Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer's disease.

Vodovotz, Yoram; Lucia, M. Scott; Flanders, K. C.; Chesler, Louis; Xie, Qiao-wen; Smith, Thomas W.; Weidner, Jeffrey R.; Mumford, Richard A.; Webber, Robert J.; Nathan, Carl; Roberts, Anita B.; Lippa, C F; Sporn, Michael B.

doi:10.1084/jem.184.4.1425

Cited by 264 publications

(179 citation statements)

References 30 publications

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“…Antibodies-1E8-B8 (Research and Diagnostic Antibodies) is a monoclonal antibody specific for the iNOS isoform and can detect both human and murine iNOS (8,14). The monoclonal antibody against glyceraldehyde-3-phosphate dehydrogenase was from Advanced Immunochemical.…”

Section: Methodsmentioning

confidence: 99%

Inducible Nitric-oxide Synthase Is Regulated by the Proteasome Degradation Pathway

Musial

Eissa

2001

Journal of Biological Chemistry

142

103

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Inducible nitric-oxide synthase (iNOS) is responsible for nitric oxide (NO) synthesis from L-arginine in response to inflammatory mediators. To determine the degradation pathway of iNOS, human epithelial kidney HEK293 cells with stable expression of human iNOS were incubated in the presence of various degradation pathway inhibitors. Treatment with the proteasomal inhibitors lactacystin, MG132, and N-acetyl-L-leucinyl-Lleucinyl-L-norleucinal resulted in the accumulation of iNOS, indicating that these inhibitors blocked its degradation. Moreover, proteasomal inhibition blocked iNOS degradation in a dose-and time-dependent manner as well as when NO synthesis was inhibited by N -nitro-Larginine methyl ester. Furthermore, proteasomal inhibition blocked the degradation of an iNOS splice variant that lacked the capacity to dimerize and of an iNOS mutant that lacks L-arginine binding ability, suggesting that iNOS is targeted by proteasomes, notwithstanding its capacity to produce NO, dimerize, or bind the substrate. In contrast to proteasomal inhibitors, the calpain inhibitor calpastatin and the lysosomal inhibitors transepoxysuccinyl-L-leucylamido-4-guanidino butane, leupeptin, pepstatin-A, chloroquine, and NH 4 Cl did not lead to significant accumulation of iNOS. Interestingly, when cytokines were used to induce iNOS in RT4 human epithelial cells, the effect of proteasomal inhibition was dichotomous. Lactacystin added prior to cytokine stimulation prevented iNOS induction by blocking the degradation of the NF-B inhibitor IB-␣, thus preventing activation of NF-B. In contrast, lactacystin added 48 h after iNOS induction led to the accumulation of iNOS. Similarly, in murine macrophage cell line RAW 264.7, lactacystin blocked iNOS degradation when added 48 h after iNOS induction by lipopolysaccharide. These data identify the proteasome as the primary degradation pathway for iNOS. Nitric oxide (NO),1 an important signaling and cytotoxic molecule, is synthesized from L-arginine by isoforms of nitricoxide synthase (NOS) (1, 2). As a signaling molecule, NO is produced by two constitutive Ca 2ϩ -dependent isoforms, neuronal and endothelial NOS (or NOS1 and NOSIII, respectively). Ca 2ϩ -activated calmodulin binds to and transiently activates constitutive NOS dimers (2, 3). Because of the transient nature of elevated Ca 2ϩ levels, the activity of NO produced is shortlived. As an agent of inflammation and cell-mediated immunity, NO is produced by a Ca 2ϩ -independent cytokine-inducible NOS (iNOS or NOSII) that is widely expressed in diverse cell types under transcriptional regulation by inflammatory mediators (4 -6). Calmodulin is tightly bound to iNOS even at basal Ca 2ϩ levels, and therefore iNOS is notably distinguished from the constitutive isoforms by its prolonged production of a relatively large amount of NO (7). iNOS has been implicated in the pathogenesis of many diseases including Alzheimer's disease, pulmonary tuberculosis, asthma, lung cancer, transplant rejection, cerebral infarct, glaucoma, bacterial pneumonia, infl...

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Section: Methodsmentioning

confidence: 99%

Inducible Nitric-oxide Synthase Is Regulated by the Proteasome Degradation Pathway

Musial

Eissa

2001

Journal of Biological Chemistry

142

103

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“…For examples, neurons can produce COX-2-derived prostanoids (Davis and Laroche 2003;Natarajan and Bright 2002;Pavlov and Tracey 2005), several cytokines such as IL-1b and IL-18 (de Rivero Vaccari et al 2008;Fann et al 2013;Zou and Crews 2012), complement and macrophage colony-stimulating factor (Du Yan et al 1997). Moreover, in the brain of AD individuals, an inflammation-induced enzyme named iNOS has been reported to be expressed by degenerating neurons (Heneka et al 2001;Lee et al 1999;Vodovotz et al 1996).…”

Section: Neuronmentioning

confidence: 99%

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Zhang

et al. 2015

Arch. Immunol. Ther. Exp.

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Alzheimer's disease (AD) is a complex agerelated neurodegenerative disorder of the central nervous system. Since the first description of AD in 1907, many hypotheses have been established to explain its causes. The inflammation theory is one of them. Pathological and biochemical studies of brains from AD individuals have provided solid evidence of the activation of inflammatory pathways. Furthermore, people with long-term medication of anti-inflammatory drugs have shown a reduced risk to develop the disease. After three decades of genetic study in AD, dozens of loci harboring genetic variants influencing inflammatory pathways in AD patients has been identified through genome-wide association studies (GWAS). The most well-known GWAS risk factor that is responsible for immune response and inflammation in AD development should be APOE e4 allele. However, a growing number of other GWAS risk AD candidate genes in inflammation have recently been discovered. In the present study, we try to review the inflammation in AD and immunity-associated GWAS risk genes like HLA-DRB5/DRB1, INPP5D, MEF2C, CR1, CLU and TREM2.

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“…10,12 Since ASK1 has been suggested to be involved in NO-induced death of PC12 cells, 28 we examined whether Ab-induced ASK1 activation is mediated by NO. Treatment of PC12 cells with NOR1, an NO donor that can spontaneously release NO, strongly activated endogenous ASK1, whereas L-NAME (inhibitor of NO formation by NOS) had only a marginal effect on Ab-induced ASK1 activation (Figure 3a).…”

Section: Ros Mediates Ab-induced Ask1 Activationmentioning

confidence: 99%

“…Pathologic studies have suggested a functional link between NO and AD, in that neurofibrillary tangles in AD brain contain inducible NOS and exhibit nitrotyrosine formation in proteins. 10,11 Induction of neurotoxicity by FAD-linked mutations of PS1 is inhibited by NOS inhibitors. 12 These findings suggest that ROS and NO may be important mediators of Ab-induced neuronal cell death in the development of AD.…”

Section: Introductionmentioning

confidence: 99%

Amyloid β induces neuronal cell death through ROS-mediated ASK1 activation

et al. 2004

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Amyloid b (Ab) is a main component of senile plaques in Alzheimer's disease and induces neuronal cell death. Reactive oxygen species (ROS), nitric oxide and endoplasmic reticulum (ER) stress have been implicated in Ab-induced neurotoxicity. We have reported that apoptosis signalregulating kinase 1 (ASK1) is required for ROS-and ER stress-induced JNK activation and apoptosis. Here we show the involvement of ASK1 in Ab-induced neuronal cell death. Ab activated ASK1 mainly through production of ROS but not through ER stress in cultured neuronal cells. Importantly, ASK1 À/À neurons were defective in Ab-induced JNK activation and cell death. These results indicate that ROS-mediated ASK1 activation is a key mechanism for Ab-induced neurotoxicity, which plays a central role in Alzheimer's disease.

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Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer's disease.

Cited by 264 publications

References 30 publications

Inducible Nitric-oxide Synthase Is Regulated by the Proteasome Degradation Pathway

Inducible Nitric-oxide Synthase Is Regulated by the Proteasome Degradation Pathway

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Amyloid β induces neuronal cell death through ROS-mediated ASK1 activation

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