Disease-related regressive alterations of forebrain cholinergic system in SOD1 mutant transgenic mice

Crochemore, Christophe; Peña-Altamira, Emiliano; Virgili, Marco; Monti, Barbara; Contestabile, Antonio

doi:10.1016/j.neuint.2004.12.004

Cited by 21 publications

(20 citation statements)

References 64 publications

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“…1B). A similar situation was also noticed regarding the hippocampus of G93A mice, in which ChAT activity was significantly decreased in normally fed animals, as previously reported, 4 but not in those supplemented with VPA (Fig. 1C).…”

Section: Resultssupporting

confidence: 89%

“…9,21 Noticeably, VPA administration was also able to counteract the cholinergic deficit that occurs in the hippocampus of advanced symptomatic mice, which is related to degenerative changes of the basal forebrain cholinergic system, previously described by us. 4 Our novel observation that RA significantly shortens the lifespan of G93A mice is somewhat surprising in light of the data that suggest deficiency of RAmediated signaling could underlie the sporadic forms of ALS. 15 Experiments of gene expression in the spinal cord of ALS patients and animal models have shown altered transcription of several genes involved in neuronal survival/death, including some genes of the pathways mediated by RA receptors.…”

Section: Discussionmentioning

confidence: 92%

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Long‐term dietary administration of valproic acid does not affect, while retinoic acid decreases, the lifespan of G93A mice, a model for amyotrophic lateral sclerosis

et al. 2009

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Mice bearing the mutated gene for Cu/Zn superoxide dismutase (G93A) are a good model for human amyotrophic lateral sclerosis (ALS). They develop progressive limb paralysis paralleled by loss of motor neurons of the cervical and lumbar spinal cord, which starts at 3-3.5 months of age and ends with death at 4-5 months. Several treatments have been attempted to delay clinical symptoms and to extend lifespan, and some have had modest beneficial effects. One such treatment, based on long-term administration of valproic acid (VPA), resulted in controversial results. We report here that, while dietary supplementation with high VPA dosage slows down motor neuron death, as assessed by measurement of a specific marker for cholinergic neurons in the spinal cord, it has no significant effect on lifespan. Recently, the hypothesis has been put forward that a deficiency of retinoic acid (RA) and its signaling may have a role in ALS. We report that long-term dietary supplementation with RA has no effect on the decrease of the cholinergic marker in the spinal cord, but it significantly shortens lifespan of G93A mice.

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Section: Resultssupporting

confidence: 89%

Section: Discussionmentioning

confidence: 92%

Long‐term dietary administration of valproic acid does not affect, while retinoic acid decreases, the lifespan of G93A mice, a model for amyotrophic lateral sclerosis

et al. 2009

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“…They develop paralysis symptoms by 3 months of age, undergo sizable motor neuron degeneration in the lumbar and cervical spinal cord by 100-115 days of age and show rapid disease progression with death occurring around 135 days of age (Crochemore et al 2005;Gurney 1994;Rowland 2000). The transcriptional profiles in the LSC, cortex and hippocampus of presymptomatic (55 days old) and symptomatic (110 days old), G93A mice were compared both with those of agematched WT-TgSOD1 mice and with those of non-Tg littermates.…”

Section: Resultsmentioning

confidence: 99%

“…We here investigated the relationship between disease progression and gene expression by comparing transcriptional profiles in affected spinal cord of mutant G93A-SOD1-expressing (G93A), wild-type SOD1 transgenic (WT-TgSOD1) and nontransgenic (non-Tg) mice. Gene expression was evaluated at two distinct ages: 55 and 110 days, representing presymptomatic and full-blown disease statuses in G93A mice, respectively (Crochemore et al 2005;Gurney 1994;Rowland 2000). At both ages, both mutation-related changes and variations associated with SOD1 transgenedriven overexpression were identified.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Profiling in the Lumbar Spinal Cord of a Mouse Model of Amyotrophic Lateral Sclerosis: A Role for Wild-Type Superoxide Dismutase 1 in Sporadic Disease?

D’Arrigo¹,

Colavito²,

Peña-Altamira

et al. 2010

J Mol Neurosci

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Mice bearing mutations of copper-zinc-superoxide dismutase recapitulate spinal cord motor neuron degeneration and disease progression occurring in human amyotrophic lateral sclerosis. We have investigated the relationship between disease progression and altered gene expression by comparing the transcriptional profiles in lumbar spinal cord, fronto-parietal cortex and hippocampus of mutant G93A-SOD1, wild-type SOD1 transgenic and non-transgenic mice. Gene expression was evaluated at 55 and 110 days of age, representing pre-symptomatic and advanced disease stages of G93A mice, respectively. Whereas no significant variations were detectable in cortical and hippocampal areas, several mutation-related changes were detected in the lumbar spinal cord at the symptomatic stage, consistent with a condition of neuronal distress. Also, at both ages, we found a number of transgene-related changes, i.e. variations occurring in both transgenic groups independently of the G93A mutation, with wild-type SOD1- and G93A-SOD1-overexpressing mice displaying global transcriptional similarity at 110 days of age. Some of the changes in common between the two transgenic groups involve genes implicated in oxidative stress, inflammation, spinocerebellar degeneration and other neurodegenerative disorders. The finding that gene expressional alterations potentially associated to cellular distress are shared by wild-type and mutant human SOD1-overexpressing mice raises the possibility that mutated (in familial ALS) or otherwise dysregulated (in sporadic ALS) SOD1 expression is a common pathogenetic substrate of the disease.

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“…In G93A mice at a symptomatic stage of the disease, assays of cholinergic activity at the main sites of motor neuron degeneration, i.e. the lumbar and the cervical spinal cord as well as the brain stem, revealed decreased ChAT catalytic activity [19] . In our study, the differentiated NSC-34 cells showed a more pronounced reduction in fluorescence and thus were largely affected.…”

Section: Vegf Supplementation Restores Chat Expressionmentioning

confidence: 97%

Vascular Endothelial Growth Factor Attenuates Neurodegenerative Changes in the NSC-34 Motor Neuron Cell Line Induced by Cerebrospinal Fluid of Sporadic Amyotrophic Lateral Sclerosis Patients

et al. 2011

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Background: Motor neuron disease or amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord as well as motor cortex. Recently, vascular endothelial growth factor (VEGF) has been identified as a neurotrophic factor in animal models of familial ALS and other neurological diseases. Objective: The present study was designed to investigate the neuroprotective role of VEGF in the more prevalent sporadic form of ALS. Methods: We studied the effect of VEGF on the NSC-34 cell line exposed to cerebrospinal fluid (CSF) from sporadic ALS patients (ALS-CSF) in terms of lactate dehydrogenase (LDH) assay as well as choline acetyltransferase (ChAT) and phosphorylated neurofilament expression by immunocytochemistry and confocal microscopy. NSC-34 cells were exposed to CSF from patients with definite ALS and compared to controls. LDH activity was assessed in the growth media, prior to and 24 h after the addition of VEGF to the cells. At similar time points, the cells were fixed and processed for immunocytochemistry to evaluate ChAT and phosphorylated neurofilament expression. Results: Exposure to ALS-CSF caused morphological changes of NSC-34 cells like reduced differentiation and aggregation of phosphorylated neurofilaments. Enhanced LDH activity and reduced ChAT immunoreactivity were also observed. Addition of VEGF to NSC-34 cells exposed to ALS-CSF was protective in terms of reduced LDH activity and restoration of ChAT expression. Conclusion: The present study confirms that VEGF exerts a neuroprotective effect on the NSC-34 cell line by attenuating the degenerative changes induced by ALS-CSF. It thus has therapeutic potential in sporadic ALS.

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Disease-related regressive alterations of forebrain cholinergic system in SOD1 mutant transgenic mice

Cited by 21 publications

References 64 publications

Long‐term dietary administration of valproic acid does not affect, while retinoic acid decreases, the lifespan of G93A mice, a model for amyotrophic lateral sclerosis

Long‐term dietary administration of valproic acid does not affect, while retinoic acid decreases, the lifespan of G93A mice, a model for amyotrophic lateral sclerosis

Transcriptional Profiling in the Lumbar Spinal Cord of a Mouse Model of Amyotrophic Lateral Sclerosis: A Role for Wild-Type Superoxide Dismutase 1 in Sporadic Disease?

Vascular Endothelial Growth Factor Attenuates Neurodegenerative Changes in the NSC-34 Motor Neuron Cell Line Induced by Cerebrospinal Fluid of Sporadic Amyotrophic Lateral Sclerosis Patients

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