bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuronal transfer of the human Cu/Zn superoxide dismutase gene increases the resistance of dopaminergic neurons to 6‐hydroxydopamine
Authors: Barkats Martine , Millecamps Stéphanie , Bilang‐Bleuel Alicia , Mallet Jacques 
Published: March 2003

AbstractSeveral mechanisms are thought to be involved in the progressive decline in neurons of the substantia nigra pars compacta (SNpc) that leads to Parkinson's disease (PD). Neurotoxin 6‐hydroxydopamine (6‐OHDA), which induces parkinsonian symptoms in experimental animals, is thought to be formed endogenously in patients with PD through dopamine (DA) oxidation and may cause dopaminergic cell death via a free radical mechanism. We therefore investigated protection against 6‐OHDA by inhibiting oxidative stress using a gene transfer strategy. We overexpressed the antioxidative Cu/Zn‐superoxide dismutase (SOD1) enzyme in primary culture dopaminergic cells by infection with an adenovirus carrying the human SOD1 gene (Ad‐hSOD1). Survival of the dopaminergic cells exposed to 6‐OHDA was 50% higher among the SOD1‐producing cells than the cells infected with control adenoviruses. In contrast, no significant increased survival of (6‐OHDA)‐treated dopaminergic cells was observed when they were infected with an adenovirus expressing the H2O2‐scavenging glutathione peroxidase (GPx) enzyme. These results underline the major contribution of superoxide in the dopaminergic cell death process induced by 6‐OHDA in primary cultures. Overall, this study demonstrates that the survival of the dopaminergic neurons can be highly increased by the adenoviral gene transfer of SOD1. An antioxidant gene transfer strategy using viral vectors expressing SOD1 is therefore potentially beneficial for protecting dopaminergic neurons in PD.
Expression of CD47/integrin‐associated protein induces death of cultured cerebral cortical neurons
Authors: Koshimizu Hisatsugu , Araki Toshiyuki , Takai Satomi , Yokomaku Daisaku , Ishikawa Yasuyuki , Kubota Misae , Sano Shin‐ichiro , Hatanaka Hiroshi , Yamada Masashi 
Published: March 2003

AbstractThe death and survival of neuronal cells are regulated by various signaling pathways during development of the brain and in neuronal diseases. Previously, we demonstrated that the neuronal adhesion molecule brain immunoglobulin‐like molecule with tyrosine‐based activation motifs/SHP substrate 1 (BIT/SHPS‐1) is involved in brain‐derived neurotrophic factor (BDNF)‐promoted neuronal cell survival. Here, we report the apoptosis‐inducing effect of CD47/integrin‐associated protein (IAP), the heterophilic binding partner of BIT/SHPS‐1, on neuronal cells. We generated a recombinant adenovirus vector expressing a neuronal form of CD47/IAP, and found that the expression of CD47/IAP by infection with CD47/IAP adenovirus induced the death of cultured cerebral cortical neurons. The numbers of TdT‐mediated biotin–dUTP nick‐end labelling (TUNEL)‐positive neurons and of cells displaying apoptotic nuclei increased by expression of CD47/IAP. Neuronal cell death was prevented by the addition of the broad‐spectrum caspase inhibitor Z‐VAD‐fmk. Furthermore, we observed that co‐expression of CD47/IAP with BIT/SHPS‐1 enhanced neuronal cell death, and that BDNF prevented it. These results suggest that CD47/IAP is involved in a novel pathway which regulates caspase‐dependent apoptosis of cultured cerebral cortical neurons. CD47/IAP‐induced death of cultured cortical neurons may be regulated by the interaction of CD47/IAP with BIT/SHPS‐1 and by BDNF.
Caspase cleavage of members of the amyloid precursor family of proteins
Authors: Galvan Veronica , Chen Sylvia , Lu Daniel , Logvinova Anna , Goldsmith Paul , Koo Edward H. , Bredesen Dale E. 
Published: March 2003

AbstractThe synapse loss and neuronal cell death characteristic of Alzheimer's disease (AD) are believed to result in large part from the neurotoxic effects of β‐amyloid peptide (Aβ), a 40–42 amino acid peptide(s) derived proteolytically from β‐amyloid precursor protein (APP). However, APP is also cleaved intracellularly to generate a second cytotoxic peptide, C31, and this cleavage event occurs in vivo as well as in vitro and preferentially in the brains of AD patients (Lu et al. 2000). Here we show that APPC31 is toxic to neurons in primary culture, and that like APP, the APP family members APLP1 and possibly APLP2 are cleaved by caspases at their C‐termini. The carboxy‐terminal peptide derived from caspase cleavage of APLP1 shows a degree of neurotoxicity comparable to APPC31. Our results suggest that even though APLP1 and APLP2 cannot generate Aβ, they may potentially contribute to the pathology of AD by generating peptide fragments whose toxicity is comparable to that of APPC31.
Generation of C‐terminally truncated amyloid‐β peptides is dependent on γ‐secretase activity
Authors: Beher Dirk , Wrigley Jonathan D. J. , Owens Andrew P. , Shearman Mark S. 
Published: March 2003

AbstractAberrant production of amyloid‐β peptides by processing of the β‐amyloid precursor protein leads to the formation of characteristic extracellular protein deposits which are thought to be the cause of Alzheimer's disease. Therefore, inhibiting the key enzymes responsible for amyloid‐β peptide generation, β‐ and γ‐secretase may offer an opportunity to intervene with the progression of the disease. In human brain and cell culture systems a heterogeneous population of amyloid‐β peptides with various truncations is detected and at present, it is unclear how they are produced. We have used a combination of surface enhanced laser desorption/ionization time‐of‐flight mass spectrometry (SELDI‐TOF MS) and a specific inhibitor of γ‐secretase to investigate whether the production of all amyloid‐β peptide species requires the action of γ‐secretase. Using this approach, we demonstrate that the production of all truncated amyloid‐β peptides except those released by the action of the nonamyloidogenic α‐secretase enzyme or potentially beta‐site βAPP cleaving enzyme 2 depends on γ‐secretase activity. This indicates that none of these peptides are generated by a separate enzyme entity and a specific inhibitor of the γ‐secretase enzyme should havethe potential to block the generation of all amyloidogenicpeptides. Furthermore in the presence of γ‐secretase inhibitors, the observation of increased cleavage of the membrane‐bound βAPP C‐terminal fragment C99 by α‐secretase suggests that during its trafficking C99 encounters compartments in which α‐secretase activity resides.
1‐Methyl‐4‐phenylpyridinium ion, a toxin that can cause parkinsonism, alters branched structures of DNA
Authors: Iwaasa Mitsutoshi , Umeda Shuyo , Ohsato Takashi , Takamatsu Chihiro , Fukuoh Atushi , Iwasaki Hiroshi , Shinagawa Hideo , Hamasaki Naotaka , Kang Dongchon 
Published: March 2003

AbstractDuring replication, human mitochondrial DNA (mtDNA) takes on a triple‐stranded structure known as a D‐loop, which is implicated in replication and transcription. 1‐Methyl‐4‐phenylpyridinium ion (MPP+), a toxin inducing parkinsonism, inhibits mtDNA replication, possibly by resolving the D‐loops. For initiation of mtDNA replication, mitochondria are thought to have another triple‐stranded structure, an R‐loop. The R‐loop, which is resolved by a bacterial junction‐specific helicase, RecG, is also resolved by MPP+. Because mitochondrial D‐loops are likewise resolved by RecG, the D‐ and R‐loops may share a similar branched structure. MPP+ resolves cruciform DNA in supercoiled DNA. MPP+ converts a stacked conformation to an extended conformation in a synthetic Holliday junction. This conversion is reversed by 1 mm Mg2+, as is the resolution of the D‐loops or cruciform DNA. These observations suggest that the junction structure of mitochondrial D‐ and R‐loops is affected by MPP+.
No correlation between aggregates of Cu/Zn superoxide dismutase and cell death in familial amyotrophic lateral sclerosis
Authors: Lee J. P. , Gerin C. , Bindokas V. P. , Miller R. , Ghadge G. , Roos R. P. 
Published: March 2003

AbstractAggregates of Cu/Zn superoxide dismutase (SOD) have been demonstrated in familial amyotrophic lateral sclerosis (FALS) and other neurodegenerative diseases; however, their role in disease pathogenesis is unclear. In this study, we investigated the presence of SOD aggregates in nerve growth factor (NGF)‐differentiated PC12 cells and cell viability following: (i) transduction with replication‐deficient recombinant adenoviruses (AdVs) expressing wild‐type SOD (SODWT) or mutant SOD (SODMT, V148G or A4V); (ii) transfection of yellow fluorescent protein‐tagged SODWT (SODWT‐YFP) or SODMT (SODA4V‐YFP, SODV148G‐YFP). SOD aggregates were more prominent in cells following transduction of AdSODMT than AdSODWT and following treatment with H2O2, suggesting that mutant SOD leads to oxidation of cellular components. In addition, cells expressing SODMT‐YFP yielded SOD aggregates that were significantly larger and more frequent than SOD aggregates in cells expressing SODWT‐YFP. Proteasome inhibitors, but not cathepsin B inhibitors, increased aggregate formation but did not increase cell death. In addition, treatments that increased cell viability did not significantly decrease SOD aggregates. Taken together, our data demonstrate that there is no association between SOD aggregates and cell death in FALS.
Deletion of the glutamate carboxypeptidase II gene in mice reveals a second enzyme activity that hydrolyzes N‐acetylaspartylglutamate
Authors: Bacich Dean J. , Ramadan Epolia , O'Keefe Denise S. , Bukhari Noreen , Wegorzewska Iga , Ojeifo Olumide , Olszewski Rafal , Wrenn Craige C. , Bzdega Tomasz , Wroblewska Barbara , Heston Warren D. W. , Neale Joseph H. 
Published: March 2003

AbstractGlutamate carboxypeptidase II (GCPII, EC 3.14.17.21) is a membrane‐bound enzyme found on the extracellular face ofglia. The gene for this enzyme is designated FOLH1 in humans and Folh1 in mice. This enzyme has been proposed to be responsible for inactivation of the neurotransmitter N‐acetylaspartylglutamate (NAAG) following synaptic release. Mice harboring a disruption of the gene for GCPII/Folh1 were generated by inserting into the genome a targeting cassette in which the intron–exon boundary sequences of exons 1 and 2 were removed and stop codons were inserted in exons 1 and 2. Messenger RNA for GCPII was not detected by northern blotting or RT‐PCR analysis of RNA from the brains of –/– mutant mice nor was GCPII protein detected on western blots of this tissue. These GCPII null mutant mice developed normally to adulthood and exhibited a normal range of neurologic responses and behaviors including mating, open field activity and retention of position in rotorod tests. No significant differences were observed among responses of wild type, heterozygous mutant and homozygous mutant mice on tail flick and hot plate latency tests. Glutamate, NAAG and mRNA for metabotropic glutamate receptor type 3 levels were not significantly altered in response to the deletion of glutamate carboxypeptidase II. A novel membrane‐bound NAAG peptidase activity was discovered in brain, spinal cord and kidney of the GCPII knock out mice. The kinetic values for brain NAAG peptidase activity in the wild type and GCPII nullmutant were Vmax = 45 and 3 pmol/mg/min and Km = 2650 nm and 2494 nm, respectively. With the exception of magnesium and copper, this novel peptidase activity had a similar requirement for metal ions as GCPII. Two potent inhibitors of GCPII, 4,4′‐phosphinicobis‐(butane‐1,3 dicarboxilic acid) (FN6) and 2‐(phosphonomethyl)pentanedioic acid (2‐PMPA) inhibited the residual activity. The IC50 value for 2‐PMPA was about 1 nm for wild‐type brain membrane NAAG peptidase activity consistent with its activity against cloned ratand human GCPII, and 88 nm for the activity in brain membranes of the null mutants.
Increased vulnerability of dopaminergic neurons in MPTP‐lesioned interleukin‐6 deficient mice
Authors: Bolin Laurel M. , Strycharska‐Orczyk Iwona , Murray Richard , Langston J. William , Di Monte Donato 
Published: March 2003

AbstractTo test the hypothesis that neuroinflammation contributes to dopaminergic neuron death in the MPTP‐lesioned mouse, we compared nigrostriatal degeneration in interleukin (IL)‐6 (+/+) with IL‐6 (–/–) mice. In the absence of IL‐6, a single injection of MPTP (30 mg/kg) resulted in significantly greater striatal dopamine depletion than that measured in IL‐6 (+/+) mice. The observed dopamine depletion was MPTP dose dependent. This loss of striatal dopamine and a significantly greater loss of TH+ cells in the substantia nigra pars compacta in IL‐6 (–/–) mice as compared with control IL‐6 (+/+) mice, suggest that IL‐6 is neuroprotective in the MPTP‐lesioned nigrostriatal system. Co‐localization experiments identified striatal astrocytes as the source of IL‐6 in IL‐6 (+/+) mice at 1 and 7 days postinjection of MPTP. The increased sensitivity of dopaminergic neurons to neurotoxicant in the absence of IL‐6, is compatible with a neuroprotective activity of IL‐6 in the injured nigrostriatal system.
Involvement of Gadd153 in the pathogenic action of presenilin‐1 mutations
Authors: Milhavet Ollivier , Martindale Jennifer L. , Camandola Simonetta , Chan Sic L. , Gary Devin S. , Cheng Aiwu , Holbrook Nikki J. , Mattson Mark P. 
Published: March 2003

AbstractMutations in the presenilin‐1 (PS1) gene cause early onset familial Alzheimer's disease (FAD) by a mechanism believed to involve perturbed endoplasmic reticulum (ER) function and altered proteolytic processing of the amyloid precursor protein. We investigated the molecular mechanisms underlying cell death and ER dysfunction in cultured cells and knock‐in mice expressing FAD PS1 mutations. We report that PS1 mutations cause a marked increase in basal protein levels of the pro‐apoptotic transcription factor Gadd153. PS1 mutations increase Gadd153 protein translation without affecting mRNA levels, while decreasing levels of the anti‐apoptotic protein Bcl‐2. Moreover, an exaggerated Gadd153 response to stress induced by ER stress agents was observed in PS1 mutant cells. Cell death in response to ER stress is enhanced by PS1 mutations, and this endangering effect is attenuated by anti‐sense‐mediated suppression of Gadd153 production. An abnormality in the translational regulation of Gadd153 may sensitize cells to the detrimental effects of ER stress and contribute to the pathogenic actions of PS1 mutations in FAD.
Signaling mechanisms that regulate actin‐based motility processes in the nervous system
Authors: Meyer Gary , Feldman Eva L. 
Published: March 2003

AbstractActin‐based motility is critical for nervous system development. Both the migration of neurons and the extension of neurites require organized actin polymerization to push the cell membrane forward. Numerous extracellular stimulants of motility and axon guidance cues regulate actin‐based motility through the rho GTPases (rho, rac, and cdc42). The rho GTPases reorganize the actin cytoskeleton, leading to stress fiber, filopodium, or lamellipodium formation. The activity of the rho GTPases is regulated by a variety of proteins that either stimulate GTP uptake (activation) or hydrolysis (inactivation). These proteins potentially link extracellular signals to the activation state of rho GTPases. Effectors downstream of the rho GTPases that directly influence actin polymerization have been identified and are involved in neurite development. The Arp2/3 complex nucleates the formation of new actin branches that extend the membrane forward. Ena/VASP proteins can cause the formation of longer actin filaments, characteristic of growth cone actin morphology, by preventing the capping of barbed ends. Actin‐depolymerizing factor (ADF)/cofilin depolymerizes and severs actin branches in older parts of the actin meshwork, freeing monomers to be re‐incorporated into actively growing filaments. The signaling mechanisms by which extracellular cues that guide axons to their targets lead to direct effects on actin filament dynamics are becoming better understood.
Increased methamphetamine‐induced locomotor activity and behavioral sensitization in histamine‐deficient mice
Authors: Kubota Yasuhiko , Ito Chihiro , Sakurai Eiichi , Sakurai Eiko , Watanabe Takehiko , Ohtsu Hiroshi 
Published: March 2003

AbstractWe have recently suggested that the brain histamine has an inhibitory role on the behavioral effects of methamphetamine by pharmacological studies. In this study, we used the histidine decarboxylase gene knockout mice and measured the spontaneous locomotor activity, the changes of locomotion by single and repeated administrations of methamphetamine, and the contents of brain monoamines and amino acids at 1 h after a single administration of methamphetamine. In the histidine decarboxylase gene knockout mice, spontaneous locomotor activity during the dark period was significantly lower than in the wild‐type mice. Interestingly, methamphetamine‐induced locomotor hyperactivity and behavioral sensitization were facilitated more in the histidine decarboxylase gene knockout mice. In the neurochemical study, noradrenaline and O‐phosphoserine were decreased in the midbrain of the saline‐treated histidine decarboxylase gene knockout mice. On the other hand, single administration of methamphetamine decreased GABA content of the midbrain of the wild‐type mice, but did not alter that of histidine decarboxylase gene knockout mice. These results suggest that the histamine neuron system plays a role as an awakening amine in concert with the noradrenaline neuron system, whereas it has an inhibitory role on the behavioral effects of methamphetamine through the interaction with the GABAergic neuron system.
The neuropathogenic contributions of lysosomal dysfunction
Authors: Bahr Ben A. , Bendiske Jennifer 
Published: March 2003

AbstractMultiple lines of evidence implicate lysosomes in a variety of pathogenic events that produce neurodegeneration. Genetic mutations that cause specific enzyme deficiencies account for more than 40 lysosomal storage disorders. These mostly pre‐adult diseases are associated with abnormal brain development and mental retardation. Such disorders are characterized by intracellular deposition and protein aggregation, events also found in age‐related neurodegenerative diseases including (i) Alzheimer's disease and related tauopathies (ii) Lewy body disorders and synucleinopathies such as Parkinson's disease, and (iii) Huntington's disease and other polyglutamine expansion disorders. Of particular interest for this review is evidence that alterations to the lysosomal system contribute to protein deposits associated with different types of age‐related neurodegeneration. Lysosomes are in fact highly susceptible to free radical oxidative stress in the aging brain, leading to the gradual loss of their processing capacity over the lifespan of an individual. Several studies point to this lysosomal disturbance as being involved in amyloidogenic processing, formation of paired helical filaments, and the aggregation of α‐synuclein and mutant huntingtin proteins. Most notably, experimentally induced lysosomal dysfunction, both in vitro and in vivo, recapitulates important pathological features of age‐related diseases including the link between protein deposition and synaptic loss.
Neuroprotective effects of bcl‐2 overexpression in hippocampal cultures: interactions with pathways of oxidative damage
Authors: Howard Sarah , Bottino Clement , Brooke Sheila , Cheng Elise , Giffard Rona G. , Sapolsky Robert 
Published: March 2003

AbstractOverexpression of bcl‐2protects neurons from numerous necrotic insults, both in vitro and in vivo. While the bulk of such protection is thought to arise from Bcl‐2 blocking cytochrome c release from mitochondria, thereby blocking apoptosis, the protein can target other steps in apoptosis, and can protect against necrotic cell death as well. There is evidence that these additional actions may be antioxidant in nature, in that Bcl‐2 has been reported to protect against generators of reactive oxygen species (ROS), to increase antioxidant defenses and to decrease levels of ROS and of oxidative damage. Despite this, there are also reports arguing against either the occurrence, or the importance of these antioxidant actions. We have examined these issues in neuron‐enriched primary hippocampal cultures, with overexpression of bcl‐2 driven by a herpes simplex virus amplicon: (i) Bcl‐2 protected strongly against glutamate, whose toxicity is at least partially ROS‐dependent. Such protection involved reduction in mitochondrially derived superoxide. Despite that, Bcl‐2 had no effect on levels of lipid peroxidation, which is thought to be the primary locus of glutamate‐induced oxidative damage; (ii) Bcl‐2 was also mildly protective against the pro‐oxidant adriamycin. However, it did so without reducing levels of superoxide, hydrogen peroxide or lipid peroxidation; (iii) Bcl‐2 protected against permanent anoxia, an insult likely to involve little to no ROS generation. These findings suggest that Bcl‐2 can have antioxidant actions that may nonetheless not be central to its protective effects, can protect against an ROS generator without targeting steps specific to oxidative biochemistry, and can protect in the absence of ROS generation. Thus, the antioxidant actions of Bcl‐2 are neither necessary nor sufficient to explain its protective actions against these insults in hippocampal neurons.
High transcytosis of melanotransferrin (P97) across the blood–brain barrier
Authors: Demeule Michel , Poirier Julie , Jodoin Julie , Bertrand Yanick , Desrosiers Richard R. , Dagenais Claude , Nguyen Tran , Lanthier Julie , Gabathuler Reinhard , Kennard Malcolm , Jefferies Wilfred A. , Karkan Delara , Tsai Sam , Fenart Laurence , Cecchelli Roméo , Béliveau Richard 
Published: March 2003

AbstractThe blood–brain barrier (BBB) performs a neuroprotective function by tightly controlling access to the brain; consequently it also impedes access of proteins as well as pharmacological agents to cerebral tissues. We demonstrate here that recombinant human melanotransferrin (P97) is highly accumulated into the mouse brain following intravenous injection and in situ brain perfusion. Moreover, P97 transcytosis across bovine brain capillary endothelial cell (BBCEC) monolayers is at least 14‐fold higher than that of holo‐transferrin, with no apparent intra‐endothelial degradation. This high transcytosis of P97 was not related to changes in the BBCEC monolayer integrity. In addition, the transendothelial transport of P97 was sensitive to temperature and was both concentration‐ and conformation‐dependent, suggesting that the transport of P97 is due to receptor‐mediated endocytosis. In spite of the high degree of sequence identity between P97 and transferrin, a different receptor than the one for transferrin is involved in P97 transendothelial transport. A member of the low‐density lipoprotein receptor protein family, likely LRP, seems to be involved in P97 transendothelial transport. The brain accumulation, high rate of P97 transcytosis and its very low level in the blood suggest that P97 could be advantageously employed as a new delivery system to target drugs directly to the brain.