Novel differential interaction of TNF receptor subtypes with Alzheimer's amyloid-β-peptide signals neuron death and survival (original) (raw)
Related papers
Journal of Biological Chemistry, 1996
The inducible isoform II of nitric-oxide synthase (iNOS) was recently cloned from brain and identified in astroglial cells. Induced nitric oxide biosynthesis occurs in brain cells only if extracellular cerebrospinal fluid contains L-arginine. This study demonstrates for the first time that induced iNOS activity is strictly dependent on concomitant induction of an alternatively spliced transcript of the cat-2 gene encoding high affinity Larginine transporter System y ؉ in cultured rat astrocytes. Inhibition profiles of radiolabeled L-arginine and L-leucine uptake identified the dominance of Na ؉-independent transport System y ؉ serving cationic amino acids, with insignificant activities of Systems y ؉ L, b o,؉ , or B o,؉. A reverse transcription-polymerase chain reaction/sequencing/cloning strategy was used to identify a single 123-base nucleotide sequence coding the high affinity domain of alternatively spliced CAT-2 (not CAT-2a) in astrocytes activated by lipopolysaccharide/interferon-␥. Using this sequence as a cDNA probe, it was determined that CAT-2 mRNA, iNOS mRNA, and System y ؉ activity were concomitantly and strongly induced in astrocytes. Constitutive CAT-1 mRNA was weakly present in neurons and astrocytes, was not inducible in either cell type, and contributed <3% to total System y ؉ activity. Although astroglial iNOS K m ϳ 10 M L-arginine for intracellular substrate, hyperbolic kinetics of inducible iNOS activity measured as a function of extracellular L-arginine concentration gave K m ϳ50 M L-arginine with intact cells. The same K m ϳ 50 M was obtained for induced membrane transport System y ؉ activity. iNOS activity was reduced to zero in the absence of extracellular L-arginine uptake via System y ؉. These findings expand the current understanding of NO biosynthesis modulation and implicate a coordinated regulation of intracellular iNOS enzyme activity with membrane Larginine transport in brain.
Neurobiology of Aging, 2002
The mechanism linking the APOE4 gene with increased susceptibility for Alzheimer's disease (AD) and poorer outcomes following closed head injury and stroke is unknown. One potential link is activation of the innate immune system in the CNS. Our previously published data demonstrated that apolipoprotein E regulates production of nitric oxide, a critical cytoactive factor released by immune active macrophages. To determine if immune regulation is different in the presence of apolipoprotein E4 compared to apolipoprotein E3, we have measured NO production by peritoneal and CNS macrophages (microglia) cultured from transgenic mice that only express the human apoE4 or apoE3 protein isoform. Significantly more NO was produced in APOE4 mice compared to APOE3 transgenic mice that only express human apoE3 protein. Similarly, monocyte derived macrophages from humans carrying APOE4 gene alleles also produce significantly greater NO than those individuals with APOE3. The mechanism for this isoform-specific difference in NO production is not known and multiple sites in the NO production pathway may be affected. Expression of inducible nitric oxide synthase (iNOS) mRNA and protein are not significantly different between the APOE3 and APOE4 mice, suggesting that induction of iNOS is not a primary cause of the increased NO production in APOE4 animals. One alternative regulatory mechanism that demonstrates isoform specificity is arginine transport, which is greater in microglia from APOE4 transgenic mice compared to microglia from APOE3 mice. Increased transport is consistent with an increased production of NO and may reflect a direct or indirect effect of the APOE genotype on microglial arginine uptake and microglial activation in general. Overall, greater NO production in APOE4 carriers where characteristically high levels of oxidative/nitrosative stress are found in diseases such as AD provides a mechanism that potentially explains the genetic association between APOE4 and human diseases.
Brain research
Role of nitric oxide (NO) in inflammationary diseases such as multiple sclerosis (MS) has been proposed previously. We sought to examine if NO plays centrally a key role in MS related phenomena; demyelination or neuroinflammation. Female Wistar rats (weighing 200-250 g) were mounted in a stereotaxic apparatus and received injections of l-arginine aimed at corpus callosum (AP: 1.2, L: ±1.8, V: 3.2). The drug (50-200 μg/rat) was microinjected intra-corpus callosum repeatedly (3-5 times/each per day). Control groups solely received saline (1 μg/rat) into the corpus callosum. The animals were tested for the novelty seeking behavior using the conditioning task. Memory impairment was examined using the shuttle box and Y-maze. l-NAME was pre-injected to l-arginine to involve the NO. All animals' brains were also processed for histological evaluation. l-arginine produced significant changes in the novelty seeking behavior but not in the memory formation, evidenced by passive avoidance a...
Experimental Neurology, 2007
Argininosuccinate-synthetase (ASS), argininosuccinate-lyase (ASL) and nitric oxide synthase (NOS) act in the l-arginine-NO-l-citrulline cycle. In the rat brain, ASS is expressed in neurons, ASL in neurons and astroglia in the striatum, both are co-expressed with nNOS in medium-sized neurons. Microglia cells express iNOS and ASS after activation but no information is available on ASL and on ASS/ASL/iNOS co-expression in this glial population. The present aim was to ascertain, by immunohistochemistry, whether the microglia cells of the rat striatum and fronto-parietal cortex express ASL and ASS in control conditions and after transient ischemia induced by middle cerebral artery occlusion, and whether ASL and ASS are co-expressed with iNOS. The study was conducted 24, 72 and 144 h after reperfusion in two groups of ischemic rats with different tissue damage and survival. ASS and ASL are not expressed by microglia cells in controls while are present in most of the activated microglia cells in the ischemic rats. In those animals with longer survival, ASS and ASL were no more detectable at 144 h, while, in the animals with shorter survival, they were co-expressed with iNOS, but only at 72 h. In the cortex, at variance with the striatum, almost all of nNOS-positive neurons co-expressed ASS and ASL. In conclusion, only activated microglia cells express ASS and ASL, this expression precedes that of iNOS and does not necessarily imply its appearance. Therefore, local factors such as the NO produced by nNOS/ASS/ASL-positive neurons, could influence ASS/ASL-positive microglia cells avoiding or allowing the induction, in these cells, of iNOS.
1995
Background: Activation of glial cells, including astrocytes and microglia, has been implicated in the inflammatory responses underlying brain injury and neurodegenerative diseases including Alzheimer's and Parkinson's diseases. Although cultured astrocytes and microglia are capable of responding to pro-inflammatory cytokines and lipopolysaccharide (LPS) in the induction and release of inflammatory factors, no detailed analysis has been carried out to compare the induction of iNOS and sPLA2-IIA. In this study, we investigated the effects of cytokines (TNFalpha, IL-1beta, and IFN-gamma) and LPS + IFN-gamma to induce temporal changes in cell morphology and induction of p-ERK1/2, iNOS and sPLA 2-IIA expression in immortalized rat (HAPI) and mouse (BV-2) microglial cells, immortalized rat astrocytes (DITNC), and primary microglia and astrocytes. Methods/Results: Cytokines (TNF-alpha, IL-1beta, and IFN-gamma) and LPS + IFN-gamma induced a timedependent increase in fine processes (filopodia) in microglial cells but not in astrocytes. Filopodia production was attributed to IFN-gamma and was dependent on ERK1/2 activation. Cytokines induced an early (15 min) and a delayed phase (1~4 h) increase in p-ERK1/2 expression in microglial cells, and the delayed phase increase corresponded to the increase in filopodia production. In general, microglial cells are more active in responding to cytokines and LPS than astrocytes in the induction of NO. Although IFN-gamma and LPS could individually induce NO, additive production was observed when IFN-gamma was added together with LPS. On the other hand, while TNF-alpha, IL-1beta, and LPS could individually induce sPLA 2-IIA mRNA and protein expression, this induction process does not require IFN-gamma. Interestingly, neither rat immortalized nor primary microglial cells were capable of responding to cytokines and LPS in the induction of sPLA2-IIA expression. Conclusion: These results demonstrated the utility of BV-2 and HAPI cells as models for investigation on cytokine and LPS induction of iNOS, and DITNC astrocytes for induction of sPLA2-IIA. In addition, results further demonstrated that cytokine-induced sPLA2-IIA is attributed mainly to astrocytes and not microglial cells.
L-arginine transport is increased in macrophages generating nitric oxide
Biochemical …, 1992
Transport of L-arginine and nitrite production were examined in the murine macrophage cell line J774. Bacterial lipopolysaccharide (LPS) induced a doseand time-dependent stimulation of nitrite production, which was further increased in the presence of interferon-y. Nitrite synthesis was absolutely dependent on extracellular L-arginine and inhibited in the presence of L-lysine or L-ornithine. In unactivated J774 cells L-arginine transport was saturable, with an apparent Km of 0. 14 + 0.04 mm and Vma. of 15 + 2 nmol/h per 106 cells. LPS (1 ,ug/ml) induced a time-dependent stimulation of L-arginine transport, and after 24 h the Vm.. increased to 34 + 2 nmol/h per 106 cells. These findings indicate that activation of J774 cells with LPS produces an increase in both L-arginine transport and nitrite synthesis. The elevated rate of L-arginine transport in activated J774 cells may provide a mechanism for sustained substrate supply during enhanced utilization of L-arginine for the generation of NO.
Arginine deprivation and immune suppression in a mouse model of Alzheimer's disease
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015
The pathogenesis of Alzheimer's disease (AD) is a critical unsolved question; and although recent studies have demonstrated a strong association between altered brain immune responses and disease progression, the mechanistic cause of neuronal dysfunction and death is unknown. We have previously described the unique CVN-AD mouse model of AD, in which immune-mediated nitric oxide is lowered to mimic human levels, resulting in a mouse model that demonstrates the cardinal features of AD, including amyloid deposition, hyperphosphorylated and aggregated tau, behavioral changes, and age-dependent hippocampal neuronal loss. Using this mouse model, we studied longitudinal changes in brain immunity in relation to neuronal loss and, contrary to the predominant view that AD pathology is driven by proinflammatory factors, we find that the pathology in CVN-AD mice is driven by local immune suppression. Areas of hippocampal neuronal death are associated with the presence of immunosuppressive C...
The Metabolic Coupling of Arginine Metabolism to Nitric Oxide Generation by Astrocytes
Antioxidants & Redox Signaling, 2006
Arginine, the only known precursor of nitric oxide, enters the brain parenchyma from the blood through the endothelial cells or from the cerebral spinal fluid through the ependymal cells. Astrocytes, whose processes abut the endothelium and ependymum, take up arginine through cationic amino acid transporters and release arginine through this transport system to the synapses that astrocytes shield. Some of these synapses are excitatory, and liberate glutamate into the synaptic cleft. Glutamate induces arginine release from astrocytes, making it available to the neuron. Neurons can take up arginine to be used in nitric oxide-mediated processes, such as neurotransmission. Thus, neural and nonneural cells act in concert to affect neuron physiology in an elegantly integrated system. This review focuses on the components of the interaction between astrocytes and neurons in nitric oxide biology.
The Role of Arginine–Nitric Oxide Pathway in Patients with Alzheimer Disease
Biological Trace Element Research, 2008
There is a reciprocal regulation of arginase and nitric oxide synthase in L-arginine-metabolizing pathways. There are various evidences of the role of nitric oxide in several neuropsychiatric disorders including Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease. However, there is no study that has investigated the role of arginase as an important part of the arginine regulatory system affecting nitric oxide synthase activity in Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease. This study aims to investigate arginase, manganese (a cofactor of arginase), and total nitrite levels (a metabolite of NO) and their relationship to the arginine-NO pathway in patients with Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease. Arginase activities, Mn, and total nitrite levels were measured in plasma from 47 patients with Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease and 43 healthy control subjects. Plasma arginase activities and manganese were found to be significantly lower and total nitrite level higher in patients with Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease compared with controls. Our results suggest that the arginine-NO pathway is involved in the pathogenesis of Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease.
Translational Neuroscience, 2018
Arginine is one of the most versatile semi-essential amino acids. Further to the primary role in protein biosynthesis, arginine is involved in the urea cycle, and it is a precursor of nitric oxide. Arginine deficiency is associated with neurodegenerative diseases such as Parkinson's, Huntington's and Alzheimer's diseases (AD). In this study, we administer arginine intracerebroventricularly in a murine model of AD and evaluate cognitive functions in a set of behavioral tests. In addition, the effect of arginine on synaptic plasticity was tested electrophysiologically by assessment of the hippocampal long-term potentiation (LTP). The effect of arginine on β amyloidosis was tested immunohistochemically. A role of arginine in the prevention of cytotoxicity and apoptosis was evaluated in vitro on PC-12 cells. The results indicate that intracerebroventricular administration of arginine improves spatial memory acquisition in 3xTg-AD mice, however, without significantly reducing intraneuronal β amyloidosis. Arginine shows little or no impact on LTP and does not rescue LTP deterioration induced by Aβ. Nevertheless, arginine possesses neuroprotective and antiapoptotic properties.