bluuebunny/crossref_metadata_2025_split huggingface dataset:
Important differences between human and mouse APOE gene promoters: limitation of mouse APOE model in studying Alzheimer’s disease
Authors: Maloney Bryan , Ge Yuan‐Wen , Alley George M. , Lahiri Debomoy K. 
Published: September 2007

AbstractApolipoprotein E (ApoE), encoded by the apolipoprotein E gene (APOE), plays an important role in the pathogenesis of Alzheimer’s disease (AD). The APOE ε4 variant is strongly associated with AD. APOE promoter polymorphisms have also been reported to associate with higher AD risk. Mouse models of APOE expression have long been used to study the pathogenesis of AD. Elucidating the role of the APOE gene in AD requires understanding of how its regulation differs between mouse and human APOE genes, and how the differences influence AD risk. We compared the structure and function of both the human APOE gene promoter (hAPOEP) and mouse APOE gene promoter (mAPOEP) regions. Homology is less than 40% at 180 bp or more upstream of the two species’ transcription start site (TSS, +1). Functional analysis revealed both similarities and important differences between the two sequences, significantly affected by human versus rodent cell line origin. We likewise probed nuclear extracts from several cell lines of different origins (astrocytic, glial, and neuronal) and mouse brain with specific hAPOEP and mAPOEP fragments. Each fragment shared DNA–protein interactions with the other but, notably, also bound distinct factors, demonstrated by gel shift and southwestern analyses. We determined possible identities for these distinct factors. These results suggest that regulation of mouse and human APOE genes may be sufficiently unique to justify the use of both the human APOE promoter sequence in transgenic rodent models and non‐rodent AD models for studying factors involved in AD pathogenesis.
Protection of dopaminergic neurons by electroconvulsive shock in an animal model of Parkinson’s disease
Authors: Anastasia Agustín , De Erausquin Gabriel A. , Wojnacki José , Mascó Daniel H. 
Published: September 2007

AbstractElectroconvulsive shock (ECS) improves motor function in Parkinson’s disease. In rats, ECS stimulates the expression of various factors some of which have been proposed to exert neuroprotective actions. We have investigated the effects of ECS on 6‐hydroxydopamine (6‐OHDA)‐injected rats. Three weeks after a unilateral administration of 6‐OHDA, 85–95% nigral dopaminergic neurons are lost. Chronic ECS prevented this cell loss, protect the nigrostriatal pathway (assessed by FloroGold retrograde labeling) and reduce motor impairment in 6‐OHDA‐treated animals. Injection of 6‐OHDA caused loss of expression of glial cell‐line derived neurotrophic factor (GDNF) in the substantia nigra. Chronic ECS completely prevented this loss of GDNF expression in 6‐OHDA‐treated animals. We also found that protected dopaminergic neurons co‐express GDNF receptor proteins. These results strongly suggest that endogenous changes in GDNF expression may participate in the neuroprotective mechanism of ECS against 6‐OHDA induced toxicity.
Post‐synaptic density perturbs insulin‐induced Kv1.3 channel modulation via a clustering mechanism involving the SH3 domain
Authors: Marks D. R. , Fadool D. A. 
Published: September 2007

AbstractThe olfactory bulb (OB) contains the highest concentration of the insulin receptor (IR) kinase in the central nervous system; however, its functional role and modulation in this region remains poorly understood. IR kinase contains a number of proline‐rich motifs, making it an excellent candidate for modulation by SH3 domain‐containing adaptor proteins. Kv1.3, a voltage‐gated Shaker potassium channel and tyrosine phosphorylation substrate of IR kinase, contains several proline‐rich sequences and a canonical post‐synaptic density 95 (PSD‐95)/discs large/zO‐1 domain (PDZ) recognition motif common to most Shaker family members. We sought to determine if a functional relationship existed between Kv1.3, IR kinase, and the SH3/PDZ adaptor protein PSD‐95. Through patch‐clamp electrophysiology, immunochemistry, and co‐immunoprecipitation, we found that while Kv1.3 and PSD‐95 alone interact via the canonical C‐terminal PDZ recognition motif of the channel, this molecular site of interaction acts to cluster the channels but the PSD‐95 SH3‐guanylate kinase domain functionally modulates Kv1.3 activity via two proline‐rich domains in its N‐ and C‐terminal. Therefore, these data suggest that adaptor domains responsible for ion‐channel clustering and functional modulation are not necessarily coupled. Moreover, IR kinase and Kv1.3 can only be co‐immunoprecipitated in the presence of PSD‐95 as the adapting linker. Functionally, insulin‐dependent Kv1.3 phosphorylation that causes channel current suppression is blocked via interaction with the PSD‐95 SH3‐guanylate kinase domain. Because all the three proteins co‐localize in multiple lamina of the OB that are known to be rich in synaptic connections, membrane excitability and synaptic transmission at critical locations in the OB have the capacity to be finely regulated.
Combinatorial co‐expression of pheromone receptors, V2Rs
Authors: Silvotti Lucia , Moiani Arianna , Gatti Rita , Tirindelli Roberto 
Published: September 2007

AbstractBasal neurons of the vomeronasal organ of the mouse express a superfamily of about 120 pheromone receptors, named V2Rs, that are grouped in four families, A, B, C, and D, according to sequence homology. Family‐A, ‐B, and ‐D V2Rs are expressed as one receptor gene per cell, but we previously reported their co‐expression with family‐C V2Rs. Here, we show that basal neurons can be further grouped according to the combinatorial expression of different V2Rs. Altogether, these findings suggest that in each basal neuron a transcriptional program is active for expressing a combination of two compatible receptors and for excluding, at the same time, the expression of all other V2Rs. Further analyses revealed non‐random combinations of co‐expression between family‐C V2Rs and genes of the class Ib major histocompatibility complex. Thus, each basal neuron of the vomeronasal organ represents a highly qualified sensory unit for detecting very specific combinations of pheromonal cues.
Reorganization of prion protein membrane environment during low potassium‐induced apoptosis in primary rat cerebellar neurons
Authors: Rivaroli Anna , Prioni Simona , Loberto Nicoletta , Bettiga Arianna , Chigorno Vanna , Prinetti Alessandro , Sonnino Sandro 
Published: September 2007

AbstractWe studied the changes occurring in the membrane environment of prion protein (PrP) during apoptosis induced by low potassium in primary rat cerebellar neurons. Ceramide levels increased during apoptosis‐inducing treatment, being doubled with respect to time‐matched controls after 24 h. Sphingomyelin levels were parallely decreased, while cholesterol and ganglioside contents were not affected. Changes in ceramide and sphingomyelin composition were exclusively restricted to a detergent‐resistant membrane fraction. The pro‐apoptotic treatment was accompanied by the down‐regulation of PrP and of the non‐receptor kinase Fyn. The levels of PrP and Fyn were correspondingly reduced in the detergent‐resistant membrane fraction. In control cells, the membrane microenvironment separated by immunoprecipitation with anti‐PrP antibody contained 80% of the detergent‐resistant PrP and 35% and 38% of the sphingolipids and cholesterol respectively. Upon low potassium treatment, 20% of the PrP originally present in the detergent‐resistant fraction was immunoprecipitated, together with 19% of sphingolipids and 22% of cholesterol. Thus, PrP in the immunoprecipitate from apoptotic cells was ninefold less than in control ones, while sphingolipids and cholesterol were about 50% with respect to controls cells. The molar ratio between cholesterol, sphingomyelin and ceramide was 15 : 6 : 1 in the PrP‐rich environment from control neurons, and 6 : 2 : 1 in that from apoptotic cells.
Identification of NCAM‐binding peptides promoting neurite outgrowth via a heterotrimeric G‐protein‐coupled pathway
Authors: Hansen Raino Kristian , Christensen Claus , Korshunova Irina , Kriebel Martin , Burkarth Nadine , Kiselyov Vladislav V. , Olsen Marianne , Østergaard Søren , Holm Arne , Volkmer Hansjürgen , Walmod Peter S. , Berezin Vladimir , Bock Elisabeth 
Published: September 2007

AbstractA combinatorial library of undecapeptides was produced and utilized for the isolation of peptide binding to the fibronectin type 3 modules (F3I–F3II) of the neural cell adhesion molecule (NCAM). The isolated peptides were sequenced and produced as dendrimers. Two of the peptides (denoted ENFIN2 and ENFIN11) were confirmed to bind to F3I–F3II of NCAM by surface plasmon resonance. The peptides induced neurite outgrowth in primary cerebellar neurons and PC12E2 cells, but had no apparent neuroprotective properties. NCAM is known to activate different intracellular pathways, including signaling through the fibroblast growth factor receptor, the Src‐related non‐receptor tyrosine kinase Fyn, and heterotrimeric G‐proteins. Interestingly, neurite outgrowth stimulated by ENFIN2 and ENFIN11 was independent of signaling through fibroblast growth factor receptor and Fyn, but could be inhibited with pertussis toxin, an inhibitor of certain heterotrimeric G‐proteins. Neurite outgrowth induced by trans‐homophilic NCAM was unaffected by the peptides, whereas knockdown of NCAM completely abrogated ENFIN2‐ and ENFIN11‐induced neuritogenesis. These observations suggest that ENFIN2 and ENFIN11 induce neurite outgrowth in an NCAM‐dependent manner through G‐protein‐coupled signal transduction pathways. Thus, ENFIN2 and ENFIN11 may be valuable for exploring this particular type of NCAM‐mediated signaling.
The extracellular matrix in multiple sclerosis pathology
Authors: Van Horssen Jack , Dijkstra Christine D. , De Vries Helga E. 
Published: September 2007

AbstractThe extracellular matrix (ECM) is a substrate upon which cells migrate, proliferate and differentiate. It is involved in the maintenance of cytoarchitecture, regulation of homeostasis, and it influences interactions between cells and molecules via specific receptors. Although a substantial body of knowledge has accumulated concerning the role of the ECM in peripheral tissues, little is known of the structure and function of the ECM in the CNS. However, marked changes in the expression of ECM constituents have been documented in various neurological disorders, including multiple sclerosis. This review focuses on the structure and function of the ECM in the CNS and in particular on the occurrence and involvement of ECM changes in the pathology of multiple sclerosis. Increased knowledge of the expression and functional role of ECM proteins in the CNS can lead to a better understanding of complex neurobiological processes both under normal as well as pathological conditions.
Human embryonic stem cell‐derived neural precursors as a continuous, stable, and on‐demand source for human dopamine neurons
Authors: Ko Ji‐Yun , Park Chang‐Hwan , Koh Hyun‐Chul , Cho Youl‐Hee , Kyhm Jee‐Hong , Kim Young‐Soo , Lee Inchul , Lee Yong‐Sung , Lee Sang‐Hun 
Published: September 2007

AbstractHuman embryonic stem (hES) cells can be guided to differentiate into ventral midbrain‐type neural precursor (NP) cells that proliferate in vitro by specific mitogens. We investigated the potential of these NP cells derived from hES cells (hES‐NP) for the large‐scale generation of human dopamine (DA) neurons for functional analyses and therapeutic applications. To address this, hES‐NP cells were expanded in vitro for 1.5 months with six passages, and their proliferation and differentiation properties determined over the NP passages. Interestingly, the total hES‐NP cell number was increased by > 2 × 104‐folds over the in vitro period without alteration of phenotypic gene expression. They also sustained their differentiation capacity toward neuronal cells, exhibiting in vitro pre‐synaptic DA neuronal functionality. Furthermore, the hES‐NP cells can be cryopreserved without losing their proliferative and developmental potential. Upon transplantation into a Parkinson’s disease rat model, the multi‐passaged hES‐NP cells survived, integrated into the host striatum, and differentiated toward the neuronal cells expressing DA phenotypes. A significant reduction in the amphetamine‐induced rotation score of Parkinson’s disease rats was observed by the cell transplantation. Taken together, these findings indicate that hES‐NP cell expansion is exploitable for a large‐scale generation of experimental and transplantable DA neurons of human‐origin.
Peptide transporter 2 (PEPT2) expression in brain protects against 5‐aminolevulinic acid neurotoxicity
Authors: Hu Yongjun , Shen Hong , Keep Richard F. , Smith David E. 
Published: September 2007

AbstractThe proton‐coupled oligopeptide transporter PEPT2 (or SLC15A2) is the major protein involved in the reclamation of peptide‐bound amino acids and peptide‐like drugs in kidney. PEPT2 is also important in effluxing peptides and peptidomimetics from CSF at the choroid plexus, thereby limiting their exposure in brain. In this study, we report a neuroprotective role for PEPT2 in modulating the toxicity of a heme precursor, 5‐aminolevulinic acid (5‐ALA). Our findings demonstrate that in PEPT2‐deficient mice, 5‐ALA administration results in reduced survivability, a worsening of neuromuscular dysfunction, and CSF concentrations of substrate that are 8–30 times higher than that in wild‐type control animals. The ability of PEPT2 to limit 5‐ALA exposure in CSF suggests that it may also have relevance as a secondary genetic modifier of conditions (such as acute hepatic porphyrias and lead poisoning) in which 5‐ALA metabolism is altered and in which 5‐ALA toxicity is important.
Spinal cord mitochondria display lower calcium retention capacity compared with brain mitochondria without inherent differences in sensitivity to cyclophilin D inhibition
Authors: Morota Saori , Hansson Magnus J. , Ishii Nagao , Kudo Yoshihisa , Elmér Eskil , Uchino Hiroyuki 
Published: September 2007

AbstractThe mitochondrial permeability transition (mPT) is a potential pathogenic mechanism in neurodegeneration. Varying sensitivity to calcium‐induced mPT has been demonstrated for regions within the CNS possibly correlating with vulnerability following insults. The spinal cord is selectively vulnerable in e.g. amyotrophic lateral sclerosis and increased mPT sensitivity of mitochondria derived from the spinal cord has previously been demonstrated. In this study, we introduce whole‐body hypothermia prior to removal of CNS tissue to minimize the effects of differential tissue extraction prior to isolation of spinal cord and cortical brain mitochondria. Spinal cord mitochondria were able to retain considerably less calcium when administered as continuous infusion, which was not related to a general increased sensitivity of the mPT to calcium, its desensitization to calcium by the cyclophilin D inhibitor cyclosporin‐A, or to differences in respiratory parameters. Spinal cord mitochondria maintained a higher concentration of extramitochondrial calcium during infusion than brain mitochondria possibly related to an increased set‐point concentration for calcium uptake. A hampered transport and retention capacity of calcium may translate into an increased susceptibility of the spinal cord to neurodegenerative processes involving calcium‐mediated damage.
Neuronal nitric oxide synthase contributes to chronic stress‐induced depression by suppressing hippocampal neurogenesis
Authors: Zhou Qi‐Gang , Hu Yao , Hua Yao , Hu Mei , Luo Chun‐Xia , Han Xiao , Zhu Xin‐Jian , Wang Bin , Xu Jin‐Shu , Zhu Dong‐Ya 
Published: September 2007

AbstractIncreasing evidence suggests that depression may be associated with a lack of hippocampal neurogenesis. It is well established that neuronal nitric oxide synthase (nNOS)‐derived NO exerts a negative control on the hippocampal neurogenesis. Using genetic and pharmacological methods, we investigated the roles of nNOS in depression induced by chronic mild stress (CMS) in mice. Hippocampal nNOS over‐expression was first observed 4 days and remained elevated 21 and 56 days after exposure to CMS. The mice exposed to CMS exhibited behavioral changes typical of depression, and impaired neurogenesis in the hippocampus. The CMS‐induced behavioral despair and hippocampal neurogenesis impairment were prevented and reversed in the null mutant mice lacking nNOS gene (nNOS−/−) and in the mice receiving nNOS inhibitor. Disrupting hippocampal neurogenesis blocked the antidepressant effect of nNOS inhibition. Moreover, nNOS−/− mice exhibited antidepressant‐like properties. Our findings suggest that nNOS over‐expression in the hippocampus is essential for chronic stress‐induced depression and inhibiting nNOS signaling in brain may represent a novel approach for the treatment of depressive disorders.
Reduced neuronal nitric oxide synthase is involved in ischemia‐induced hippocampal neurogenesis by up‐regulating inducible nitric oxide synthase expression
Authors: Luo Chun Xia , Zhu Xin Jian , Zhou Qi Gang , Wang Bin , Wang Wei , Cai Hui Hui , Sun Yong Jun , Hu Mei , Jiang Jun , Hua Yao , Han Xiao , Zhu Dong Ya 
Published: September 2007

AbstractNitric oxide (NO), a free radical with signaling functions in the CNS, is implicated in some developmental processes, including neuronal survival, precursor proliferation, and differentiation. However, neuronal nitric oxide synthase (nNOS) ‐derived NO and inducible nitric oxide synthase (iNOS) ‐derived NO play opposite role in regulating neurogenesis in the dentate gyrus after cerebral ischemia. In this study, we show that focal cerebral ischemia reduced nNOS expression and enzymatic activity in the hippocampus. Ischemia‐induced cell proliferation in the dentate gyrus was augmented in the null mutant mice lacking nNOS gene (nNOS−/−) and in the rats receiving 7‐nitroindazole, a selective nNOS inhibitor, after stroke. Inhibition of nNOS ameliorated ischemic injury, up‐regulated iNOS expression, and enzymatic activity in the ischemic hippocampus. Inhibition of nNOS increased and iNOS inhibitor decreased cAMP response element‐binding protein phosphorylation in the ipsilateral hippocampus in the late stage of stroke. Moreover, the effects of 7‐nitroindazole on neurogenesis after ischemia disappeared in the null mutant mice lacking iNOS gene (iNOS−/−). These results suggest that reduced nNOS is involved in ischemia‐induced hippocampal neurogenesis by up‐regulating iNOS expression and cAMP response element‐binding protein phosphorylation.
Visible light induces matrix metalloproteinase‐9 expression in rat eye
Authors: Papp Andrea M. , Nyilas Rita , Szepesi Zsuzsanna , Lőrincz Magor L. , Takács Eszter , Ábrahám István , Szilágyi Nóra , Tóth Júlia , Medveczky Péter , Szilágyi László , Juhász Gábor , Juhász Gábor 
Published: September 2007

AbstractUp‐regulation of matrix metalloproteinase‐9 (MMP‐9, gelatinase B) in the nervous system has been demonstrated when excitotoxicity‐induced tissue remodeling and neuronal death occurs. Induction of MMP‐9 by a natural stimulus has not been observed yet. Using RT‐PCR and gelatin‐zymography we demonstrated MMP‐9 induction at transcriptional and protein levels in different structures of the rat eye following over‐stimulation with white light. MMP‐9 elevation occurred in the retina without reduction in photoreceptor number or major anatomical reorganization. A transient decrease in electroretinogram b‐wave indicated the functional recovery. Retrobulbar injection of a broad‐spectrum MMP‐inhibitor GM6001, slowed the recovery rate of b‐wave amplitude. Even room‐light applied to dark‐adapted awake animals induced MMP‐9 increase in the retina, which suggests a role for MMP‐9 in physiological functional plasticity of the nervous system, such as light adaptation. This is the first demonstration of MMP‐9 induction by a sensory stimulus.
Neurexin Iβ and neuroligin are localized on opposite membranes in mature central synapses
Authors: Berninghausen Otto , Rahman M. Atiqur , Silva John‐Paul , Davletov Bazbek , Hopkins Colin , Ushkaryov Yuri A. 
Published: September 2007

AbstractSynaptogenesis requires formation of trans‐synaptic complexes between neuronal cell‐adhesion receptors. Heterophilic receptor pairs, such as neurexin Iβ and neuroligin, can mediate distinct intracellular signals and form different cytoplasmic scaffolds in the pre‐ and post‐synaptic neuron, and may be particularly important for synaptogenesis. However, the functions of neurexin and neuroligin depend on their distribution in the synapse. Neuroligin has been experimentally assigned to the post‐synaptic membrane, while the localization of neurexin remains unclear. To study the subcellular distribution of neurexin Iβ and neuroligin in mature cerebrocortical synapses, we have developed a novel method for the physical separation of junctional membranes and their direct analysis by western blotting. Using urea and dithiothreitol, we disrupted trans‐synaptic protein links, without dissolving the lipid phase, and fractionated the pre‐ and post‐synaptic membranes. The purity of these fractions was validated by electron microscopy and western blotting using multiple synaptic markers. A quantitative analysis has confirmed that neuroligin is localized strictly in the post‐synaptic membrane. We have also demonstrated that neurexin Iβ is largely (96%) pre‐synaptic. Thus, neurexin Iβ and neuroligin normally form trans‐synaptic complexes and can transduce bidirectional signals.
Interrupting activator protein‐1 signaling in conscious rats can modify neuropeptide Y gene expression and feeding behavior of phenylpropanolamine
Authors: Hsieh Yih‐Shou , Yang Shun‐Fa , Chu Shu‐Chen , Kuo Dong‐Yih 
Published: September 2007

AbstractThe mechanism for phenylpropanolamine (PPA)‐induced anorexia has been attributed to its inhibitory action on hypothalamic neuropeptide Y (NPY), an orexigenic agent abundant in the brain. However, molecular mechanisms behind this effect are not well known. In this study, we investigated whether activator protein‐1 (AP‐1) signaling was involved. Rats were daily treated with PPA for 4 days. Changes in hypothalamic NPY, c‐fos, c‐jun, superoxide dismutase (SOD)‐1, and SOD‐2 mRNA contents were measured and compared. Results showed that c‐fos and c‐jun mRNA levels were increased following PPA treatment, which were relevant to a reduction in NPY mRNA level. To further determine if c‐fos/c‐jun genes were involved in PPA anorexia, infusions of antisense oligonucleotide into cerebroventricle were performed before daily PPA treatment in freely moving rats. Results showed that either c‐fos or c‐jun knock down could block PPA anorexia and restore NPY mRNA content to normal level. It is suggested that AP‐1 signaling may participate in the central regulation of PPA‐mediated appetite suppression via the modulation of NPY gene expression. Moreover, this modulation might be partly because of the neuroprotective effect of AP‐1 since SOD gene was activated during PPA treatment.