bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclooxygenase‐1 and ‐2 enzymes differentially regulate the brain upstream NF‐κB pathway and downstream enzymes involved in prostaglandin biosynthesis
Authors: Choi Sang‐Ho , Langenbach Robert , Bosetti Francesca 
Published: June 2006

AbstractWe have recently reported that cyclooxygenase (COX)‐2‐deficiency affects brain upstream and downstream enzymes in the arachidonic acid (AA) metabolic pathway to prostaglandin E2 (PGE2), as well as enzyme activity, protein and mRNA levels of the reciprocal isozyme, COX‐1. To gain a better insight into the specific roles of COX isoforms and characterize the interactions between upstream and downstream enzymes in brain AA cascade, we examined the expression and activity of COX‐2 and phospholipase A2 enzymes (cPLA2 and sPLA2), as well as the expression of terminal prostaglandin E synthases (cPGES, mPGES‐1, and − 2) in wild type and COX‐1–/– mice. We found that brain PGE2 concentration was significantly increased, whereas thromboxane B2 (TXB2) concentration was decreased in COX‐1–/– mice. There was a compensatory up‐regulation of COX‐2, accompanied by the activation of the NF‐κB pathway, and also an increase in the upstream cPLA2 and sPLA2 enzymes. The mechanism of NF‐κB activation in the COX‐1–/– mice involved the up‐regulation of protein expression of the p50 and p65 subunits of NF‐κB, as well as the increased protein levels of phosphorylated IκBα and of phosphorylated IKKα/β. Overall, our data suggest that COX‐1 and COX‐2 play a distinct role in brain PG biosynthesis, with basal PGE2 production being metabolically coupled with COX‐2 and TXB2 production being preferentially linked to COX‐1. Additionally, COX‐1 deficiency can affect the expression of reciprocal and coupled enzymes, COX‐2, Ca2+‐dependent PLA2, and terminal mPGES‐2, to overcome defects in brain AA cascade.
Peptide neuroprotection through specific interaction with brain tubulin
Authors: Divinski Inna , Holtser‐Cochav Miri , Vulih‐Schultzman Inna , Steingart Ruth A. , Gozes Illana 
Published: June 2006

AbstractThis study aimed to identify the neuronal target for the potent neuroprotective peptide NAP. When added to pheochromocytoma cells (neuronal model), NAP was found in the intracellular milieu and was co‐localized with microtubules. NAP induced neurite outgrowth and protected primary neurons against microtubule‐associated ZnCl2toxicity. Rapid microtubule reorganization into distinct microtubules ensued after NAP addition to both pheochromocytoma cells and primary cerebral cortical neurons, but not to fibrobalsts. While binding neuronal tubulin and protecting pheochromocytoma cells against oxidative stress, NAP did not bind tubulin extracted from fibroblasts, nor did it protect those cells against oxidative stress. Affinity chromatography identified the brain‐specific βIII‐tubulin as a major NAP binding protein. Paclitaxel (a microtubule aggregating agent that interacts with β‐tubulin) reduced NAP tubulin binding. Thus, the underlying mechanism for the neuroprotection offered by NAP is targeting neuronal microtubules that are essential for neuronal survival and function.
Neurotoxic mechanisms of 2,9‐dimethyl‐β‐carbolinium ion in primary dopaminergic culture
Authors: Hamann Juliane , Rommelspacher Hans , Storch Alexander , Reichmann Heinz , Gille Gabriele 
Published: June 2006

Abstractβ‐Carbolines are potential endogenous and exogenous neurotoxicants that may contribute to the pathogenesis of Parkinson's disease. The 2,9‐dimethyl‐β‐carbolinium ion (either 2,9‐dimethyl‐β‐norharmanium or 2,9‐Me2NH+) was found to be neurotoxic in primary mesencephalic cultures and to be a potent inhibitor of mitochondrial complex I. However, the precise mechanisms of cell death remained obscure. Here, we investigated the mechanism of cell death in primary dopaminergic cultures of the mouse mesencephalon mediated by 2,9‐Me2NH+. The β‐carboline caused preferential death of dopaminergic neurones, which could not be attributed to cellular uptake via the dopamine transporter. Transient incubation with 2,9‐Me2NH+ for 48 h caused a progressive deterioration in the morphology of dopaminergic neurones during a 5‐day recovery period and persistent damage to the overall culture. An increase in free radical production and caspase‐3 activity, as well as a decrease of respiratory activity, mitochondrial membrane potential and ATP content, contributed to toxicity and pointed to an apoptotic mode of cell death, although a significant quantity of cells dying via necrosis were present simultaneously. These data underline the preferential susceptibility of dopaminergic neurones to 2,9‐Me2NH+ as a potent, oxidative stress generating neurotoxin.
Do axonal defects in tau and amyloid precursor protein transgenic animals model axonopathy in Alzheimer's disease?
Authors: Götz Jürgen , Ittner Lars M. , Kins Stefan 
Published: June 2006

AbstractThe subcellular localization of organelles, mRNAs and proteins is particularly challenging in neurons. Owing to their extended morphology, with axons in humans exceeding a meter in length, in addition to which they are not renewed but persist for the entire lifespan, it is no surprise that neurons are highly vulnerable to any perturbation of their sophisticated transport machinery. There is emerging evidence that impaired transport is not only causative for a range of motor disorders, but possibly also for Alzheimer's disease (AD) and related neurodegenerative disorders. Support for this hypothesis comes from transgenic animal models. Overexpression of human tau and amyloid precursor protein (APP) in mice and flies models the key hallmark histopathological characteristics of AD, such as somatodendritic accumulation of phosphorylated forms of tau and β‐amyloid (Aβ) peptide‐containing amyloid plaques, as well as axonopathy. The latter has also been demonstrated in mutant mice with altered levels of Alzheimer‐associated genes, such as presenilin (PS). In Aβ‐producing APP transgenic mice, axonopathy was observed before the onset of plaque formation and tau hyperphosphorylation. In human AD brain, an axonopathy was revealed for early but not late Braak stages. The overall picture is that key players in AD, such as tau, APP and PS, perturb axonal transport early on in AD, causing impaired synaptic plasticity and reducing survival rates. It will be challenging to determine the molecular mechanisms of these different axonopathies, as this might assist in the development of new therapeutic strategies.
Cycloheximide treatment to identify components of the transitional transcriptome in PACAP‐induced PC12 cell differentiation
Authors: Ravni Aurélia , Eiden Lee E. , Vaudry Hubert , Gonzalez Bruno J. , Vaudry David 
Published: June 2006

AbstractPituitary adenylate cyclase‐activating polypeptide (PACAP) promotes neurite outgrowth, reduces proliferation and inhibits apoptosis of PC12 cells. We have partially characterized the transcriptome changes induced by PACAP after 6 h of treatment, when commitment to differentiation has occurred. Here, we have investigated the effects of a 6‐h treatment with PACAP (10−7 m) in the presence of cycloheximide (5 µm) to identify, via superinduction, components of the transitional transcriptome initially induced by PACAP and potentially participating in the regulation of late‐response genes required for differentiation. Approximately 100 new transcripts were identified in this screen, i.e. as many individual genes as make up the 6‐h PACAP differentiation transcriptome itself. Six known transcripts in this cohort were then measured at several time points between 0 and 6 h by real‐time PCR to determine whether these transcripts are induced early following PACAP treatment in the absence of cycloheximide, and therefore may be of functional importance in differentiation. Five out of the six transcripts were indeed induced by PACAP alone soon (between 30 min and 3 h) after cell treatment.β‐Cell translocation gene 2, antiproliferative (Btg2),serum/glucocorticoid‐regulated kinase (Sgk),nuclear factor for the κ chain of B‐cells(NFκB),seven in absentia homologue 2 (Siah2)andFBJ osteosarcoma related oncogene(Fos) showed a 2.5–200‐fold induction by PACAP between 15 min and 3 h, and mRNA levels returned either to baseline or near baseline after 6 h. This work provides new information concerning genes whose transient regulation early after PACAP exposure may contribute to the expression of the differentiated transcriptome in PC12 cells, and should help to elucidate the molecular mechanisms involved in the control of nerve cell survival and differentiation.
Presynaptic enzymatic neurotoxins
Authors: Rossetto Ornella , Morbiato Laura , Caccin Paola , Rigoni Michela , Montecucco Cesare 
Published: June 2006

AbstractBotulinum neurotoxins produced by anaerobic bacteria of the genus Clostridium are the most toxic proteins known, with mouse LD50 values in the 1–5 ng/kg range, and are solely responsible for the pathophysiology of botulism. These metalloproteinases enter peripheral cholinergic nerve terminals and cleave proteins of the neuroexocytosis apparatus, causing a persistent, but reversible, inhibition of neurotransmitter release. They are used in the therapy of many human syndromes caused by hyperactive nerve terminals. Snake presynaptic PLA2 neurotoxins block nerve terminals by binding to the nerve membrane and catalyzing phospholipid hydrolysis with production of lysophospholipids and fatty acids. These compounds change the membrane conformation, causing enhanced fusion of synaptic vesicle via hemifusion intermediate with release of neurotransmitter and, at the same time, inhibition of vesicle fission and recycling. It is possible to envisage clinical applications of the lysophospholipid/fatty acid mixture to inhibit hyperactive superficial nerve terminals.
Calpain product of WT‐CRMP2 reduces the amount of surface NR2B NMDA receptor subunit
Authors: Bretin Sylvie , Rogemond Véronique , Marin Philippe , Maus Marion , Torrens Yvette , Honnorat Jérôme , Glowinski Jacques , Prémont Joël , Gauchy Christian 
Published: June 2006

AbstractThe brain is particularly vulnerable to ischaemia; however, neurons can become tolerant to ischaemic insult. This tolerance has been shown to involve activation of NMDA receptors, but its mechanisms have not yet been fully elucidated. Using a preconditioning protocol, we show that neurons surviving to a transient NMDA exposure become resistant to the glutamatergic agonist. Using a proteomic approach, we found that alterations of the protein pattern of NMDA‐resistant neurons are restricted mainly to the five collapsin response mediator proteins (CRMPs). A sustained increase in calpain activity following NMDA treatment is responsible for the production of cleaved CRMPs. Finally, we provide evidence for the involvement of the cleaved form of WT‐CRMP2 in the down‐regulation of NR2B. Our data suggests that, beside their role in neuronal morphogenesis, CRMPs may contribute to neuronal plasticity.
Calsenilin interacts with transcriptional co‐repressor C‐terminal binding protein(s)
Authors: Zaidi Nikhat F. , Kuplast Kristy G. , Washicosky Kevin J. , Kajiwara Yuji , Buxbaum Joseph D. , Wasco Wilma 
Published: June 2006

AbstractCalsenilin/potassium channel‐interacting protein (KChIP)3/ downstream regulatory element sequence antagonist modulator (DREAM) is a neuronal calcium‐binding protein that has been shown to have multiple functions in the cell, including the regulation of presenilin processing, repression of transcription and modulation of A‐type potassium channels. To gain a better understanding of the precise role of calsenilin in specific cellular compartments, an interactor hunt for proteins that bind to the N‐terminal domain of calsenilin was carried out. Using a yeast two‐hybrid system and co‐immunoprecipitation studies, we have identified the transcriptional co‐repressor C‐terminal binding protein (CtBP)2 as an interactor for calsenilin and have shown that the two proteins can interact in vivo. In co‐immunoprecipitation studies, calsenilin also interacted with CtBP1, a CtBP2 homolog. Our data also showed a calsenilin‐dependent increase in c‐fos protein levels in CtBP knockout fibroblasts, suggesting that CtBP may modulate the transcriptional repression of c‐fos by calsenilin. Furthermore, the finding that histone deacetylase protein and activity were associated with the calsenilin–CtBP immunocomplex suggests a mechanism by which calsenilin–CtBP may act to repress transcription. Finally, we demonstrated that calsenilin and CtBP are present in synaptic vesicles and can interact in vivo.
The p53 family in nervous system development and disease
Authors: Jacobs W. Bradley , Kaplan David R. , Miller Freda D. 
Published: June 2006

AbstractThe p53 family, consisting of the tumor suppressors p53, p63 and p73, play a vital role as regulators of survival and apoptosis in the developing, adult and injured nervous system. These proteins function as key survival and apoptosis checkpoints in neurons, acting as either rheostats or sensors responsible for integrating multiple pro‐apoptotic and survival cues. A dramatic example of this checkpoint function is observed in developing sympathetic neurons, where a pro‐survival and truncated form of p73 antagonizes the apoptotic functions of p53 and p63. Thus the levels and activities of the different p53 family members may ultimately determine whether neurons either live or die during nervous system development and disease.
Kiss‐and‐run and full‐collapse fusion as modes of exo‐endocytosis in neurosecretion
Authors: Harata Nobutoshi C. , Aravanis Alexander M. , Tsien Richard W. 
Published: June 2006

AbstractNeurotransmitters and hormones are released from neurosecretory cells by exocytosis (fusion) of synaptic vesicles, large dense‐core vesicles and other types of vesicles or granules. The exocytosis is terminated and followed by endocytosis (retrieval). More than fifty years of research have established full‐collapse fusion and clathrin‐mediated endocytosis as essential modes of exo‐endocytosis. Kiss‐and‐run and vesicle reuse represent alternative modes, but their prevalence and importance have yet to be elucidated, especially in neurons of the mammalian CNS. Here we examine various modes of exo‐endocytosis across a wide range of neurosecretory systems. Full‐collapse fusion and kiss‐and‐run coexist in many systems and play active roles in exocytotic events. In small nerve terminals of CNS, kiss‐and‐run has an additional role of enabling nerve terminals to conserve scarce vesicular resources and respond to high‐frequency inputs. Full‐collapse fusion and kiss‐and‐run will each contribute to maintaining cellular communication over a wide range of frequencies.
Nitric oxide, cell bioenergetics and neurodegeneration
Authors: Moncada Salvador , Bolaños Juan P. 
Published: June 2006

AbstractFollowing stimulation of NMDA receptors, neurons transiently synthesize nitric oxide (NO) in a calcium/calmodulin‐dependent manner through the activation of neuronal NO synthase. Nitric oxide acts as a messenger, activating soluble guanylyl cyclase and participating in the transduction signalling pathways involving cyclic GMP. Nitric oxide also binds to cytochrome c oxidase, and is able to inhibit cell respiration in a process that is reversible and in competition with oxygen. This action can also lead to the release of superoxide anion from the mitochondrial respiratory chain. Here, we discuss recent evidence that this mitochondrial interaction represents a molecular switch for cell signalling pathways involved in the control of physiological functions. These include superoxide‐ or oxygen‐dependent modulation of gene transcription, calcium‐dependent cell signalling responses, changes in the mitochondrial membrane potential or AMP‐activated protein kinase‐dependent control of glycolysis. In pathophysiological conditions, such as brain ischaemia or neurological disorders, NO is formed excessively by NMDA receptor over‐activation in neurons, or by inducible NO synthase from neighbouring glia (microglial cells and astrocytes). Elevated NO concentrations can then interact with superoxide anion, generated by the mitochondria or by other mechanisms, leading to the formation of the powerful oxidant species peroxynitrite. During pathological conditions activation of the NAD+‐consuming enzyme poly(APD‐ribose) polymerase‐1 (PARP‐1) is also a likely mechanism for NO‐mediated energy failure and neurotoxicity. Activation of PARP‐1 is, however, a repair process, which in milder forms of oxidative stress protects neurons from death. Thus, whilst NO plays a physiological role in neuronal cell signalling, its over‐production may cause neuronal energy compromise leading to neurodegeneration.
Molecular mechanisms for Alzheimer's disease: implications for neuroimaging and therapeutics
Authors: Masters Colin L. , Cappai Roberto , Barnham Kevin J. , Villemagne Victor L. 
Published: June 2006

AbstractAlzheimer's disease is a progressive neurodegenerative disorder characterised by the gradual onset of dementia. The pathological hallmarks of the disease are β‐amyloid (Aβ) plaques, neurofibrillary tangles, synaptic loss and reactive gliosis. The current therapeutic effort is directed towards developing drugs that reduce Aβ burden or toxicity by inhibiting secretase cleavage, Aβ aggregation, Aβ toxicity, Aβ metal interactions or by promoting Aβ clearance. A number of clinical trials are currently in progress based on these different therapeutic strategies and they should indicate which, if any, of these approaches will be efficacious. Current diagnosis of Alzheimer's disease is made by clinical, neuropsychologic and neuroimaging assessments. Routine structural neuroimaging evaluation with computed tomography and magnetic resonance imaging is based on non‐specific features such as atrophy, a late feature in the progression of the disease, hence the crucial importance of developing new approaches for early and specific recognition at the prodromal stages of Alzheimer's disease. Functional neuroimaging techniques such as functional magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography and single photon emission computed tomography, possibly in conjunction with other related Aβ biomarkers in plasma and CSF, could prove to be valuable in the differential diagnosis of Alzheimer's disease, as well as in assessing prognosis. With the advent of new therapeutic strategies there is increasing interest in the development of magnetic resonance imaging contrast agents and positron emission tomography and single photon emission computed tomography radioligands that will permit the assessment of Aβ burdenin vivo.
The role of mitochondria in inherited neurodegenerative diseases
Authors: Kwong Jennifer Q. , Beal M. Flint , Manfredi Giovanni 
Published: June 2006

AbstractIn the past decade, the genetic causes underlying familial forms of many neurodegenerative disorders, such as Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich ataxia, hereditary spastic paraplegia, dominant optic atrophy, Charcot‐Marie‐Tooth type 2A, neuropathy ataxia and retinitis pigmentosa, and Leber's hereditary optic atrophy have been elucidated. However, the common pathogenic mechanisms of neuronal death are still largely unknown. Recently, mitochondrial dysfunction has emerged as a potential ‘lowest common denominator’ linking these disorders. In this review, we discuss the body of evidence supporting the role of mitochondria in the pathogenesis of hereditary neurodegenerative diseases. We summarize the principal features of genetic diseases caused by abnormalities of mitochondrial proteins encoded by the mitochondrial or the nuclear genomes. We then address genetic diseases where mutant proteins are localized in multiple cell compartments, including mitochondria and where mitochondrial defects are likely to be directly caused by the mutant proteins. Finally, we describe examples of neurodegenerative disorders where mitochondrial dysfunction may be ‘secondary’ and probably concomitant with degenerative events in other cell organelles, but may still play an important role in the neuronal decay. Understanding the contribution of mitochondrial dysfunction to neurodegeneration and its pathophysiological basis will significantly impact our ability to develop more effective therapies for neurodegenerative diseases.
SNAP25 is a pre‐synaptic target for the depressant action of reactive oxygen species on transmitter release
Authors: Giniatullin A. R. , Darios F. , Shakirzyanova A. , Davletov B. , Giniatullin R. 
Published: June 2006

AbstractReactive oxygen species (ROS) participate in various physiological and pathological processes in the nervous system, but the specific pathways that mediate ROS signalling remain largely unknown. Using electrophysiological techniques and biochemical evaluation of isolated fusion proteins, we explored the sensitivity to standard oxidative stress of the entire synapse, the pre‐synaptic machinery and essential fusion proteins underlying transmitter exocytosis. Oxidative stress induced by H2O2 plus Fe2+ inhibited both evoked and spontaneous quantal release from frog or mouse motor nerve endings, while it left post‐synaptic sensitivity unchanged. The depressant effect of H2O2 on acetylcholine release was pertussis toxin‐insensitive, ruling out G‐protein cascades. Experiments with ionomycin, a Ca2+ ionophore, revealed that ROS directly impaired the function of releasing machinery. In line with this, SNAP25, one of three essential fusion proteins, showed a selectively high sensitivity to the oxidative signals. Several ROS scavengers enhanced evoked synaptic transmission, consistent with tonic inhibition by endogenous ROS. Our data suggest that ROS‐induced impairment of releasing machinery is mediated by SNAP25, which appears to be a pre‐synaptic ROS sensor. This mechanism of ROS signalling could have widespread implications in the nervous system and might contribute to the pathogenesis of neurodegenerative diseases.