshima M, Suzuki H, Misawa H. LAG-3 expression in microglia regulated by IFN-γ/STAT1 pathway and metalloproteases. Front Cell Neurosci 2023; 17:1308972. [PMID: 38026700 PMCID: PMC10663313 DOI: 10.3389/fncel.2023.1308972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 10/26/2023] [Indexed: 12/01/2023] Open
Abstract
Microglia are resident innate immune cells in the central nervous system (CNS) and play important roles in the development of CNS homeostasis. Excessive activation and neurotoxicity of microglia are observed in several CNS disorders, but the mechanisms regulating their activation remain unclear. Immune checkpoint molecules are expressed on activated immune cells and regulate their activation in peripheral immunity. However, the expression mechanism of immune checkpoint molecules in activated microglia is still unknown. Here, we analyzed the expression of immune checkpoint molecules in activated microglia using the mouse microglial cell line BV2 and primary cultured microglia. The expression of lymphocyte activation gene-3 (LAG-3), a type of immune checkpoint molecule, was increased in microglia activated by IFN-γ. IFN-γ-induced LAG-3 expression in microglia was suppressed by transfection of siRNA targeting STAT1. LAG-3 has two forms, membrane and soluble, and both forms were upregulated in microglia activated by IFN-γ. The production of soluble LAG-3 was suppressed by treatment with inhibitors of metalloproteinases such as ADAM10 and ADAM17. IFN-γ administration into cisterna magna of mice increased LAG-3 expression in spinal microglia. Furthermore, LAG-3 knockdown in microglia promoted nitric oxide production by IFN-γ. Our results demonstrate that LAG-3 expression in microglia is induced by the IFN-γ-STAT1 pathway and soluble LAG-3 production is regulated via cleavage of membranous LAG-3 by metalloproteinases including ADAM10 and ADAM17.
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Affiliation(s)
- Yuta Morisaki
- Division of Pharmacology, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | | | | | - Hidemi Misawa
- Division of Pharmacology, Faculty of Pharmacy, Keio University, Tokyo, Japan
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2
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Ibrahim WW, Sayed RH, Kandil EA, Wadie W. Niacin mitigates blood-brain barrier tight junctional proteins dysregulation and cerebral inflammation in ketamine rat model of psychosis: Role of GPR109A receptor. Prog Neuropsychopharmacol Biol Psychiatry 2022; 119:110583. [PMID: 35690118 DOI: 10.1016/j.pnpbp.2022.110583] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 06/05/2022] [Accepted: 06/05/2022] [Indexed: 01/25/2023]
Abstract
Dysregulated inflammatory responses and blood-brain barrier (BBB) dysfunction are recognized as central factors in the development of psychiatric disorders. The present study was designed to evaluate the effect of niacin on BBB integrity in ketamine-induced model of psychosis. Meanwhile, mepenzolate bromide (MPN), a GPR109A receptor blocker, was used to investigate the role of this receptor on the observed niacin's effect. Male Wistar rats received ketamine (30 mg/kg/day, i.p) for 5 consecutive days and then niacin (40 mg/kg/day, p.o), with or without MPN (5 mg/kg/day, i.p), was given for the subsequent 15 days. Three days before the end of experiment, rats were behaviorally tested using open field, novel object recognition, social interaction, and forced swimming tests. Niacin significantly ameliorated ketamine-induced behavioral deficits, amended gamma aminobutyric acid and glutamate concentration, decreased tumor necrosis factor-α and matrix metallopeptidase 9 levels, and increased netrin-1 contents in the hippocampus of rats. Niacin also augmented the hippocampal expression of ZO-1, occludin, and claudin-5 proteins, indicating the ability of niacin to restore the BBB integrity. Moreover, the histopathologic changes in hippocampal neurons were alleviated. Since all the beneficial effects of niacin in the present investigation were partially abolished by the co-administration of MPN; GPR109A receptor was proven to partially mediate the observed antipsychotic effects of niacin. These data revealed that GPR109A-mediated signaling pathways might represent potential targets for therapeutic interventions to prevent or slow the progression of psychosis.
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Affiliation(s)
- Weam W Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt
| | - Rabab H Sayed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt.
| | - Esraa A Kandil
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt
| | - Walaa Wadie
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt
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3
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Murray TE, Richards CM, Robert-Gostlin VN, Bernath AK, Lindhout IA, Klegeris A. Potential neurotoxic activity of diverse molecules released by astrocytes. Brain Res Bull 2022; 189:80-101. [PMID: 35988785 DOI: 10.1016/j.brainresbull.2022.08.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 07/04/2022] [Accepted: 08/14/2022] [Indexed: 11/02/2022]
Abstract
Astrocytes are the main support cells of the central nervous system. They also participate in neuroimmune reactions. In response to pathological and immune stimuli, astrocytes transform to reactive states characterized by increased release of inflammatory mediators. Some of these molecules are neuroprotective and inflammation resolving while others, including reactive oxygen species (ROS), nitric oxide (NO), matrix metalloproteinase (MMP)- 9, L-glutamate, and tumor necrosis factor α (TNF), are well-established toxins known to cause damage to surrounding cells and tissues. We hypothesized that similar to microglia, the brain immune cells, reactive astrocytes can release a broader set of diverse molecules that are potentially neurotoxic. A literature search was conducted to identify such molecules using the following two criteria: 1) evidence of their expression and secretion by astrocytes and 2) direct neurotoxic action. This review describes 14 structurally diverse molecules as less-established astrocyte neurotoxins, including C-X-C motif chemokine ligand (CXCL)10, CXCL12/CXCL12(5-67), FS-7-associated surface antigen ligand (FasL), macrophage inflammatory protein (MIP)- 2α, TNF-related apoptosis inducing ligand (TRAIL), pro-nerve growth factor (proNGF), pro-brain-derived neurotrophic factor (proBDNF), chondroitin sulfate proteoglycans (CSPGs), cathepsin (Cat)B, group IIA secretory phospholipase A2 (sPLA2-IIA), amyloid beta peptides (Aβ), high mobility group box (HMGB)1, ceramides, and lipocalin (LCN)2. For some of these molecules, further studies are required to establish either their direct neurotoxic effects or the full spectrum of stimuli that induce their release by astrocytes. Only limited studies with human-derived astrocytes and neurons are available for most of these potential neurotoxins, which is a knowledge gap that should be addressed in the future. We also summarize available evidence of the role these molecules play in select neuropathologies where reactive astrocytes are a key feature. A comprehensive understanding of the full spectrum of neurotoxins released by reactive astrocytes is key to understanding neuroinflammatory diseases characterized by the adverse activation of these cells and may guide the development of novel treatment strategies.
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Affiliation(s)
- Taryn E Murray
- Department of Biology, University of British Columbia Okanagan Campus, Kelowna, British Columbia V1V 1V7, Canada
| | - Christy M Richards
- Department of Biology, University of British Columbia Okanagan Campus, Kelowna, British Columbia V1V 1V7, Canada
| | - Victoria N Robert-Gostlin
- Department of Biology, University of British Columbia Okanagan Campus, Kelowna, British Columbia V1V 1V7, Canada
| | - Anna K Bernath
- Department of Biology, University of British Columbia Okanagan Campus, Kelowna, British Columbia V1V 1V7, Canada
| | - Ivan A Lindhout
- Department of Biology, University of British Columbia Okanagan Campus, Kelowna, British Columbia V1V 1V7, Canada
| | - Andis Klegeris
- Department of Biology, University of British Columbia Okanagan Campus, Kelowna, British Columbia V1V 1V7, Canada.
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Wan D, Yang L, Ren J, Huang H, Zhang C, Chen L, Su X, Huang Q, Niu J, Sun T, Wang P. Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in the hippocampus of lithium-pilocarpine-induced acute epileptic rats. Mol Biol Rep 2022; 49:5805-5810. [PMID: 35715602 DOI: 10.1007/s11033-022-07277-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 02/10/2022] [Accepted: 02/16/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Epilepsy is characterised by abnormal neuronal discharges, including aberrant expression of extracellular matrix (ECM) components and synaptic plasticity stabilisation. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) interact to remodel the ECM in the central nervous system (CNS), to modulate synaptic plasticity in epileptogenesis. METHODS AND RESULTS In the present study, the expression of MMP activators (tPA and uPA), 10 MMPs, and 3 TIMPs was detected by western blot analysis and quantitative polymerase chain reaction (RT-qPCR) to assess their potential pathogenetic role in the epileptogenesis in the hippocampus of lithium-pilocarpine hydrochloride-induced epileptic rats. Our results showed that The expression of MMP7 and MMP14 was impeded in the hippocampus of lithium-pilocarpine-induced acute epileptic rats compared with that in controls. The transcriptional level of tPA was enhanced on day 1 post-seizure in the hippocampus, while the levels of several MMPs and TIMPs did not change on days 1 and 3 post-seizure compared with that in controls. CONCLUSIONS The expression of MMPs and TIMPs reflects a novel feature of epileptogenesis and may offer new perspectives for future therapeutic interventions.
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Affiliation(s)
- Ding Wan
- Department of Neurosurgery, General Hospital of Ningxia Medical University, 804 Shengli Street, Yinchuan, 750004, Ningxia, China.,Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, Ningxia, China
| | - Lu Yang
- Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, Ningxia, China
| | - Jia Ren
- School of Clinical Medicine, Ningxia Medical University, 750004, Yinchuan, China
| | - Haiyue Huang
- Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, Ningxia, China
| | - Chen Zhang
- School of Clinical Medicine, Ningxia Medical University, 750004, Yinchuan, China
| | - Le Chen
- School of Clinical Medicine, Ningxia Medical University, 750004, Yinchuan, China
| | - Xueyao Su
- School of Clinical Medicine, Ningxia Medical University, 750004, Yinchuan, China
| | - Qi Huang
- Department of Neurosurgery, General Hospital of Ningxia Medical University, 804 Shengli Street, Yinchuan, 750004, Ningxia, China
| | - Jianguo Niu
- Ningxia Key Laboratory of Cerebrocranial Diseases, Department of Anatomy, Ningxia Medical University, 750004, Yinchuan, China
| | - Tao Sun
- Department of Neurosurgery, General Hospital of Ningxia Medical University, 804 Shengli Street, Yinchuan, 750004, Ningxia, China. .,Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, Ningxia, China.
| | - Peng Wang
- Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, Ningxia, China.
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T cell apoptosis characterizes severe Covid-19 disease. Cell Death Differ 2022; 29:1486-1499. [PMID: 35066575 PMCID: PMC8782710 DOI: 10.1038/s41418-022-00936-x] [Citation(s) in RCA: 97] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 01/06/2022] [Accepted: 01/10/2022] [Indexed: 02/02/2023] Open
Abstract
Severe SARS-CoV-2 infections are characterized by lymphopenia, but the mechanisms involved are still elusive. Based on our knowledge of HIV pathophysiology, we hypothesized that SARS-CoV-2 infection-mediated lymphopenia could also be related to T cell apoptosis. By comparing intensive care unit (ICU) and non-ICU COVID-19 patients with age-matched healthy donors, we found a strong positive correlation between plasma levels of soluble FasL (sFasL) and T cell surface expression of Fas/CD95 with the propensity of T cells to die and CD4 T cell counts. Plasma levels of sFasL and T cell death are correlated with CXCL10 which is part of the signature of 4 biomarkers of disease severity (ROC, 0.98). We also found that members of the Bcl-2 family had modulated in the T cells of COVID-19 patients. More importantly, we demonstrated that the pan-caspase inhibitor, Q-VD, prevents T cell death by apoptosis and enhances Th1 transcripts. Altogether, our results are compatible with a model in which T-cell apoptosis accounts for T lymphopenia in individuals with severe COVID-19. Therefore, a strategy aimed at blocking caspase activation could be beneficial for preventing immunodeficiency in COVID-19 patients.
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Rempe RG, Hartz AMS, Bauer B. Matrix metalloproteinases in the brain and blood-brain barrier: Versatile breakers and makers. J Cereb Blood Flow Metab 2016; 36:1481-507. [PMID: 27323783 PMCID: PMC5012524 DOI: 10.1177/0271678x16655551] [Citation(s) in RCA: 457] [Impact Index Per Article: 50.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 05/26/2016] [Indexed: 02/01/2023]
Abstract
Matrix metalloproteinases are versatile endopeptidases with many different functions in the body in health and disease. In the brain, matrix metalloproteinases are critical for tissue formation, neuronal network remodeling, and blood-brain barrier integrity. Many reviews have been published on matrix metalloproteinases before, most of which focus on the two best studied matrix metalloproteinases, the gelatinases MMP-2 and MMP-9, and their role in one or two diseases. In this review, we provide a broad overview of the role various matrix metalloproteinases play in brain disorders. We summarize and review current knowledge and understanding of matrix metalloproteinases in the brain and at the blood-brain barrier in neuroinflammation, multiple sclerosis, cerebral aneurysms, stroke, epilepsy, Alzheimer's disease, Parkinson's disease, and brain cancer. We discuss the detrimental effects matrix metalloproteinases can have in these conditions, contributing to blood-brain barrier leakage, neuroinflammation, neurotoxicity, demyelination, tumor angiogenesis, and cancer metastasis. We also discuss the beneficial role matrix metalloproteinases can play in neuroprotection and anti-inflammation. Finally, we address matrix metalloproteinases as potential therapeutic targets. Together, in this comprehensive review, we summarize current understanding and knowledge of matrix metalloproteinases in the brain and at the blood-brain barrier in brain disorders.
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Affiliation(s)
- Ralf G Rempe
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA
| | - Anika M S Hartz
- Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY, USA
| | - Björn Bauer
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA
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7
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Ebsen H, Lettau M, Kabelitz D, Janssen O. Subcellular localization and activation of ADAM proteases in the context of FasL shedding in T lymphocytes. Mol Immunol 2015; 65:416-28. [PMID: 25745808 DOI: 10.1016/j.molimm.2015.02.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Revised: 01/20/2015] [Accepted: 02/08/2015] [Indexed: 10/23/2022]
Abstract
The "A Disintegrin And Metalloproteinases" (ADAMs) form a subgroup of the metzincin endopeptidases. Proteolytically active members of this protein family act as sheddases and govern key processes in development and inflammation by regulating cell surface expression and release of cytokines, growth factors, adhesion molecules and their receptors. In T lymphocytes, ADAM10 sheds the death factor Fas Ligand (FasL) and thereby regulates T cell activation, death and effector function. Although FasL shedding by ADAM10 was confirmed in several studies, its regulation is still poorly defined. We recently reported that ADAM10 is highly abundant on T cells whereas its close relative ADAM17 is expressed at low levels and transiently appears at the cell surface upon stimulation. Since FasL is also stored intracellularly and brought to the plasma membrane upon stimulation, we addressed where the death factor gets exposed to ADAM proteases. We report for the first time that both ADAM10 and ADAM17 are associated with FasL-containing secretory lysosomes. Moreover, we demonstrate that TCR/CD3/CD28-stimulation induces a partial positioning of both proteases and FasL to lipid rafts and only the activation-induced raft-positioning results in FasL processing. TCR/CD3/CD28-induced FasL proteolysis is markedly affected by reducing both ADAM10 and ADAM17 protein levels, indicating that in human T cells also ADAM17 is implicated in FasL processing. Since FasL shedding is affected by cholesterol depletion and by inhibition of Src kinases or palmitoylation, we conclude that it requires mobilization and co-positioning of ADAM proteases in lipid raft-like platforms associated with an activation of raft-associated Src-family kinases.
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Affiliation(s)
- Henriette Ebsen
- University of Kiel, Institute of Immunology, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3 Bldg 17, D-24105 Kiel, Germany
| | - Marcus Lettau
- University of Kiel, Institute of Immunology, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3 Bldg 17, D-24105 Kiel, Germany
| | - Dieter Kabelitz
- University of Kiel, Institute of Immunology, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3 Bldg 17, D-24105 Kiel, Germany
| | - Ottmar Janssen
- University of Kiel, Institute of Immunology, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller-Str. 3 Bldg 17, D-24105 Kiel, Germany.
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8
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Ettcheto M, Junyent F, de Lemos L, Pallas M, Folch J, Beas-Zarate C, Verdaguer E, Gómez-Sintes R, Lucas JJ, Auladell C, Camins A. Mice Lacking Functional Fas Death Receptors Are Protected from Kainic Acid-Induced Apoptosis in the Hippocampus. Mol Neurobiol 2014; 52:120-9. [PMID: 25119776 DOI: 10.1007/s12035-014-8836-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Accepted: 07/25/2014] [Indexed: 01/08/2023]
Abstract
The Fas receptor (FasR)/Fas ligand (FasL) system plays a significant role in the process of neuronal loss in neurological disorders. Thus, in the present study, we used a real-time PCR array focused apoptosis (Mouse Apoptosis RT(2) PCR Array) to study the role of the Fas pathway in the apoptotic process that occurs in a kainic acid (KA) mice experimental model. In fact, significant changes in the transcriptional activity of a total of 23 genes were found in the hippocampus of wild-type C57BL/6 mice after 12 h of KA treatment compared to untreated mice. Among the up-regulated genes, we found key factors involved in the extrinsic apoptotic pathway, such as tnf, fas and fasL, and also in caspase genes (caspase -4, caspase-8 and caspase-3). To discern the importance of the FasR/FasL pathway, mice lacking the functional Fas death receptor (lpr) were also treated with KA. After 24 h of neurotoxin treatment, lpr mice exhibited a reduced number of apoptotic positive cells, determined by the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) method in different regions of the hippocampus, when compared to wild-type mice. In addition, treatment of lpr mice with KA did not produce significant changes in the transcriptional activity of genes related to apoptosis in the hippocampus, either in the fas and fas ligand genes or in caspase-4 and caspase-8 and the executioner caspase-3 genes, as occurred in wild-type C57BL/6 mice. Thus, these data provide direct evidence that Fas signalling plays a key role in the induction of apoptosis in the hippocampus following KA treatment, making the inhibition of the death receptor pathway a potentially suitable target for excitotoxicity neuroprotection in neurological conditions such as epilepsy.
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Affiliation(s)
- Miren Ettcheto
- Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona, Avda/Diagonal 643, E-08028, Barcelona, Spain
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9
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Manicone AM. Role of the pulmonary epithelium and inflammatory signals in acute lung injury. Expert Rev Clin Immunol 2014. [DOI: 10.1586/1744666x.5.1.63] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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10
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Luna S, Cameron DJ, Ethell DW. Amyloid-β and APP deficiencies cause severe cerebrovascular defects: important work for an old villain. PLoS One 2013; 8:e75052. [PMID: 24040383 PMCID: PMC3764155 DOI: 10.1371/journal.pone.0075052] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Accepted: 08/08/2013] [Indexed: 11/21/2022] Open
Abstract
Alzheimer’s disease (AD) is marked by neuritic plaques that contain insoluble deposits of amyloid-β (Aβ), yet the physiological function of this peptide has remained unclear for more than two decades. Using genetics and pharmacology we have established that Aβ plays an important role in regulating capillary bed density within the brain, a function that is distinct from other cleavage products of amyloid precursor protein (APP). APP-deficient zebrafish had fewer cerebrovascular branches and shorter vessels in the hindbrain than wild-type embryos; this phenotype was rescued by treatment with human Aβ peptide, but not a smaller APP fragment called p3. Similar vascular defects were seen in zebrafish treated with a β-secretase inhibitor (BSI) that blocked endogenous Aβ production. BSI-induced vascular defects were also improved by treatment with human Aβ, but not p3. Our results demonstrate a direct correlation between extracellular levels of Aβ and cerebrovascular density in the developing hindbrain. These findings may be relevant to AD etiology where high levels of Aβ in the brain parenchyma precede the development of neuritic plaques and dense aberrantly-branched blood vessel networks that appear between them. The ability of Aβ to modify blood vessels may coordinate capillary density with local metabolic activity, which could explain the evolutionary conservation of this peptide from lobe-finned fish to man.
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Affiliation(s)
- Salvadore Luna
- Molecular Neurobiology, Western University of Health Sciences, Pomona, California, United States of America
- Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, United States of America
| | - D. Joshua Cameron
- Molecular Neurobiology, Western University of Health Sciences, Pomona, California, United States of America
- College of Optometry, Western University of Health Sciences, Pomona, California, United States of America
| | - Douglas W. Ethell
- Molecular Neurobiology, Western University of Health Sciences, Pomona, California, United States of America
- Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, United States of America
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, United States of America
- * E-mail:
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Neuronal apoptosis and motor deficits in mice with genetic inhibition of GSK-3 are Fas-dependent. PLoS One 2013; 8:e70952. [PMID: 23940673 PMCID: PMC3734180 DOI: 10.1371/journal.pone.0070952] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Accepted: 06/24/2013] [Indexed: 11/19/2022] Open
Abstract
Glycogen synthase kinase-3 (GSK-3) inhibitors have been postulated as useful therapeutic tools for the treatment of chronic neurodegenerative and neuropsychiatric diseases. Nevertheless the clinical use of these inhibitors has been limited by their common side effects. Lithium, a non-selective GSK-3 inhibitor has been classically administered to treat bipolar patients but its prescription is decreasing due to its frequent side effects such as hand tremor. This toxicity seems to be higher in the elderly and a clinical trial with lithium for Alzheimer’s disease was stopped due to high rate of discontinuation. We have previously described a mechanism for the adverse effects of chronic lithium that involves neuronal apoptosis via Fas signaling. As lithium inhibits many other enzymatic activities such as inositol monophosphatase and histone deacetylase, here we aim to genetically test whether GSK-3 inhibition induces those adverse effects through Fas receptor. For this purpose we took advantage of a transgenic mouse line with decreased GSK-3 activity (Tet/DN-GSK-3 mice) that shows increased rate of neuronal apoptosis as well as motor deficits and brought it to a Fas deficient background (lpr mice). We found that apoptosis induced by GSK-3 inhibition was absent in Fas deficient background. Interestingly, motor deficits were also absent in Fas deficient Tet/DN-GSK-3 mice. These results demonstrate that Fas signaling contributes to the neurological toxicity of GSK-3 inhibition and suggest that a combination of GSK-3 inhibitors with blockers of Fas signaling could help to improve the application of GSK-3 inhibitors to clinics.
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12
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Region-specific expression of Dickkopf-like1 in the adult brain. Abbreviated title: Dkkl1 in the adult brain. Neurosci Lett 2013; 535:84-9. [PMID: 23295900 DOI: 10.1016/j.neulet.2012.12.040] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Revised: 12/15/2012] [Accepted: 12/20/2012] [Indexed: 11/20/2022]
Abstract
In the adult, the dickkopf family member Dickkopf-like1 (Dkkl1) has been described as a testicular protein involved in the regulation of spermatocyte apoptosis. However, microarray studies additionally suggested that Dkkl1 regulation is involved in various tumors including high grade gliomas. Since investigations of Dkkl1 in the adult central nervous system are lacking, we analyzed Dkkl1 expression in the adult mouse brain and found a region specific expression pattern with a profoundly high cortical expression. Analysis of transgenic mice in which the lacZ gene was inserted into the Dkkl1 locus further pointed to NeuN-positive neurons as the main source of Dkkl1 in the normal adult brain. In Dkkl1(-/-) mutant mice, gross brain morphology as well as hippocampal and cortical lamination appeared normal. Similarly, neuronal density in cortical layer V was not altered. Thus, Dkkl1 may not be essential for normal brain organization, but could exert import functions during pathological conditions such as tumorigenesis and cancer progression.
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13
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Cameron DJ, Galvin C, Alkam T, Sidhu H, Ellison J, Luna S, Ethell DW. Alzheimer's-related peptide amyloid-β plays a conserved role in angiogenesis. PLoS One 2012; 7:e39598. [PMID: 22792182 PMCID: PMC3392248 DOI: 10.1371/journal.pone.0039598] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Accepted: 05/24/2012] [Indexed: 11/19/2022] Open
Abstract
Alzheimer's disease research has been at an impasse in recent years with lingering questions about the involvement of Amyloid-β (Aβ). Early versions of the amyloid hypothesis considered Aβ something of an undesirable byproduct of APP processing that wreaks havoc on the human neocortex, yet evolutionary conservation--over three hundred million years--indicates this peptide plays an important biological role in survival and reproductive fitness. Here we describe how Aβ regulates blood vessel branching in tissues as varied as human umbilical vein and zebrafish hindbrain. High physiological concentrations of Aβ monomer induced angiogenesis by a conserved mechanism that blocks γ-secretase processing of a Notch intermediate, NEXT, and reduces the expression of downstream Notch target genes. Our findings allude to an integration of signaling pathways that utilize γ-secretase activity, which may have significant implications for our understanding of Alzheimer's pathogenesis vis-à-vis vascular changes that set the stage for ensuing neurodegeneration.
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Affiliation(s)
- D. Joshua Cameron
- Molecular Neurobiology, Western University of Health Sciences, Pomona, California, United States of America
- College of Optometry, Western University of Health Sciences, Pomona, California, United States of America
| | - Cooper Galvin
- Molecular Neurobiology, Western University of Health Sciences, Pomona, California, United States of America
| | - Tursun Alkam
- Molecular Neurobiology, Western University of Health Sciences, Pomona, California, United States of America
- Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, United States of America
| | - Harpreet Sidhu
- Molecular Neurobiology, Western University of Health Sciences, Pomona, California, United States of America
| | - John Ellison
- Molecular Neurobiology, Western University of Health Sciences, Pomona, California, United States of America
| | - Salvadore Luna
- Molecular Neurobiology, Western University of Health Sciences, Pomona, California, United States of America
- Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, United States of America
| | - Douglas W. Ethell
- Molecular Neurobiology, Western University of Health Sciences, Pomona, California, United States of America
- Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, United States of America
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, United States of America
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14
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Hoogwater FJH, Steller EJA, Westendorp BF, Borel Rinkes IHM, Kranenburg O. CD95 signaling in colorectal cancer. Biochim Biophys Acta Rev Cancer 2012; 1826:189-98. [PMID: 22498253 DOI: 10.1016/j.bbcan.2012.03.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Revised: 03/09/2012] [Accepted: 03/10/2012] [Indexed: 02/07/2023]
Abstract
CD95 and its ligand (CD95L) are widely expressed in colorectal tumors, but their role in shaping tumor behavior is unclear. CD95 activation on tumor cells can lead to apoptosis, while CD95L attracts neutrophils, suggesting a function in tumor suppression. However, CD95 can also promote tumorigenesis, at least in part by activating non-apoptotic signaling pathways that stimulate tumor cell proliferation, invasion and survival. In addition, CD95 signaling in stromal cells and tumor-infiltrating inflammatory cells has to be taken into account when addressing the function of CD95 and its ligand in colorectal tumor biology. We present a model in which the tumor-suppressing and tumor-promoting activities of CD95/CD95L together determine colorectal tumor behavior. We also discuss how these multiple activities are changing our view of CD95 and CD95L as potential therapeutic targets in the treatment of colorectal cancer. We conclude that locking CD95 in apoptosis-mode may be a more promising anti-cancer strategy than simply inhibiting or stimulating CD95.
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15
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Le AP, Friedman WJ. Matrix metalloproteinase-7 regulates cleavage of pro-nerve growth factor and is neuroprotective following kainic acid-induced seizures. J Neurosci 2012; 32:703-12. [PMID: 22238106 PMCID: PMC3874860 DOI: 10.1523/jneurosci.4128-11.2012] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2011] [Revised: 10/31/2011] [Accepted: 11/02/2011] [Indexed: 11/21/2022] Open
Abstract
The neurotrophin nerve growth factor (NGF) regulates neuronal growth, differentiation, and survival during development. However, the precursor of NGF, proNGF, is a potent apoptotic ligand for the p75 neurotrophin receptor (p75(NTR))-sortilin complex. The mechanisms that regulate cleavage of proNGF, therefore, are critical determinants of whether this factor promotes neuronal survival or death. In this study, we demonstrate that, following kainic acid-induced seizures, the proNGF processing enzyme matrix metalloproteinase 7 (MMP-7) and its inhibitor TIMP-1 (tissue inhibitor of matrix metalloproteinase 1) are regulated in a manner that prevents proneurotrophin cleavage and leads to increased proNGF in the extracellular milieu. Furthermore, we demonstrate both in vitro and in vivo that exogenous MMP-7 enhances proNGF cleavage and provides neuroprotection following kainic acid treatment. These data demonstrate that increased extracellular proNGF levels following seizures are stabilized by altered MMP-7 enzymatic activity, leading to increased neuronal death via activation of p75(NTR).
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Affiliation(s)
- Audrey P. Le
- Department of Biological Sciences, Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102
| | - Wilma J. Friedman
- Department of Biological Sciences, Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102
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16
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Ateh DD, Leinster VH, Lambert SR, Shah A, Khan A, Walklin HJ, Johnstone JV, Ibrahim NI, Kadam MM, Malik Z, Gironès M, Veldhuis GJ, Warnes G, Marino S, McNeish IA, Martin JE. The intracellular uptake of CD95 modified paclitaxel-loaded poly(lactic-co-glycolic acid) microparticles. Biomaterials 2011; 32:8538-47. [DOI: 10.1016/j.biomaterials.2011.07.060] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2011] [Accepted: 07/19/2011] [Indexed: 12/31/2022]
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17
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Ahmed T, Gilani AH. A comparative study of curcuminoids to measure their effect on inflammatory and apoptotic gene expression in an Aβ plus ibotenic acid-infused rat model of Alzheimer's disease. Brain Res 2011; 1400:1-18. [PMID: 21640982 DOI: 10.1016/j.brainres.2011.05.022] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2011] [Revised: 05/02/2011] [Accepted: 05/11/2011] [Indexed: 02/04/2023]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder, which depicts features of chronic inflammatory conditions resulting in cellular death and has limited therapeutic options. We aimed to explore the effect of a curcuminoid mixture and its individual components on inflammatory and apoptotic genes expression in AD using an Aβ+ibotenic acid-infused rat model. After 5 days of treatment with demethoxycurcumin, hippocampal IL-1β levels were decreased to 118.54 ± 47.48 and 136.67 ± 31.96% respectively at 30 and 10mg/kg, compared with the amyloid treated group (373.99 ± 15.28%). After 5 days of treatment, the curcuminoid mixture and demethoxycurcumin effectively decreased GFAP levels in the hippocampus. When studied for their effect on apoptotic genes expression, the curcuminoid mixture and bisdemethoxycurcumin effectively decreased caspase-3 level in the hippocampus after 20 days of treatment, where bisdemethoxycurcumin showed a maximal rescuing effect (92.35 ± 3.07%) at 3mg/kg. The curcuminoid mixture at 30 mg/kg decreased hippocampal FasL level to 70.56 ± 3.36% after 5 days of treatment and 19.01 ± 2.03% after 20 days. In the case of Fas receptor levels, demethoxycurcumin decreased levels after 5 days of treatment with all three doses showing a maximal effect (189.76 ± 15.01%) at 10mg/kg. Each compound was effective after 20 days in reducing Fas receptor levels in the hippocampus. This study revealed the important effect of curcuminoids on genes expression, showing that, each component of the curcuminoid mixture distinctly affects gene expression, thus highlighting the therapeutic potential of curcuminoids in AD.
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Affiliation(s)
- Touqeer Ahmed
- Natural Products Research Unit, Department of Biological and Biomedical Sciences, The Aga Khan University Medical College, Karachi-Pakistan
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18
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Craig-Schapiro R, Kuhn M, Xiong C, Pickering EH, Liu J, Misko TP, Perrin RJ, Bales KR, Soares H, Fagan AM, Holtzman DM. Multiplexed immunoassay panel identifies novel CSF biomarkers for Alzheimer's disease diagnosis and prognosis. PLoS One 2011; 6:e18850. [PMID: 21526197 PMCID: PMC3079734 DOI: 10.1371/journal.pone.0018850] [Citation(s) in RCA: 170] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2010] [Accepted: 03/21/2011] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Clinicopathological studies suggest that Alzheimer's disease (AD) pathology begins ∼10-15 years before the resulting cognitive impairment draws medical attention. Biomarkers that can detect AD pathology in its early stages and predict dementia onset would, therefore, be invaluable for patient care and efficient clinical trial design. We utilized a targeted proteomics approach to discover novel cerebrospinal fluid (CSF) biomarkers that can augment the diagnostic and prognostic accuracy of current leading CSF biomarkers (Aβ42, tau, p-tau181). METHODS AND FINDINGS Using a multiplexed Luminex platform, 190 analytes were measured in 333 CSF samples from cognitively normal (Clinical Dementia Rating [CDR] 0), very mildly demented (CDR 0.5), and mildly demented (CDR 1) individuals. Mean levels of 37 analytes (12 after Bonferroni correction) were found to differ between CDR 0 and CDR>0 groups. Receiver-operating characteristic curve analyses revealed that small combinations of a subset of these markers (cystatin C, VEGF, TRAIL-R3, PAI-1, PP, NT-proBNP, MMP-10, MIF, GRO-α, fibrinogen, FAS, eotaxin-3) enhanced the ability of the best-performing established CSF biomarker, the tau/Aβ42 ratio, to discriminate CDR>0 from CDR 0 individuals. Multiple machine learning algorithms likewise showed that the novel biomarker panels improved the diagnostic performance of the current leading biomarkers. Importantly, most of the markers that best discriminated CDR 0 from CDR>0 individuals in the more targeted ROC analyses were also identified as top predictors in the machine learning models, reconfirming their potential as biomarkers for early-stage AD. Cox proportional hazards models demonstrated that an optimal panel of markers for predicting risk of developing cognitive impairment (CDR 0 to CDR>0 conversion) consisted of calbindin, Aβ42, and age. CONCLUSIONS/SIGNIFICANCE Using a targeted proteomic screen, we identified novel candidate biomarkers that complement the best current CSF biomarkers for distinguishing very mildly/mildly demented from cognitively normal individuals. Additionally, we identified a novel biomarker (calbindin) with significant prognostic potential.
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Affiliation(s)
- Rebecca Craig-Schapiro
- Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Max Kuhn
- Neuroscience Research Unit, Pfizer Global Research and Development, Groton, Connecticut, United States of America
- Neuroscience Research Unit, Pfizer Global Research and Development, St. Louis, Missouri, United States of America
| | - Chengjie Xiong
- The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, United States of America
- Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Eve H. Pickering
- Neuroscience Research Unit, Pfizer Global Research and Development, Groton, Connecticut, United States of America
- Neuroscience Research Unit, Pfizer Global Research and Development, St. Louis, Missouri, United States of America
| | - Jingxia Liu
- Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Thomas P. Misko
- Neuroscience Research Unit, Pfizer Global Research and Development, Groton, Connecticut, United States of America
- Neuroscience Research Unit, Pfizer Global Research and Development, St. Louis, Missouri, United States of America
| | - Richard J. Perrin
- The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, United States of America
- Division of Neuropathology, Washington University School of Medicine, St. Louis, Missouri, United States of America
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Kelly R. Bales
- Neuroscience Research Unit, Pfizer Global Research and Development, Groton, Connecticut, United States of America
- Neuroscience Research Unit, Pfizer Global Research and Development, St. Louis, Missouri, United States of America
| | - Holly Soares
- Neuroscience Research Unit, Pfizer Global Research and Development, Groton, Connecticut, United States of America
- Neuroscience Research Unit, Pfizer Global Research and Development, St. Louis, Missouri, United States of America
| | - Anne M. Fagan
- Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States of America
- The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, United States of America
- Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - David M. Holtzman
- Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States of America
- The Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, United States of America
- Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, United States of America
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Hernandez-Guillamon M, Mawhirt S, Fossati S, Blais S, Pares M, Penalba A, Boada M, Couraud PO, Neubert TA, Montaner J, Ghiso J, Rostagno A. Matrix metalloproteinase 2 (MMP-2) degrades soluble vasculotropic amyloid-beta E22Q and L34V mutants, delaying their toxicity for human brain microvascular endothelial cells. J Biol Chem 2010; 285:27144-27158. [PMID: 20576603 PMCID: PMC2930713 DOI: 10.1074/jbc.m110.135228] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2010] [Revised: 06/21/2010] [Indexed: 11/06/2022] Open
Abstract
Patients carrying mutations within the amyloid-beta (Abeta) sequence develop severe early-onset cerebral amyloid angiopathy with some of the related variants manifesting primarily with hemorrhagic phenotypes. Matrix metalloproteases (MMPs) are typically associated with blood brain barrier disruption and hemorrhagic transformations after ischemic stroke. However, their contribution to cerebral amyloid angiopathy-related hemorrhage remains unclear. Human brain endothelial cells challenged with Abeta synthetic homologues containing mutations known to be associated in vivo with hemorrhagic manifestations (AbetaE22Q and AbetaL34V) showed enhanced production and activation of MMP-2, evaluated via Multiplex MMP antibody arrays, gel zymography, and Western blot, which in turn proteolytically cleaved in situ the Abeta peptides. Immunoprecipitation followed by mass spectrometry analysis highlighted the generation of specific C-terminal proteolytic fragments, in particular the accumulation of Abeta-(1-16), a result validated in vitro with recombinant MMP-2 and quantitatively evaluated using deuterium-labeled internal standards. Silencing MMP-2 gene expression resulted in reduced Abeta degradation and enhanced apoptosis. Secretion and activation of MMP-2 as well as susceptibility of the Abeta peptides to MMP-2 degradation were dependent on the peptide conformation, with fibrillar elements of AbetaE22Q exhibiting negligible effects. Our results indicate that MMP-2 release and activation differentially degrades Abeta species, delaying their toxicity for endothelial cells. However, taking into consideration MMP ability to degrade basement membrane components, these protective effects might also undesirably compromise blood brain barrier integrity and precipitate a hemorrhagic phenotype.
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Affiliation(s)
- Mar Hernandez-Guillamon
- Neurovascular Research Laboratory, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Stephanie Mawhirt
- Department of Pathology, New York University School of Medicine, New York, New York 10016
| | - Silvia Fossati
- Department of Pathology, New York University School of Medicine, New York, New York 10016
| | - Steven Blais
- Department of Pharmacology, , New York University School of Medicine, New York, New York 10016; Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, New York 10016
| | - Mireia Pares
- Neurovascular Research Laboratory, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Anna Penalba
- Neurovascular Research Laboratory, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Merce Boada
- Neurovascular Unit, Department of Neurology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | | | - Thomas A Neubert
- Department of Pharmacology, , New York University School of Medicine, New York, New York 10016; Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, New York 10016
| | - Joan Montaner
- Neurovascular Research Laboratory, Institut de Recerca, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; Neurovascular Unit, Department of Neurology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Jorge Ghiso
- Department of Pathology, New York University School of Medicine, New York, New York 10016; Department of Psychiatry, New York University School of Medicine, New York, New York 10016
| | - Agueda Rostagno
- Department of Pathology, New York University School of Medicine, New York, New York 10016.
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20
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Abstract
Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal cell death are unresolved. Morphological, biochemical, genetic, as well as cell and animal model studies reveal that mitochondria could have roles in this neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations, triggering neurodegeneration according to a cell death matrix theory. In AD, alterations in enzymes involved in oxidative phosphorylation, oxidative damage, and mitochondrial binding of Aβ and amyloid precursor protein have been reported. In PD, mutations in putative mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This review summarizes how mitochondrial pathobiology might contribute to neuronal death in AD, PD, and ALS and could serve as a target for drug therapy.
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21
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Mizoguchi H, Takuma K, Fukuzaki E, Ibi D, Someya E, Akazawa KH, Alkam T, Tsunekawa H, Mouri A, Noda Y, Nabeshima T, Yamada K. Matrix metalloprotease-9 inhibition improves amyloid beta-mediated cognitive impairment and neurotoxicity in mice. J Pharmacol Exp Ther 2009; 331:14-22. [PMID: 19587312 DOI: 10.1124/jpet.109.154724] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
In Alzheimer's disease (AD), the expression of matrix metalloproteases (MMPs), which are capable of degrading extracellular matrix proteins, is increased in the brain. Previous studies with cultured glial cells have demonstrated that amyloid beta (Abeta) protein can induce the expression of MMPs, which could be involved in the degradation of Abeta. In the present study, we investigated the role of MMP-2 and MMP-9 in cognitive impairment induced by the injection of Abeta in mice. The intracerebroventricular injection of Abeta25-35, Abeta1-40, and Abeta1-42, but not Abeta40-1, transiently increased MMP-9, but not MMP-2, activity and protein expression in the hippocampus. Immunohistochemistry revealed the expression of MMP-9 to be increased in both neurons and glial cells in the hippocampus after Abeta treatment. The Abeta-induced cognitive impairment in vivo as well as neurotoxicity in vitro was significantly alleviated in MMP-9 homozygous knockout mice and by treatment with MMP inhibitors. These results suggest the increase in MMP-9 expression in the hippocampus to be involved in the development of cognitive impairment induced by Abeta1-40. Thus, specific inhibitors of MMP-9 may have therapeutic potential for the treatment of AD. Our findings suggest that, as opposed to expectations based on previous findings, MMP-9 plays a causal role in Abeta-induced cognitive impairment and neurotoxicity.
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22
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Douraghi-Zadeh D, Matharu B, Razvi A, Austen B. The protective effects of the nutraceutical, colostrinin, against Alzheimer's disease, is mediated via prevention of apoptosis in human neurones induced by aggregated beta-amyloid. J Nutr Health Aging 2009; 13:522-7. [PMID: 19536420 DOI: 10.1007/s12603-009-0102-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
OBJECTIVE It has previously been demonstrated that oral administration of ovine Colostrinin (CLN), a proline-rich polypeptide isolated from ovine colostrum, can effectively treat Alzheimer's disease patients. This study aims to determine whether CLN has effects on the aggregation and toxicity of synthetic beta-amyloid (Abeta), implicated as a causative agent of AD. DESIGN AND MEASUREMENTS Using cell assays, we examined if pre-treatment of neuronal cells with CLN confers protection. RESULTS The data from cytotoxicity assays (using MTT and LDH) demonstrated that pre-treatment of human neuronal SHSY-5Y cells with 5 microg/ml CLN, for 24 hours, confers neuroprotection against Abeta-induced neurotoxicity. Twenty-four hour pre-treatment with 5 microg/ml CLN was also shown to reduce Abeta 1-40-induced apoptosis in human neuronal cells as determined via qualitative and quantitative apoptosis assays. CONCLUSION The neuroprotection conferred with CLN pre-treatment was reduced with the Fas ligand (FasL) binding antibody Nok1, suggesting that the effects of CLN may involve a Fas:soluble FasL interaction. These findings indicate that CLN could possibly play a role in the prevention of AD pathogenesis, though the inhibition of Fas-mediated apoptosis.
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Affiliation(s)
- D Douraghi-Zadeh
- Neurodegeneration Unit, Basic Medical Sciences, St. George's, University of London, Cranmer Terrace, Tooting, London, UK
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23
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Manicone AM. Role of the pulmonary epithelium and inflammatory signals in acute lung injury. Expert Rev Clin Immunol 2009; 5:63-75. [PMID: 19885383 PMCID: PMC2745180 DOI: 10.1586/177666x.5.1.63] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Acute lung injury (ALI) is a clinical disease marked by respiratory failure due to disruption of the epithelial and endothelial barrier, flooding of the alveolar compartment with protein-rich fluid and recruitment of neutrophils into the alveolar space. ALI affects approximately 200,000 patients annually in the USA and results in approximately 75,000 deaths. It is associated with prolonged mechanical ventilation, intensive medical care, high morbidity and mortality, and rising healthcare costs. Owing to its impact on public health, great strides have been made towards understanding the pathobiology of ALI to affect outcome. This review will focus on the role of the epithelial cell in the pathogenesis and resolution of ALI and the role of various inflammatory mediators in ALI.
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Affiliation(s)
- Anne M Manicone
- Center for Lung Biology, 815, Mercer Street, Box 358050, Seattle, WA 98115, USA,
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24
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Abstract
Human studies and animal models suggest that mechanical as well as biological processes contribute to acute lung injury. While mechanical stresses and bacterial products can directly alter the endothelial and epithelial barriers in the lungs, a growing body of evidence suggests that synergistic interactions between low levels of mechanical stress and bacterial products in the lungs can cause or exacerbate acute lung injury. New approaches to disrupting these synergistic interactions between mechanical stress and innate immunity have the potential to reduce the incidence or improve the outcome of acute lung injury in humans.
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25
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Buxton PG, Bitar M, Gellynck K, Parkar M, Brown RA, Young AM, Knowles JC, Nazhat SN. Dense collagen matrix accelerates osteogenic differentiation and rescues the apoptotic response to MMP inhibition. Bone 2008; 43:377-385. [PMID: 18502716 DOI: 10.1016/j.bone.2008.03.028] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2007] [Revised: 02/28/2008] [Accepted: 03/25/2008] [Indexed: 11/23/2022]
Abstract
Bone is distinguished from other tissues by its mechanical properties, in particular stiffness. However, we know little of how osteoblasts react to the stiffness of their microenvironment; in this study we describe their response to a dense (>10 wt.%) collagenous 3D environment. Primary pre-osteoblasts were seeded within a novel form of native collagen, dense collagen, and cultured for up to 14 days in the presence and absence of osteogenic supplements: analysis was via Q-PCR, histology, fluorescent in situ zymography, MMP loss-of-function and tensile testing. Differentiation as measured through the up-regulation of Bsp (247-fold), Alp (14.2-fold), Col1A1 (4.5-fold), Mmp-13 (8.0-fold) and Runx2 (1.2-fold) transcripts was greatly accelerated compared to 2D plastic at 7 and 14 days in the same medium. The scale of this enhancement was confirmed through the use of growth factor stimulation on 2D via the addition of BMP-6 and the Hedgehog agonist purmorphamine. In concert, these molecules were capable of the same level of osteo-induction (measured by Bsp and Alp expression) as the dense collagen alone. Mineralisation was initially localised to remodelled pericellular regions, but by 14 days embedded cells were discernible within regions of apatite (confirmed by MicroRaman). Tensile testing of the matrices showed that this had resulted in a significant increase in Young's modulus at low strain values, consistent with a stiffening of the matrix. To determine the need for matrix remodelling in the mineralisation event the broad spectrum MMP Inhibitor Ilomastat was used. It was found that in its presence mineralisation could still occur (though serum-specific) and the apoptosis associated with MMP inhibition in hydrated collagen gels was abrogated. Analysis of gene expression indicated that this was due to the up-regulation of Mmp-13 in the presence of Ilomastat in dense collagen (400-fold), demonstrating a powerful feedback loop and a potential mechanism for the rescue from apoptosis. Osteoid-like matrix (dense collagen) is therefore a potent stimulant of osteoblast differentiation in vitro and provides an environment that enables survival and differentiation in the presence of MMP inhibition.
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Affiliation(s)
- P G Buxton
- Biomaterials and Tissue Engineering, UCL Eastman Dental Institute, 256 Gray's Inn Road, London, WC1X 8LD, UK.
| | - M Bitar
- Biomaterials and Tissue Engineering, UCL Eastman Dental Institute, 256 Gray's Inn Road, London, WC1X 8LD, UK; Materials Biology Interactions Group, Swiss Federal Laboratories for Materials Testing and Research (EMPA), Lerchenfeldstr 5, CH-9014 St. Gallen, Switzerland.
| | - K Gellynck
- Biomaterials and Tissue Engineering, UCL Eastman Dental Institute, 256 Gray's Inn Road, London, WC1X 8LD, UK.
| | - M Parkar
- Biomaterials and Tissue Engineering, UCL Eastman Dental Institute, 256 Gray's Inn Road, London, WC1X 8LD, UK.
| | - R A Brown
- UCL Institute of Orthopaedics and Musculoskeletal Science, Royal National Orthopaedic Hospital, Stanmore, London, UK.
| | - A M Young
- Biomaterials and Tissue Engineering, UCL Eastman Dental Institute, 256 Gray's Inn Road, London, WC1X 8LD, UK.
| | - J C Knowles
- Biomaterials and Tissue Engineering, UCL Eastman Dental Institute, 256 Gray's Inn Road, London, WC1X 8LD, UK.
| | - S N Nazhat
- Department of Mining and Materials Engineering, McGill University, Montreal, Quebec, Canada H3A 2B2.
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26
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Murphy G, Murthy A, Khokha R. Clipping, shedding and RIPping keep immunity on cue. Trends Immunol 2008; 29:75-82. [PMID: 18182322 DOI: 10.1016/j.it.2007.10.009] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2007] [Revised: 10/18/2007] [Accepted: 10/23/2007] [Indexed: 01/10/2023]
Abstract
Exposure to infectious agents elicits defense mechanisms that necessitate a timely immune response. The immediate delivery of essential cues for immune activation is provided, in part, by proteolytic processing. A large repertoire of molecules orchestrates the activation, migration, and effector function of immune cells. The diversity of this repertoire matches well with the broad array of substrates that can be cleaved by proteinases, and many of these substrates are proving to be essential for proper immune-cell function. Here, we discuss how two specific classes of metal-dependent proteinases, the matrix metalloproteinases and the disintegrin metalloproteinases, have consequences well beyond classical cell-matrix and cell-cell interactions and motility, and we review their roles in immune-cell maturation, clonal expansion, and cytotoxic functions.
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Affiliation(s)
- Gillian Murphy
- Department of Oncology, University of Cambridge and Cancer Research UK Cambridge Institute, Cambridge, UK.
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27
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Cauwe B, Van den Steen PE, Opdenakker G. The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases. Crit Rev Biochem Mol Biol 2007; 42:113-85. [PMID: 17562450 DOI: 10.1080/10409230701340019] [Citation(s) in RCA: 274] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Matrix metalloproteinases (MMPs) constitute a family of more than 20 endopeptidases. Identification of specific matrix and non-matrix components as MMP substrates showed that, aside from their initial role as extracellular matrix modifiers, MMPs play significant roles in highly complex processes such as the regulation of cell behavior, cell-cell communication, and tumor progression. Thanks to the comprehensive examination of the expanded MMP action radius, the initial view of proteases acting in the soluble phase has evolved into a kaleidoscope of proteolytic reactions connected to the cell surface. Important classes of cell surface molecules include adhesion molecules, mediators of apoptosis, receptors, chemokines, cytokines, growth factors, proteases, intercellular junction proteins, and structural molecules. Proteolysis of cell surface proteins by MMPs may have extremely diverse biological implications, ranging from maturation and activation, to inactivation or degradation of substrates. In this way, modification of membrane-associated proteins by MMPs is crucial for communication between cells and the extracellular milieu, and determines cell fate and the integrity of tissues. Hence, insights into the processing of cell surface proteins by MMPs and the concomitant effects on physiological processes as well as on disease onset and evolution, leads the way to innovative therapeutic approaches for cancer, as well as degenerative and inflammatory diseases.
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Affiliation(s)
- Bénédicte Cauwe
- Rega Institute for Medical Research, Laboratory of Immunobiology, University of Leuven, Leuven, Belgium
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28
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Szklarczyk A, Stins M, Milward EA, Ryu H, Fitzsimmons C, Sullivan D, Conant K. Glial activation and matrix metalloproteinase release in cerebral malaria. J Neurovirol 2007; 13:2-10. [PMID: 17454443 DOI: 10.1080/13550280701258084] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Although neurological symptoms associated with cerebral malaria (CM) are largely reversible, recent studies suggest that lasting neurological sequelae can occur. This may be especially true for children, in whom persistent deficits include problems with memory and attention. Because the malaria parasite is not thought to enter the brain parenchyma, lasting deficits are likely related to factors including the host response to disease. Studies with a rodent model, and with human postmortem tissue, suggest that glial activation occurs with CM. In this review, the authors will highlight studies focused on such activation in CM. Likely causes will be discussed, which include ischemia and activation of blood brain barrier endothelial cells. The potential consequences of glial activation will also be discussed, highlighting the possibility that glial-derived proteinases contribute to structural damage of the central nervous system (CNS). Of note, for the purposes of this focused review, glial activation will refer to the activation of astrocytes and microglial cells; discussion of oligodendroglial cells will not be included. In addition, although events thought to be critical to the pathogenesis of CM and glial activation will be covered, a comprehensive review of cerebral malaria will not be presented. Excellent reviews are already available, including Coltel et al (2004; Curr Neurovasc Res 1: 91-110), Medana and Turner (2006; Int J Parasitol 36: 555-568), and Hunt et al (2006; Int J Parasitol 36: 569-582).
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Affiliation(s)
- A Szklarczyk
- Departments of Neurology, Johns Hopkins University, Baltimore, Maryland 21287, USA
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29
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Li N, Wang Y, Forbes K, Vignali KM, Heale BS, Saftig P, Hartmann D, Black RA, Rossi JJ, Blobel CP, Dempsey PJ, Workman CJ, Vignali DAA. Metalloproteases regulate T-cell proliferation and effector function via LAG-3. EMBO J 2007; 26:494-504. [PMID: 17245433 PMCID: PMC1783452 DOI: 10.1038/sj.emboj.7601520] [Citation(s) in RCA: 198] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2006] [Accepted: 11/30/2006] [Indexed: 11/09/2022] Open
Abstract
Tight control of T-cell proliferation and effector function is essential to ensure an effective but appropriate immune response. Here, we reveal that this is controlled by the metalloprotease-mediated cleavage of LAG-3, a negative regulatory protein expressed by all activated T cells. We show that LAG-3 cleavage is mediated by two transmembrane metalloproteases, ADAM10 and ADAM17, with the activity of both modulated by two distinct T-cell receptor (TCR) signaling-dependent mechanisms. ADAM10 mediates constitutive LAG-3 cleavage but increases approximately 12-fold following T-cell activation, whereas LAG-3 shedding by ADAM17 is induced by TCR signaling in a PKCtheta-dependent manner. LAG-3 must be cleaved from the cell surface to allow for normal T-cell activation as noncleavable LAG-3 mutants prevented proliferation and cytokine production. Lastly, ADAM10 knockdown reduced wild-type but not LAG-3(-/-) T-cell proliferation. These data demonstrate that LAG-3 must be cleaved to allow efficient T-cell proliferation and cytokine production and establish a novel paradigm in which T-cell expansion and function are regulated by metalloprotease cleavage with LAG-3 as its sole molecular target.
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Affiliation(s)
- Nianyu Li
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Yao Wang
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Karen Forbes
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Kate M Vignali
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Bret S Heale
- Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA
| | - Paul Saftig
- The Biochemical Institute, Christian-Albrechts University, Kiel, Germany
| | - Dieter Hartmann
- Department for Human Genetics, KU Leuven and Flanders Interuniversity Institute for Biotechnology (VIB4), Leuven, Belgium
| | - Roy A Black
- Department of Inflammation, Amgen Inc., Seattle, WA, USA
| | - John J Rossi
- Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA
| | - Carl P Blobel
- Arthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Medical College of Cornell University, New York, NY, USA
| | - Peter J Dempsey
- Pacific Northwest Research Institute, Seattle, WA, USA
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Creg J Workman
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Dario A A Vignali
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
- Department of Immunology, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA. Tel.: +1 901 495 2332; Fax: +1 901 495 3107; E-mail:
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30
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Schulte M, Reiss K, Lettau M, Maretzky T, Ludwig A, Hartmann D, de Strooper B, Janssen O, Saftig P. ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death. Cell Death Differ 2007; 14:1040-9. [PMID: 17290285 DOI: 10.1038/sj.cdd.4402101] [Citation(s) in RCA: 143] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
The apoptosis-inducing Fas ligand (FasL) is a type II transmembrane protein that is involved in the downregulation of immune reactions by activation-induced cell death (AICD) as well as in T cell-mediated cytotoxicity. Proteolytic cleavage leads to the generation of membrane-bound N-terminal fragments and a soluble FasL (sFasL) ectodomain. sFasL can be detected in the serum of patients with dysregulated inflammatory diseases and is discussed to affect Fas-FasL-mediated apoptosis. Using pharmacological approaches in 293T cells, in vitro cleavage assays as well as loss and gain of function studies in murine embryonic fibroblasts (MEFs), we demonstrate that the disintegrin and metalloprotease ADAM10 is critically involved in the shedding of FasL. In primary human T cells, FasL shedding is significantly reduced after inhibition of ADAM10. The resulting elevated FasL surface expression is associated with increased killing capacity and an increase of T cells undergoing AICD. Overall, our findings suggest that ADAM10 represents an important molecular modulator of FasL-mediated cell death.
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Affiliation(s)
- M Schulte
- Biochemical Institute, Christian-Albrecht-University, Kiel, Germany
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31
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Verma RP, Hansch C. Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs. Bioorg Med Chem 2007; 15:2223-68. [PMID: 17275314 DOI: 10.1016/j.bmc.2007.01.011] [Citation(s) in RCA: 542] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2006] [Revised: 01/09/2007] [Accepted: 01/11/2007] [Indexed: 12/20/2022]
Abstract
Matrix metalloproteinases (MMPs) are a large family of calcium-dependent zinc-containing endopeptidases, which are responsible for the tissue remodeling and degradation of the extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan. They are regulated by hormones, growth factors, and cytokines, and are involved in ovarian functions. MMPs are excreted by a variety of connective tissue and pro-inflammatory cells including fibroblasts, osteoblasts, endothelial cells, macrophages, neutrophils, and lymphocytes. These enzymes are expressed as zymogens, which are subsequently processed by other proteolytic enzymes (such as serine proteases, furin, plasmin, and others) to generate the active forms. Matrix metalloproteinases are considered as promising targets for the treatment of cancer due to their strong involvement in malignant pathologies. Clinical/preclinical studies on MMP inhibition in tumor models brought positive results raising the idea that the development of strategies to inhibit MMPs may be proved to be a powerful tool to fight against cancer. However, the presence of an inherent flexibility in the MMP active-site limits dramatically the accurate modeling of MMP-inhibitor complexes. The interest in the application of quantitative structure-activity relationships (QSARs) has steadily increased in recent decades and we hope it may be useful in elucidating the mechanisms of chemical-biological interactions for this enzyme. In the present review, an attempt has been made to explore the in-depth knowledge from the classification of this enzyme to the clinical trials of their inhibitors. A total number of 92 QSAR models (44 published and 48 new formulated QSAR models) have also been presented to understand the chemical-biological interactions. QSAR results on the inhibition of various compound series against MMP-1, -2, -3, -7, -8, -9, -12, -13, and -14 reveal a number of interesting points. The most important of these are hydrophobicity and molar refractivity, which are the most important determinants of the activity.
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Affiliation(s)
- Rajeshwar P Verma
- Department of Chemistry, Pomona College, 645 North College Avenue, Claremont, CA 91711, USA.
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32
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Ethell DW, Shippy D, Cao C, Cracchiolo JR, Runfeldt M, Blake B, Arendash GW. Aβ-specific T-cells reverse cognitive decline and synaptic loss in Alzheimer's mice. Neurobiol Dis 2006; 23:351-61. [PMID: 16733088 DOI: 10.1016/j.nbd.2006.03.008] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2006] [Revised: 02/28/2006] [Accepted: 03/31/2006] [Indexed: 10/24/2022] Open
Abstract
Active and passive Abeta immunotherapy provide behavioral benefits in AD transgenic mice, but they can also induce adverse immune over-activation and neuropathological effects. Here, we show that a restricted Abeta-specific immune re-activation can provide cognitive and pathological benefits to APPsw + PS1 transgenic mice for at least 2 1/2 months. A single infusion of Abeta-specific immune cells from Abeta-vaccinated littermates improved performance in cognitively impaired APP + PS1 mice. Recipients had lower levels of soluble Abeta in the hippocampus, less plaque-associated microglia, and more intense synaptophysin immunoreactivity, compared with untreated controls. However, Abeta-specific infusates enriched for Th1 or depleted of CD4(+) T-cells were not effective, nor were ovalbumin-specific infusates. These benefits occurred without global or brain-specific inflammatory responses. Chronically high levels of Abeta can cause immune tolerance, hypo-responsiveness, or anergy to Abeta, but our findings demonstrate that Abeta-specific immune cells can resume endogenous Abeta-lowering processes and may be an effective Abeta therapeutic.
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Affiliation(s)
- Douglas W Ethell
- Biomedical Sciences, University of California Riverside, 92521-0121, USA.
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33
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Song JH, Bellail A, Tse MCL, Yong VW, Hao C. Human astrocytes are resistant to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. J Neurosci 2006; 26:3299-308. [PMID: 16554480 PMCID: PMC6674086 DOI: 10.1523/jneurosci.5572-05.2006] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Human astrocytes express Fas yet are resistant to Fas-induced apoptosis. Here, we report that calcium/calmodulin-dependent protein kinase II (CaMKII) is constitutively activated in human astrocytes and protects the cells from apoptotic stimulation by Fas agonist. Once stimulated, Fas recruits Fas-associated death domain and caspase-8 for the assembly of the death-inducing signaling complex (DISC); however, caspase-8 cleavage is inhibited in the DISC. Inhibition of CaMKII kinase activity inhibits the expression of phosphoprotein enriched astrocytes-15 kDa/phosphoprotein enriched in diabetes (PEA-15/PED) and cellular Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein (c-FLIP), thus releasing their inhibition of caspase-8 cleavage. Inhibition of PEA-15/PED or c-FLIP by small interfering RNA sensitizes human astrocytes to Fas-induced apoptosis. In contrast, inhibition of CaMKII, PEA-15, or c-FLIP does not affect the sensitivity of human astrocytes to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL death receptors (DR4, DR5) are weakly expressed at mRNA, protein, and cell surface levels and thus fail to mediate the assembly of the DISC in human astrocytes. Overexpression of DR5 restores TRAIL signaling pathways and sensitizes the human astrocytes to TRAIL-induced apoptosis if CaMKII kinase activity or expression of PEA-15 and c-FLIP is inhibited; the results suggest that CaMKII-mediated pathways prevent TRAIL-induced apoptosis in human astrocytes under conditions in which TRAIL death receptors are upregulated. This study has therefore identified the molecular mechanisms that protect normal human astrocytes from apoptosis induced by Fas ligand and TRAIL.
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34
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Bilousova TV, Rusakov DA, Ethell DW, Ethell IM. Matrix metalloproteinase-7 disrupts dendritic spines in hippocampal neurons through NMDA receptor activation. J Neurochem 2006; 97:44-56. [PMID: 16515559 PMCID: PMC3369267 DOI: 10.1111/j.1471-4159.2006.03701.x] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Dendritic spines are protrusions from the dendritic shaft that host most excitatory synapses in the brain. Although they first emerge during neuronal maturation, dendritic spines remain plastic through adulthood, and recent advances in the molecular mechanisms governing spine morphology have shown them to be exquisitely sensitive to changes in the micro-environment. Among the many factors affecting spine morphology are components and regulators of the extracellular matrix (ECM). Modification of the ECM is critical to the repair of injuries throughout the body, including the CNS. Matrix metalloproteinase (MMP)-7/matrilysin is a key regulator of the ECM during pathogen infection, after nerve crush and in encephalitogenic disorders. We have investigated the effects of MMP-7 on dendritic spines in hippocampal neuron cultures and found that it induces the transformation of mature, short mushroom-shaped spines into long, thin filopodia reminiscent of immature spines. These changes were accompanied by a dramatic redistribution of F-actin from spine heads into thick, rope-like structures in the dendritic shaft. Strikingly, MMP-7 effects on dendritic spines were similar to those of NMDA treatment, and both could be blocked by channel-specific antagonists. These findings are the first direct evidence that MMPs can influence the morphology of mature dendritic spines, and hence synaptic stability.
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Affiliation(s)
- Tina V Bilousova
- Division of Biomedical Sciences, University of California Riverside, California 92521-0121, USA
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35
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Endres K, Postina R, Schroeder A, Mueller U, Fahrenholz F. Shedding of the amyloid precursor protein-like protein APLP2 by disintegrin-metalloproteinases. FEBS J 2005; 272:5808-20. [PMID: 16279945 DOI: 10.1111/j.1742-4658.2005.04976.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Cleavage of the amyloid precursor protein (APP) within the amyloid-beta (Abeta) sequence by the alpha-secretase prevents the formation of toxic Abeta peptides. It has been shown that the disintegrin-metalloproteinases ADAM10 and TACE (ADAM17) act as alpha-secretases and stimulate the generation of a soluble neuroprotective fragment of APP, APPsalpha. Here we demonstrate that the related APP-like protein 2 (APLP2), which has been shown to be essential for development and survival of mice, is also a substrate for both proteinases. Overexpression of either ADAM10 or TACE in HEK293 cells increased the release of neurotrophic soluble APLP2 severalfold. The strongest inhibition of APLP2 shedding in neuroblastoma cells was observed with an ADAM10-preferring inhibitor. Transgenic mice with neuron-specific overexpression of ADAM10 showed significantly increased levels of soluble APLP2 and its C-terminal fragments. To elucidate a possible regulatory mechanism of APLP2 shedding in the neuronal context, we examined retinoic acid-induced differentiation of neuroblastoma cells. Retinoic acid treatment of two neuroblastoma cell lines upregulated the expression of both APLP2 and ADAM10, thus leading to an increased release of soluble APLP2.
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Affiliation(s)
- Kristina Endres
- Institute of Biochemistry, Johannes Gutenberg-University Mainz, Germany
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36
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Mannello F, Luchetti F, Falcieri E, Papa S. Multiple roles of matrix metalloproteinases during apoptosis. Apoptosis 2005; 10:19-24. [PMID: 15711919 DOI: 10.1007/s10495-005-6058-7] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Structural, molecular and biochemical approaches have contributed to piecing together the puzzle of how matrix metalloproteinases (MMPs) work and contribute to various disease processes. However, MMPs have many unexpected substrates other than components of the extracellular matrix which profoundly influence cell behaviour, survival and death. With the current understanding of diverse/novel roles of matrix metalloproteinases--particularly their direct or indirect relevance for the early steps during programmed cell death--some seemingly contrasting results seem less surprising. To better target MMPs an appreciation of their many extracellular, intracellular and intranuclear functions, often acting in opposing directions with paradoxical roles in cell death, is carefully required.
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Affiliation(s)
- F Mannello
- Istituto di Istologia ed Analisi di Laboratorio, ITOI-CNR, Istituti Ortopedici Rizzoli, Bologna, Italy.
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37
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Abstract
While defective apoptosis predisposes to neoplasia, inappropriate apoptosis in the brain leads to permanent neurological deficits. Disregulated apoptosis has been implicated in several neurodegenerative disorders including Alzheimer's, Parkinson's, and Huntington's diseases. Recent reports have suggested that the key apoptosis regulator Fas ligand (FasL) may participate in both neuronal and immune cell apoptosis in Alzheimer's disease. FasL has also been implicated as a negative regulator for the inflammatory component of the demyelinating brain disorder multiple sclerosis (MS). Here we discuss how FasL-mediated apoptosis may balance immune cell access to the brain with Alzheimer's disease and MS representing extremes of too little and too much immune access, respectively.
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Affiliation(s)
- Douglas W Ethell
- Division of Biomedical Sciences, University of California Riverside, Riverside, California, USA.
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38
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Ding X, Yang LY, Huang GW, Wang W, Lu WQ. ADAM17 mRNA expression and pathological features of hepatocellular carcinoma. World J Gastroenterol 2004; 10:2735-9. [PMID: 15309730 PMCID: PMC4572204 DOI: 10.3748/wjg.v10.i18.2735] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To study the expression of a disintegrin and metalloproteinase 17 (ADAM17) mRNA in hepatocellular carcinoma (HCC) and to evaluate the relationship between ADAM17 mRNA expression and clinicopathological features of HCC.
METHODS: Hepatocellular carcinomas (HCC) from 31 cases were divided into small HCC (SHCC), nodular HCC (NHCC) and solitary large HCC (SLHCC) according to tumor diameter and the number of nodes. ADAM17 mRNA expressions were compared among those groups by means of semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). The relationship between ADAM17 mRNA expression level and clinicopathological features of HCC was evaluated.
RESULTS: NHCC had lower differentiation and was more frequently of microvascular invasion (10/12) than SHCC (3/11) and SLHCC (3/8) (P < 0.05), but no statistical difference was observed between SHCC and SLHCC comparing their clinicopathological features. ADAM17 mRNA expression was detected in 77.4% (24/31) of HCC tissues and was significantly higher than that in paired non-cancerous liver tissues in which only 35.5% (11/31) of the samples were detected of the expression (P < 0.05). The expression of ADAM17 mRNA was much higher in NHCC than in SHCC and SLHCC (P < 0.05), while no significant difference was discovered between SHCC and SLHCC. The quantities of ADAM17 mRNA were significantly higher in poorly differentiated HCC than in well or moderately differentiated HCC, but no statistical difference was found concerning liver cirrhosis, tumor capsule formation or microvascular invasion of the cancer.
CONCLUSION: The increased expression of ADAM17 may play a key role in the development of HCC. The expression levels of ADAM17 mRNA varied among different pathological types of HCC. Lower mRNA expression of ADAM17 mRNA in SLHCC may be associated with the better molecular pathological features of SLHCC.
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Affiliation(s)
- Xiang Ding
- Liver Cancer Laboratory, Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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39
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Abstract
While defective apoptosis predisposes to neoplasia, inappropriate apoptosis in the brain leads to permanent neurological deficits. Disregulated apoptosis has been implicated in several neurodegenerative disorders including Alzheimer's, Parkinson's, and Huntington's diseases. Recent reports have suggested that the key apoptosis regulator Fas ligand (FasL) may participate in both neuronal and immune cell apoptosis in Alzheimer's disease. FasL has also been implicated as a negative regulator for the inflammatory component of the demyelinating brain disorder multiple sclerosis (MS). Here, we discuss how FasL-mediated apoptosis may balance immune cell access to the brain with Alzheimer's disease and MS representing extremes of too little and too much immune access, respectively.
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Affiliation(s)
- Douglas W Ethell
- Division of Biomedical Sciences, University of California-Riverside, 900 University Avenue, Riverside, California 92521-0121, USA.
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40
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Falsig J, Pörzgen P, Leist M. Modification of apoptosis-related genes and CD95 signaling in cytokine-treated astrocytes. ACTA ACUST UNITED AC 2004. [DOI: 10.1002/sita.200400031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Wielockx B, Libert C, Wilson C. Matrilysin (matrix metalloproteinase-7): a new promising drug target in cancer and inflammation? Cytokine Growth Factor Rev 2004; 15:111-5. [PMID: 15110795 DOI: 10.1016/j.cytogfr.2003.12.001] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Matrilysin or MMP-7, one of the smallest of all known matrix metalloproteinases (MMPs), has been studied extensively in many different tumor types, since its discovery more than 20 years ago. However, research during the past several years has revealed that this protease also plays an essential role in innate immunity, and, more particularly, in inflammatory disorders.
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Affiliation(s)
- Ben Wielockx
- Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology, Ghent University, Ghent (Zwijnaarde), Belgium
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42
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Crocker SJ, Pagenstecher A, Campbell IL. The TIMPs tango with MMPs and more in the central nervous system. J Neurosci Res 2004; 75:1-11. [PMID: 14689443 DOI: 10.1002/jnr.10836] [Citation(s) in RCA: 99] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The matrix metalloproteinases (MMPs) are a family of zinc-dependent extracellular proteases that have been implicated in CNS development and disease. Crucial homeostatic regulation of MMPs is mediated through the expression and actions of the tissue inhibitors of metalloproteinases (TIMPs). Although the TIMPs are recognized inhibitors of the MMPs, recent studies have revealed that these proteins also can exhibit biological activities that are distinct from their interactions with or inhibition of the MMPs. With our understanding of the roles of the TIMPs in the CNS continuously emerging, this review examines the current state of knowledge regarding the multifarious and novel functions of this family of proteins, with particular attention to their increasing potential in the development, plasticity, and pathology of the CNS.
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Affiliation(s)
- Stephen J Crocker
- Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA
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43
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Rivera S, Jourquin J, Ogier C, Bernard A, Charton G, Tremblay E, Khrestchatisky M. Le système MMP/TIMP dans le système nerveux. Med Sci (Paris) 2004; 20:55-60. [PMID: 14770364 DOI: 10.1051/medsci/200420155] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
The matrix metalloproteinases (MMP) belong to a growing family of secreted or membrane-bound (MT-MMP) enzymes that cleave protein components of the extracellular matrix and bioactive factors involved in intercellular signaling. MMP activity is counterbalanced by their four physiological inhibitors, the tissue inhibitors of MMP (TIMPs). Together, MMP and TIMP control cell-cell and cell-matrix interactions associated with physiological processes. However, the breakdown of the protease-inhibitor balance may lead to the loss of tissue homeostasis and the development of degenerative and tumorigenic processes in various tissues. The emerging idea is that the MMP/TIMP system also plays a major role in the pathology and physiology of the nervous system and that mastering MMP activity will set the basis for new and more efficient therapeutic strategies against nervous system disorders.
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Affiliation(s)
- Santiago Rivera
- Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, FRE Cnrs 2533, Université de la Méditerranée, Faculté de Médecine de Marseille, IFR Jean Roche, boulevard Pierre Dramard, 13916 Marseille 20, France
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44
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Bergmeier W, Burger PC, Piffath CL, Hoffmeister KM, Hartwig JH, Nieswandt B, Wagner DD. Metalloproteinase inhibitors improve the recovery and hemostatic function of in vitro-aged or -injured mouse platelets. Blood 2003; 102:4229-35. [PMID: 12907434 DOI: 10.1182/blood-2003-04-1305] [Citation(s) in RCA: 135] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Platelet transfusions are a crucial component of support for patients with severe thrombocytopenia. Storage of platelet concentrates, however, is associated with a reduction in platelet posttransfusion recovery and hemostatic function. In this study, we established a model of mitochondrial injury that resembles platelet storage lesion. Mitochondrial injury, provoked by incubation of platelets with carbonyl cyanide m-chlorophenylhydrazone (CCCP), led to reduced posttransfusion recovery in mice, an effect that directly correlated with the duration of treatment. Damaged platelets were characterized by shape change, disruption of membrane asymmetry, surface expression of P-selectin, and profound proteolysis of GPIbalpha. Using our model, we identified a key role for endogenous metalloproteinase(s) in platelet clearance, as their inhibition markedly improved posttransfusion recovery of both the mitochondria-injured and in vitro-aged mouse platelets. Metalloproteinase inhibition also prevented proteolysis of GPIbalpha on damaged platelets, thereby improving the hemostatic function of these cells in vivo. We propose that inhibition of metalloproteinase activity during storage could significantly improve the effectiveness of platelet transfusions. Surface expression of GPIbalpha might be a powerful marker to determine the quality of platelet concentrates, because it reflects metalloproteinase activity in vitro.
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Affiliation(s)
- Wolfgang Bergmeier
- The CBR Institute for Biomedical Research, Inc., 800 Huntington Ave, Boston, MA 02115, USA
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45
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Abstract
A properly functioning immune system is dependent on programmed cell death at virtually every stage of lymphocyte development and activity. This review addresses the phenomenon of activation-induced cell death (AICD) in T lymphocytes, in which activation through the T-cell receptor results in apoptosis. AICD can occur in a cell-autonomous manner and is influenced by the nature of the initial T-cell activation events. It plays essential roles in both central and peripheral deletion events involved in tolerance and homeostasis, although it is likely that different forms of AICD proceed via different mechanisms. For example, while AICD in peripheral T cells is often caused by the induction of expression of the death ligand, Fas ligand (CD95 ligand, FasL), it does not appear to be involved in AICD in thymocytes. This and other mechanisms of AICD are discussed. One emerging model that may complement other forms of AICD involves the inducible expression of FasL by nonlymphoid tissues in response to activated T lymphocytes. Induction of nonlymphoid FasL in this manner may serve as a sensing mechanism for immune cell infiltration, which contributes to peripheral deletion.
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Affiliation(s)
- Douglas R Green
- La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
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46
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