bluuebunny/crossref_metadata_2025_split huggingface dataset:
α1 integrin activation: A link between β‐amyloid deposition and neuronal death in aging hippocampal neurons
Authors: Anderson Kelsi L. , Ferreira Adriana 
Published: February 2004

AbstractA growing body of evidence obtained using in vitro model systems indicates that the deposition of fibrillar β‐amyloid (Aβ) results in neurite degeneration and cell death in central neurons. Little is known, however, about the molecular mechanisms underlying these neurotoxic effects. We have shown previously that fibrillar Aβ induced sustained activation of the mitogen‐activated protein kinase (MAPK) followed by hyperphosphorylation of tau proteins in aging hippocampal neurons. Furthermore, the blockage of MAPK activation using specific inhibitors prevented neurite degeneration in these cells. These results suggested that the MAPK signal transduction pathway could play a key role in Aβ‐induced neurite degeneration. We sought to identify upstream elements of the MAPK signaling cascade activated by Aβ deposition. We evaluated the participation of the integrins in this pathway by monitoring the activation of MAPK in the presence of specific integrin inhibitors. Our results indicate that pretreatment of mature hippocampal neurons with either echistatin or α1 integrin‐blocking antibodies prevented Aβ‐induced MAPK activation. In addition, the blockage of α1 activation prevented cell death induced by Aβ. Similar results were obtained when α1 and β1 integrin blocking antibodies were used combined. Taken collectively, these results identify α1 integrin and the α1 plus β1 integrin complexes as potential targets for therapeutic intervention in the Aβ signaling pathway in aging neurons. © 2004 Wiley‐Liss, Inc.
Quantification of hemorphins in Alzheimer's disease brains
Authors: Poljak Anne , McLean Catriona A. , Sachdev Perminder , Brodaty Henry , Smythe George A. 
Published: February 2004

AbstractThe hemorphins are a family of opioid receptor‐binding peptides originating from the β‐chain of hemoglobin and have been found at high levels within the central and peripheral nervous systems. In addition to opioid receptor binding, hemorphins have been shown to have a number of effects on the renin‐angiotensin system, including inhibition of angiotensin‐converting enzyme and angiotensin IV receptor binding. However, relatively few studies have examined the role of hemorphins in neurological diseases. Here we report the first study of hemorphins in Alzheimer's disease (AD) brains. Quantitative MALDI‐TOF mass spectrometry was employed to assess levels of LVV and VV hemorphin‐6 and ‐7 in 10 control and 10 AD brain tissue samples. LVV hemorphin‐6 and total hemorphin levels were elevated in AD temporal neocortex but not in hippocampus, occipital lobe, or frontal lobe. The elevation of hemorphins is probably indicative of a vascular abnormality resulting from cerebral amyloid angiopathy associated with both neurodegenerative disease and aging. © 2004 Wiley‐Liss, Inc.
Comparison of nerve terminal events in vivo effecting retrograde transport of vesicles containing neurotrophins or synaptic vesicle components
Authors: Weible M.W. , Ozsarac N. , Grimes M.L. , Hendry I.A. 
Published: February 2004

AbstractAlthough vesicular retrograde transport of neurotrophins in vivo is well established, relatively little is known about the mechanisms that underlie vesicle endocytosis and formation before transport. We demonstrate that in vivo not all retrograde transport vesicles are alike, nor are they all formed using identical mechanisms. As characterized by density, there are at least two populations of vesicles present in the synaptic terminal that are retrogradely transported along the axon: those containing neurotrophins (NTs) and those resulting from synaptic vesicle recycling. Vesicles containing nerve growth factor (NGF), NT‐3, or NT‐4 had similar densities with peak values at about 1.05 g/ml. Synaptic‐derived vesicles, labeled with anti‐dopamine β‐hydroxylase (DBH), had densities with peak values at about 1.16 g/ml. We assayed the effects of pharmacologic agents in vivo on retrograde transport from the anterior eye chamber to the superior cervical ganglion. Inhibitors of phosphatidylinositol‐3‐OH (PI‐3) kinase and actin function blocked transport of both anti‐DBH and NGF, demonstrating an essential role for these molecules in retrograde transport of both vesicle types. Dynamin, a key element in synaptic vesicle recycling, was axonally transported in retrograde and anterograde directions, and compounds able to interfere with dynamin function had a differential effect on retrograde transport of NTs and anti‐DBH. Okadaic acid significantly decreased retrograde axonal transport of anti‐DBH and increased NGF retrograde transport. We conclude that there are both different and common proteins involved in endocytosis and targeting of retrograde transport of these two populations of vesicles. © 2004 Wiley‐Liss, Inc.
Fc receptors and the common γ‐chain in experimental autoimmune encephalomyelitis
Authors: Szalai Alexander J. , Barnum Scott R. 
Published: February 2004

AbstractFcγ receptors (FcγRs), composed of a ligand‐binding α‐chain (FcRα) sometimes associated with the homodimeric, cell‐signaling common γ‐chain (FcRγ), comprise an important family of effector molecules linking humoral and cell‐mediated adaptive immunity and regulating innate immunity. In peripheral autoimmune diseases, FcγRs contribute to inflammation and tissue damage through inappropriate activation of macrophages and neutrophils, release of cytokines and oxidants, and destruction of autoantibody‐opsonized cells. In the central nervous system (CNS), the role of FcγRs in autoimmune disease such as multiple sclerosis (MS) remains largely unexplored despite extensive documentation of CNS‐specific antibodies in cerebrospinal fluid and plaques. Several studies have now examined the role of FcγRs in experimental autoimmune encephalomyelitis (EAE), the animal model for MS, using mice genetically deficient in one or more FcγRs or in FcRγ. These studies indicate that none of the FcγR α‐chains are critical for EAE development and progression. In contrast, it is unequivocal that FcRγ contributes to EAE, and surprisingly it seems that this effect is independent of FcγRs. Recent studies now indicate that FcRγ expression in γδ T cells, most likely as a component of the TCR/CD3 signaling complex, is a critical requirement for EAE development. These studies support previous evidence implicating a pathogenic role for γδ T cells in EAE. © 2004 Wiley‐Liss, Inc.
Curcumin has potent anti‐amyloidogenic effects for Alzheimer's β‐amyloid fibrils in vitro
Authors: Ono Kenjiro , Hasegawa Kazuhiro , Naiki Hironobu , Yamada Masahito 
Published: February 2004

AbstractInhibition of the accumulation of amyloid β‐peptide (Aβ) and the formation of β‐amyloid fibrils (fAβ) from Aβ, as well as the destabilization of preformed fAβ in the central nervous system, would be attractive therapeutic targets for the treatment of Alzheimer's disease (AD). We reported previously that nordihydroguaiaretic acid (NDGA) and wine‐related polyphenols inhibit fAβ formation from Aβ(1–40) and Aβ(1–42) and destabilize preformed fAβ(1–40) and fAβ(1–42) dose‐dependently in vitro. Using fluorescence spectroscopic analysis with thioflavin T and electron microscopic studies, we examined the effects of curcumin (Cur) and rosmarinic acid (RA) on the formation, extension, and destabilization of fAβ(1–40) and fAβ(1–42) at pH 7.5 at 37°C in vitro. We next compared the anti‐amyloidogenic activities of Cur and RA with NDGA. Cur and RA dose‐dependently inhibited fAβ formation from Aβ(1–40) and Aβ(1–42), as well as their extension. In addition, they dose‐dependently destabilized preformed fAβs. The overall activities of Cur, RA, and NDGA were similar. The effective concentrations (EC50) of Cur, RA, and NDGA for the formation, extension, and destabilization of fAβs were in the order of 0.1–1 μM. Although the mechanism by which Cur and RA inhibit fAβ formation from Aβ and destabilize preformed fAβ in vitro remains unclear, they could be a key molecule for the development of therapeutics for AD. © 2004 Wiley‐Liss, Inc.
Cell adhesion molecule L1 promotes neurite outgrowth of septal neurons
Authors: Frappé Isabelle , Wang Christine , Caines Geoffrey , Rideout‐Gros Shawna , Aubert Isabelle 
Published: February 2004

AbstractTo establish if the cell adhesion molecule L1 could promote neurite outgrowth of septal neurons, L1‐positive substrates were prepared by genetically modifying 3T3 fibroblasts with a retroviral vector encoding human L1 under the control of a negative tetracycline‐regulatory system. In several clones of L1‐transfected fibroblasts, L1 expression at the cell surface was prominent and efficiently regulated by doxycycline, a tetracycline analogue. In co‐culture of septal neurons and fibroblasts, a two‐dimensional fractionator probe provided systematic random sampling of the neurites to be measured. Septal neurons, isolated at embryonic Day 17, were found to express L1 in vitro and to extend significantly longer neurites when plated on L1‐expressing fibroblasts compared to control fibroblasts. The neurite outgrowth‐promoting effect of L1 was inhibited after a doxycycline treatment, which specifically suppressed L1 expression from the modified fibroblasts. The findings that septal neurons at embryonic Day 17 in vitro express L1 and respond to L1‐modulation suggest that this molecule is involved in development of the septohippocampal pathway. © 2004 Wiley‐Liss, Inc.
Oxidation of vitamin E and vitamin C and inhibition of brain mitochondrial oxidative phosphorylation by peroxynitrite
Authors: Vatassery Govind T. , Lai James C.K. , DeMaster Eugene G. , Smith W. Ed , Quach Hung T. 
Published: February 2004

AbstractThe effects of peroxynitrite (PN; product of the reaction between nitric oxide and superoxide) on mitochondrial respiration as well as oxidation of α‐tocopherol and ascorbic acid were studied. Mitochondria were isolated from brain hemispheres of 4‐month‐old male Fisher rats by standard centrifugation procedures utilizing Ficoll gradients. Treatment of brain mitochondria with PN caused a concentration‐dependent impairment of oxidative phosphorylation and depletion of the endogenous antioxidants α‐tocopherol and ascorbic acid. PN‐induced mitochondrial dysfunction was characterized by 1) decreases in state 3 respiration and oxidative phosphorylation, 2) loss of respiratory control [ratio of ADP‐stimulated (state 3) to basal (state 4) respiration], and 3) uncoupling of oxidative phosphorylation. PN did not function as a pure uncoupler, insofar as the increase in state 4 respiration was accompanied by a larger decrease in state 3 respiration. This contrasts with the uncoupling action of the protonophore carbonyl cyanide m‐chlorophenylhydrozone, which increases both state 3 and state 4 respiration. PN‐induced reduction in respiratory control and oxidative phosphorylation closely paralleled the oxidation of membrane tocopherol and were preceded by loss of ascorbate. α‐Tocopherol (the most potent biological lipid antioxidant) may have a unique role in protecting mitochondrial membranes from oxidative stress. The two antioxidant nutrients α‐tocopherol and ascorbate (which interact with each other and glutathione) may be intimately involved in protecting mitochondria in situations in which excessive release of superoxide and nitric oxide occurs under normal and/or pathological conditions. © 2004 Wiley‐Liss, Inc.
Elevated expression of a regulator of the G2/M phase of the cell cycle, neuronal CIP‐1‐associated regulator of cyclin B, in Alzheimer's disease
Authors: Zhu Xiongwei , McShea Andrew , Harris Peggy L.R. , Raina Arun K. , Castellani Rudy J. , Funk Jens Oliver , Shah Sapan , Atwood Craig , Bowen Richard , Bowser Robert , Morelli Laura , Perry George , Smith Mark A. 
Published: February 2004

AbstractAdult neurons are generally accepted to be in a quiescent, nonproliferative state. However, it is becoming increasingly apparent that, in Alzheimer's disease (AD), alterations in cell cycle machinery, suggesting an attempt to reenter cell cycle, relate temporally and topographically to degenerating neurons. These findings, together with the fact that neurons lack the necessary components for completion of mitosis, have led to the notion that an ill‐regulated attempt to reenter the cell cycle is associated with disease pathogenesis and, ultimately, neuronal degeneration. To understand better the role of such cell cycle abnormalities in AD, we undertook a study of CIP‐1‐associated regulator of cyclin B (CARB), a protein that associates with two key proteins, p21 and cyclin B, involved in cellular checkpoints in the cell cycle. Our results show that there are increases in CARB localized to intraneuronal neurofibrillary tangles and granulovacuolar degeneration in susceptible hippocampal and cortical neurons in AD. By marked contrast, CARB is found only at background levels in these neuronal populations in nondiseased age‐matched controls. Our data not only provide another line of evidence indicative of cell cycle abnormalities in neurons in AD but also lend further credence to the hypothesis that susceptible neurons may be arrested at the G2/M phase of the cell cycle before they die. Therefore, therapeutics targeted toward initiators of the cell cycle are likely to prove of great efficacy for the treatment of AD. © 2004 Wiley‐Liss, Inc.
Acute transplantation of olfactory ensheathing cells or Schwann cells promotes recovery after spinal cord injury in the rat
Authors: García‐Alías Guillermo , López‐Vales Rubén , Forés Joaquim , Navarro Xavier , Verdú Enrique 
Published: February 2004

AbstractWe compared the neurological and electrophysiological outcome, glial reactivity, and spared spinal cord connectivity promoted by acute transplantation of olfactory ensheathing cells (group OEC) or Schwann cells (group SC) after a mild injury to the rat spinal cord. Animals were subjected to a photochemical injury of 2.5 min irradiation at the T8 spinal cord segment. After lesion, a suspension containing 180,000 OECs or SCs was injected. A control group (group DM) received the vehicle alone. During 3 months postsurgery, behavioral skills were assessed with open field‐BBB scale, inclined plane, and thermal algesimetry tests. Motor (MEPs) and somatosensory evoked potentials (SSEPs) were performed to evaluate the integrity of spinal cord pathways, whereas lumbar spinal reflexes were evaluated by the H reflex responses. Glial fibrillary acidic protein and proteoglycan expressions were quantified immunohistochemically at the injured spinal segments, and the preservation of corticospinal and raphespinal tracts caudal to the lesion was evaluated. Both OEC‐ and SC‐transplanted groups showed significantly better results in all the behavioral tests than the DM group. Furthermore, the OEC group had higher MEP amplitudes and lower H responses than the other two groups. At the injury site, the area of spared parenchyma was greater in transplanted than in control injured rats. OEC‐transplanted animals had reduced astrocytic reactivity and proteoglycan expression in comparison with SC‐transplanted and DM rats. Taken together, these results indicate that transplantation of both OEC and SC has potential for restoration of injured spinal cords. OEC grafts showed superior ability to reduce glial reactivity and to improve functional recovery. © 2004 Wiley‐Liss, Inc.
Neural precursor cells derived from human embryonic brain retain regional specificity
Authors: Horiguchi Satoshi , Takahashi Jun , Kishi Yo , Morizane Asuka , Okamoto Yo , Koyanagi Masaomi , Tsuji Masayuki , Tashiro Kei , Honjo Tasuku , Fujii Shingo , Hashimoto Nobuo 
Published: February 2004

AbstractRecent studies have revealed that neural precursor cells can be expanded not only from the subventricular zone and hippocampus but also from other regions of the human embryonic brain. To determine the regional differences of these precursor cells, we divided the brain of a 9‐week‐old human embryo into four parts, i.e., telencephalon, diencephalon, mesencephalon, and rhombencephalon. All cultures of the tissues yielded neurospheres, and these spheres gave rise to neurons, astrocytes, and oligodendrocytes. An analysis of clonal populations revealed that these precursor cells were multipotent, and two region‐specific differences in neural precursor cells were revealed: 1) The precursor cells from the rostral part of the brain tended to proliferate faster than those from the caudal part, and 2) the precursor cells from the diencephalon and mesencephalon gave rise to more tyrosine hydoxylase (TH)‐positive neurons than those from the telencephalon and rhombencephalon. When 50‐day‐cultured spheres were caused to differentiate, the percentage of TH‐positive cells per total cell population was 1.2% for diencephalic and mesencephalic precursors, whereas it was 0.4% for telencephalic and rhombencephalic ones. Furthermore, the TH‐positive cells from diencephalic and mesencephalic precursors were large, multipolar, and γ‐aminobutyric acid (GABA)‐negative, which suggested that these cells were midbrain dopaminergic neurons. In contrast, TH‐positive cells from telencephalic and rhombencephalic precursors were small, bipolar, and GABA‐positive. These results suggest that human neural precursor cells might have the potential to differentiate into a variety of cells but retain regional specificity. © 2004 Wiley‐Liss, Inc.
Nerve growth factor, brain‐derived neurotrophic factor, and neurotrophin‐3 are sorted to dense‐core vesicles and released via the regulated pathway in primary rat cortical neurons
Authors: Wu Y.J. , Krüttgen A. , Möller J.C. , Shine D. , Chan J.R. , Shooter E.M. , Cosgaya J.M. 
Published: February 2004

AbstractNeurotrophins (NTs) play an important role in the modulation of synaptic transmission and in morphological changes in synaptic structures. Although there is agreement that brain‐derived neurotrophic factor (BDNF) is sorted to large dense‐core vesicles (LDCVs) and released via the regulated secretory pathway, there has been some dispute regarding the mode of secretion of nerve growth factor (NGF) and neurotrophin‐3 (NT‐3), two structurally related members of the NT family. In this study, we examined the subcellular localization and release characteristics of NGF, BDNF, and NT‐3 in adenovirus‐infected primary cortical neurons. We found that all members of the NT family colocalized with markers for the endoplasmic reticulum and Golgi within cell bodies and in a punctate manner with a marker for LDCVs within processes. Moreover, their release was triggered by depolarization, indicating that NGF, BDNF, and NT‐3 are released via the regulated secretory pathway. When neurons were coinfected with two separate adenoviruses coding for NGF or BDNF, both NTs showed almost complete vesicular colocalization within single cells, suggesting that different NTs might be packaged into shared vesicles. We also examined whether the two splice variants of NGF, the short and long precursors, differ in their release characteristics. We found that neurons infected with viruses coding for either splice variant released NGF in a regulated way. Overall, our study supports the notion that all members of the NT family undergo activity‐dependent regulated release from neurons, enabling them to act as “synaptotrophins” on electrically active neurons. © 2004 Wiley‐Liss, Inc.
Cytoplasmic domain of NCAM 180 reduces NCAM‐mediated neurite outgrowth
Authors: Büttner Bettina , Reutter Werner , Horstkorte Rüdiger 
Published: February 2004

AbstractThe neural cell adhesion molecule (NCAM) is one of the best‐characterized cell adhesion molecules of the immunoglobulin superfamily. In the nervous system, NCAM is involved in cell migration, axon fasciculation and in neurite outgrowth. Neurite outgrowth is mediated by homophilic NCAM‐NCAM interactions. Alternative splicing generates three major isoforms of NCAM differing in their intracellular portion. Two of them, NCAM 180 and NCAM 140, are transmembrane proteins with large intracellular domains. The present study is concerned with novel details of the intracellular domains of NCAM 140 and NCAM 180. We expressed these NCAM isoforms consisting only of the transmembrane and intracellular domains (without extracellular domains) in PC12 cells and elaborated their function in neurite outgrowth assays. Our data demonstrate that membrane‐associated NCAM 180 interferes with neurite outgrowth, whereas membrane‐associated NCAM 140 promotes neurite outgrowth. © 2004 Wiley‐Liss, Inc.
Neuronal MEK is important for normal fear conditioning in mice
Authors: Shalin Sara C. , Zirrgiebel Ute , Honsa Katya J. , Julien Jean‐Pierre , Miller Freda D. , Kaplan David R. , Sweatt J. David 
Published: February 2004

AbstractThe extracellular signal‐regulated kinase (ERK) cascade has received much attention for its possible role in neuronal synaptic plasticity. Although ERK activation has been linked to learning behaviors and activity‐dependent neuronal function, much of the acquired data has relied upon pharmacological agents that suppress ERK function in both neurons and nonneuronal cells. To determine the function of neuronal ERK activity in learning, a new line of transgenic mice was generated wherein dominant‐negative MEK1, the upstream obligate activator of ERK1/2, was expressed by using a neuronal‐specific and pan‐neuronal Tα1 α‐tubulin promoter element. Mice expressing this construct exhibited decreased ERK1/2 activity in the hippocampus and thus were tested for learning impairments. In a battery of control tests, including open field, rotarod, and shock threshold, the transgenic mice displayed no deficits and performed as well as their wild‐type littermate counterparts. However, the mice displayed a significant impairment in contextual fear conditioning compared with the wild‐type littermates. These findings indicate that the MEK1/ERK1/2 cascade within neurons plays an important role in the processes of learning and memory. © 2004 Wiley‐Liss, Inc.
Glucose transporter GLUT8 translocation in neurons is not insulin responsive
Authors: Shin Bo‐Chul , McKnight Robert A. , Devaskar Sherin U. 
Published: February 2004

AbstractWe examined the subcellular distribution of a novel glucose transporter isoform (GLUT8) in murine N2A neuroblastoma cells. Exogenous expression of GLUT8‐green fluorescent protein (GFP) DNA constructs mimicked the endogenous GLUT8 localization to intracellular vesicles and minimally to the Giantin‐positive Golgi. This distribution was unlike the distributions of endogenous GLUT1 and GLUT3 (predominant neuronal isoform), which were limited predominantly to the plasma membrane and minimal in the cytoplasm. Although GLUT4‐GFP (insulin responsive isoform) was expressed transiently, no endogenous GLUT4 was detected in N2A cells. By employing stable transfectants that expressed GLUT8‐GFP, the effect of insulin and insulin‐like growth factor‐I, potassium chloride (depolarized state), and 3% oxygen on translocation of GLUT8 to the plasma membrane of N2A cells was examined immunohistochemically and by subfractionation, followed by Western blot analysis. None of these agents translocated GLUT8 to the plasma membrane. However, when the internalization dileucine motif (L12,13) of GLUT8 was mutated to a dialanine motif (A12,13), GLUT8 colocalized with GLUT3 in the plasma membrane. We conclude that GLUT8 translocation to the N2A cellular plasma membrane is not observed secondary to the various stimuli investigated. Mutation of the N‐terminal dileucine motif led to constitutive GLUT8 localization in the plasma membrane. The endogenous stimulus required for translocating neuronal GLUT8 is unknown. This stimulus, which is necessary for uncoupling the “cytoplasmic vesicular anchor” of GLUT8, would be crucial for its glucose‐transporting function. © 2004 Wiley‐Liss, Inc.