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C W Cotman

Publications and source records attributed to C W Cotman.

At least 55 records · Page 3Linked to original sources
PubMed2000

Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus.

Brain-derived neurotrophic factor, the most abundant of the neurotrophins in the brain, enhances the growth and maintenance of several neuronal systems, serves as a neurotransmitter modulator, and participates in use-dependent plasticity mechanisms such as long-term potentiation and learning. In recent years, evidence has been gathering that brain-derived neurotrophic factor may have an important role in the neuropathology and treatment of depression. It has recently been reported that chronic (at least two weeks) antidepressant treatment leads to an up-regulation of brain-derived neurotrophic factor messenger RNA levels in the hippocampus, an important brain area for behavioral regulation, as well as learning and memory. Our laboratory has previously shown that general physical exercise very rapidly increases brain-derived neurotrophic factor messenger RNA in this brain area. In this report, we have tested the hypothesis that the combination of these two interventions, general physical activity and antidepressant treatment, leads to increased levels of specific promoter-derived transcripts of brain-derived neurotrophic factor messenger RNA in a manner that appears to be both additive and accelerated. Our results suggest that these two very different interventions may possibly converge at the cellular level. The induction of brain-derived neurotrophic factor expression by activity/pharmacological treatment combinations could represent an important intervention for further study, to potentially improve depression treatment and management.

Animals↗
PubMed2000

Ultrastructural evidence of fibrillar beta-amyloid associated with neuronal membranes in behaviorally characterized aged dog brains.

The aged dog brain accumulates beta-amyloid in the form of diffuse senile plaques, which provides a potentially useful in vivo model system for studying the events surrounding the deposition of beta-amyloid. We used postembedding immunocytochemistry at the electron microscopic level to determine the subcellular distribution of beta-amyloid 1-40 and beta-amyloid 1-42 peptides in the prefrontal and parietal cortex of behaviorally characterized dogs ranging in age from one to 17 years. Immunogold particles signaling beta-amyloid 1-42 occurred over intracellular and extracellular fibrils that were approximately 8 nm in width. Intracellular beta-amyloid 1-42 fibrils were found in close proximity to glial fibrillary acidic protein fibers within astrocytes, but only in cells with signs of plasma membrane disruption. Neuronal labeling of beta-amyloid 1-42 appears to be associated with the plasma membrane. Membrane-bound beta-amyloid 1-42 occurs in the form of fine fibrils that are embedded in the dendritic membrane and appear to project into the extracellular space as determined by quantitative analysis of the immunogold particle distribution. Bundles of beta-amyloid 1-42 were also closely associated and/or integrated with degenerating myelin sheaths of axons. In one dog that was impaired on several cognitive tasks, extensive beta-amyloid 1-42 deposition was associated with microvacuolar changes and vascular pathology. The present findings suggest that beta-amyloid 1-42 may be generated at the dendritic plasma membrane as well as in intracellular compartments. The close association between beta-amyloid 1-42 and destroyed myelin suggests one possible new mechanism by which beta-amyloid 1-42 induces neurodegeneration.

Amyloid beta-Peptides↗
PubMed2000

A monoclonal antibody to amyloid precursor protein induces neuronal apoptosis.

Although there is considerable evidence suggesting that altered metabolism of beta-amyloid precursor protein (APP) and accumulation of its beta-amyloid fragment are key features of Alzheimer's disease (AD), the normal physiological function of APP remains elusive. We investigated the potential role of APP in neurons using the monoclonal antibody 22C11, which binds to the extracellular domain of the human, rat, or mouse APP. Exposure of cortical neurons to 22C11 induced morphological changes including neurite degeneration, nuclear condensation, and internucleosomal DNA cleavage that were consistent with neurons dying by apoptosis. Supporting a role for 22C11-mediated apoptosis occurring by binding to APP were data demonstrating that preincubation of 22C11 with either purified APP or a synthetic peptide (APP(66-81)) that contains the epitope for 22C11 significantly attenuated neuronal damage induced by 22C11. The specificity of 22C11 was further supported by data showing no apparent effects of either mouse IgG or the monoclonal antibody P2-1, which is specific for the aminoterminal end of human but not rat APP. In addition, biochemical features indicative of apoptosis were the formation of 120- and 150-kDa breakdown products of fodrin following treatment of cortical neurons with 22C11. Both the morphological and the biochemical changes induced by 22C11 were prevented following pretreatment of neurons with the general caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(O-methyl)-fluoromethyl ketone. Prior incubation of cortical neurons with GSH ethyl ester (GEE), a cell-permeable form of GSH, resulted in complete protection from the 22C11 insult, thus implicating an oxidative pathway in 22C11-mediated neuronal degeneration. This was further supported by the observation that prior treatment of neurons with buthionine sulfoximine, an inhibitor of gamma-glutamylcysteinyl synthetase, potentiated the toxic effects of 22C11. Finally, with use of compartmented cultures of hippocampal neurons, it was also demonstrated that selective application of 22C11 caused local neuritic degeneration that was prevented by the addition of GEE to the neuritic compartment. Thus, the binding of a monoclonal antibody to APP initially triggers neurite degeneration that is followed by caspase-dependent apoptosis in neuronal cultures and illustrates a novel property of this protein in neurons that may contribute to the profound neuronal cell death associated with AD.

Alzheimer Disease↗
PubMed2000

Expression of metabotropic glutamate receptor 5 is increased in astrocytes after kainate-induced epileptic seizures.

In the CNS there is a differential distribution of the metabotropic glutamate receptor 5 (mGluR5) in neurons and glia. Hippocampal nerve cells contain large amounts of the receptor transcript and protein that are expressed at very low levels in astrocytes. This is unexpected, as mGluR-induced phosphoinositide hydrolysis is substantial in cultured astrocytes and is mediated only by mGluR5 in these cells. In order to detect mGluR5 in astrocytes in vivo, we destroyed in a circumscribed part of the hippocampus nerve cells that have high level of receptor expression. Unilateral injection of kainate into the right amygdala produced epileptic seizures, as well as selective degeneration of nerve cells restricted to the ipsilateral CA3 and CA4 regions of the hippocampus, followed by the development of gliosis. In the affected fields only, mGluR5 immunoreactivity was severely reduced 3 days after kainate injection, followed by a progressive reappearance and lasting presence of the receptor protein. Receptor mRNA virtually disappeared from the pyramidal cell layer of the lesioned CA3/4 region. On the other hand, the message level increased persistently in the CA3 stratum lucidum and radiatum, the site of massive astrogliosis. In these sites, mGluR5 mRNA became detectable in double labeling studies in glial fibrillary acidic protein-positive astrocytes. We showed previously that growth factors induce a pronounced elevation of mGluR5 expression in cultured astrocytes (Miller et al. J Neurosci 15:-6109, 1995). The well-documented increase in the level of growth factors in the damaged brain may underlie the induction of the receptor expression in astrocytes in vivo, which may also be involved in repair processes in the injured nervous tissue.

Amygdala↗
PubMed1999

Sequence of neurodegeneration and accumulation of phosphorylated tau in cultured neurons after okadaic acid treatment.

Within neurofibrillary tangles and dystrophic neurites of Alzheimer's disease (AD), the cytoskeletal protein tau is abnormally hyperphosphorylated. In the present study, we examined the effect of okadaic acid (OA), a protein phosphatase inhibitor, in rat cultured neurons. Low concentrations of OA induce degeneration of neurites, rounding of cell bodies, detachment from the substratum, and eventual neuronal death. During OA-induced degeneration, SMI-31 immunoreactivity became punctate in neurites at 6 h after OA treatment, and over time, accumulated in cell bodies and dystrophic neurites. Hyperphosphorylation of tau and marked loss of MAP-2-positive dendrites occurred after 6 h of treatment with OA. Thereafter, AT-8 and PHF-1 immunoreactivity accumulated in cell bodies and subsequently appeared in distal axon-like neurites. These results demonstrate that OA treatment induced hyperphosphorylation of tau and preferential dendritic damage, with subsequent accumulation of phosphorylated tau in cell bodies and dystrophic axon-like neurites. OA-induced neurodegeneration may provide a useful model to study AD.

Animals↗
PubMed1999

Hippocampal BDNF mRNA shows a diurnal regulation, primarily in the exon III transcript.

Endogenous expression levels of brain-derived neurotrophic factor (BDNF) mRNA were assessed using in situ hybridization to investigate whether there is a natural diurnal fluctuation in BDNF mRNA expression in the hippocampus of rats housed with a normal (12:12 h) light/dark cycle. BDNF expression was increased during lights out (dark-cycle) to 134%-158% of light-cycle levels in hippocampal regions CA1, CA3, and hilus. In addition, expression levels of the four BDNF transcript forms, exons I-IV, were assessed to evaluate whether expression of specific BDNF transcripts exhibited differential endogenous fluctuation. All exons had lowest levels of expression at either noon or 6 p.m. Significant correlations were found between exon expression level and time, with elevated expression occurring at dark-cycle timepoints. The exon III transcript showed the greatest diurnal change in expression in all hippocampal fields, with dark-cycle expression elevated to 219-419% of light-cycle expression level. In addition to exon III, dark-cycle exon II mRNA levels were elevated in all hippocampal subfields, to 140-180% of light-cycle levels, suggesting that the endogenous fluctuation in BDNF expression results predominantly from activation of the promoters linked to exons II and III. Previously we have shown that physical activity increases BDNF expression. The naturally occurring rise in BDNF expression during the dark-cycle, the time when rats are most physically active, may be due to increased activity and arousal levels. Because BDNF has a role in plasticity, the increase in BDNF expression during the time that a rat is maximally interacting with its surroundings may be part of an ongoing stimulus-encoding mechanism, or may be a mechanism to maximize information storage about the environment.

Analysis of Variance↗
PubMed1999

Multiple pathways of apoptosis in PC12 cells. CrmA inhibits apoptosis induced by beta-amyloid.

Stable transfectants of PC12 cells expressing bcl-2 or crmA were generated and tested for their susceptibility to various apoptotic insults. Bcl-2 expression conferred resistance to apoptosis induced by staurosporine and by oxidative insults including hydrogen peroxide and peroxynitrite, but was less effective in inhibition of activation-induced programmed cell death induced by concanavalin A. Concanavalin A-induced apoptosis was abated, however, in cells expressing very high levels of bcl-2. In contrast, cells expressing crmA were protected from concanavalin A-induced apoptosis, but were as susceptible as control cells to apoptosis induced by staurosporine and oxidative insults. Therefore, at least two apoptotic pathways in PC12 cells can be discerned by their differential sensitivity to blockade by bcl-2 and crmA. The ability of beta-amyloid (Abeta) to induce apoptosis in these cells was assessed. CrmA transfectants were protected from apoptosis induced by Abeta1-42, but only cells expressing very high levels of bcl-2 were similarly protected. These results suggest that the apoptotic pathway activated by Abeta1-42 in PC12 cells can be differentiated from the apoptotic pathway activated by oxidative insults. Gene transfer experiments also demonstrated that expression of crmA in primary cultures of hippocampal neurons is protective against cell death induced by Abeta1-42. Together these results support the hypothesis that Abeta-induced apoptosis occurs through activation-induced programmed cell death.

Amyloid beta-Peptides↗
PubMed1999

Clinical and pathological evidence for a frontal variant of Alzheimer disease.

OBJECTIVE: To evaluate the clinical and pathological features of a subgroup of patients with Alzheimer disease (AD) who exhibited early and disproportionately severe impairments on tests of frontal lobe functioning. We hypothesized that these patients would exhibit a greater degree of either neurofibrillary tangle (NFT) or senile plaque pathology in the frontal lobes than would patients with typical AD. DESIGN AND OUTCOME MEASURES: We examined the neuropsychological profiles and senile plaque and NFT accumulation in the frontal, entorhinal, temporal, and parietal cortices in 3 patients with AD who exhibited disproportionate frontal impairments during early stages of dementia (frontal AD) and 3 matched patients with typical AD (typical AD). RESULTS: Compared with the typical AD group, the frontal AD group performed significantly worse on 2 tests of frontal lobe functioning and on the Wechsler Adult Intelligence Scale-Revised Block Design test. No significant group differences were found on other tests. Analysis of brain tissue samples demonstrated that, despite comparable entorhinal, temporal, and parietal NFT loads, the frontal AD group showed a significantly higher NFT load in the frontal cortex than the typical AD group. Senile plaque pathology in the frontal and entorhinal cortices did not differentiate the 2 groups. CONCLUSIONS: We identified a subgroup of patients with pathologically confirmed AD who presented in the early stages of dementia with disproportionate impairments on tests of frontal lobe functioning and had a greater-than-expected degree of NFT pathology in the frontal lobes, suggesting the existence of a frontal variant of AD that has distinctive clinical and pathological features.

Aged↗
PubMed1999

The presence of isoaspartic acid in beta-amyloid plaques indicates plaque age.

Extracellular deposits of fibrillar beta-amyloid are a characteristic neuropathology of Alzheimer's disease (AD). We have developed a novel antibody to a hypothesized "older isomer" of the amyloid protein. This antibody, raised against a synthetic beta-amyloid peptide containing isoaspartic acid at position 7 (isoaspartic-7-Abeta), reacts with isoaspartic-7-Abeta, a nonenzymatic modification found in long-lived proteins. Plaques stained with this antibody are thioflavine positive and are found throughout the frontal and entorhinal cortices of AD cases. In frontal cortex, isoaspartic-7-Abeta plaques are clustered but have a widespread distribution in all cortical layers. Isoaspartic-7-Abeta is found primarily in the core of individual plaques surrounded by nonisomerized amyloid. Activated microglia are associated with plaques containing isomerized and nonisomerized amyloid. In contrast to AD, isoaspartic-7-Abeta plaques in Down's syndrome (DS) cases are found primarily in the superficial layers of frontal cortex. Using image analysis isoaspartic-7-Abeta deposition was correlated with dementia severity in AD and with age in DS. The results indicate that this antibody against altered aspartyl amyloid could be a useful indicator of the age of amyloid plaques.

Adult↗
PubMed1999

Bcl-2 facilitates recovery from DNA damage after oxidative stress.

Oxidative stress is a major factor affecting the brain during aging and neurodegenerative diseases such as Alzheimer's disease (AD). Understanding the mechanisms by which neurons can be protected from oxidative stress, therefore, is critical for the prevention and treatment of such degeneration. Previous studies have shown that bcl-2 expression is increased in neurons with DNA damage in AD and bcl-2 has an antioxidant effect. The goal of this study is to document the effects of oxidative insults on mitochondrial and nuclear DNA in PC12 cells and determine the extent to which bcl-2 prevents damage or facilitates repair. Using extralong PCR to amplify nuclear and mitochondrial DNA, the time course of DNA damage and repair was determined. Within minutes after exposure of cells to low concentrations of hydrogen peroxide and peroxynitrite, significant mitochondrial and nuclear DNA damage was evident. Mitochondrial DNA was damaged to a greater degree than nuclear DNA. Expression of bcl-2 in PC12 cells inhibited nitric oxide donor (sodium nitroprusside)- and peroxynitrite-induced cell death. Although oxidative insults caused both genomic and mitochondrial DNA damage in cells expressing bcl-2, recovery from DNA damage was accelerated in these cells. These results suggest that neuronal up-regulation of bcl-2 may facilitate DNA repair after oxidative stress.

Animals↗
PubMed1999

Neuronal apoptosis induced by beta-amyloid is mediated by caspase-8.

The Alzheimer disease-associated beta-amyloid peptide has been shown to induce apoptotic neuronal death. In the present study, we test the hypothesis that the apoptotic pathway activated by beta-amyloid is similar to the pathway activated by the Fas/TNFR family of death receptors, which requires caspase-8 activity and adaptor proteins such as FADD. We demonstrate that the selective caspase-8 inhibitor IETD-fmk blocks neuronal death induced by beta-amyloid. Furthermore, using viral-mediated gene delivery, we show that neurons expressing dominant-negative FADD are protected from apoptosis induced by beta-amyloid. Together these results indicate that the apoptotic pathway activated by beta-amyloid requires both caspase-8 activity and FADD. These findings further support the hypothesis that beta-amyloid might initiate apoptosis by cross-linking death receptors of the Fas/TNFR family.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Exercise, antidepressant medications, and enhanced brain derived neurotrophic factor expression.

Physical activity and antidepressant treatment have each separately been of significant interest for the management of Alzheimer's disease (AD); particularly the behavioral problems associated with this dementing disorder. We have found that combined antidepressant treatment and physical activity have an additive, potentiating effect on BDNF mRNA expression within several areas of the rat hippocampus. During the 20-day experimental period, animals were treated daily with imipramine (15 mg/kg) or tranylcypromine (7.5 mg/kg) by intraperitoneal injection. Exercising rat groups were given access to running wheels for the duration of the experiment. BDNF mRNA levels were assessed in several cell groups of the hippocampus by in situ hybridization, using a [35S] labelled riboprobe complementary to the full-length BDNF sequence, and computer-assisted densitometry. The combination of physical activity and antidepressant treatment for the 20-day period led to a significant potentiation of full-length BDNF mRNA levels within the dentate gyrus and CA 1, CA 3, and CA 4 cellular fields, above the levels obtained with each intervention alone. These results provide impetus for the study of physical exercise as a potential enhancer of treatment response to antidepressants.

Animals↗
PubMed1999

Alzheimer's presenilin-1 mutation potentiates inositol 1,4,5-trisphosphate-mediated calcium signaling in Xenopus oocytes.

Perturbations in intracellular Ca2+ signaling may represent one mechanism underlying Alzheimer's disease (AD). The presenilin-1 gene (PS1), associated with the majority of early onset familial AD cases, has been implicated in this signaling pathway. Here we used the Xenopus oocyte expression system to investigate in greater detail the role of PS1 in intracellular Ca2+ signaling pathways. Treatment of cells expressing wild-type PS1 with a cell surface receptor agonist to stimulate the phosphoinositide second messenger pathway evoked Ca2+-activated Cl- currents that were significantly potentiated relative to controls. To determine which elements of the signal transduction pathway are responsible for the potentiation, we used photolysis of caged inositol 1,4,5-trisphosphate (IP3) and fluorescent Ca2+ imaging to demonstrate that PS1 potentiates IP3-mediated release of Ca2+ from internal stores. We show that an AD-linked mutation produces a potentiation in Ca2+ signaling that is significantly greater than that observed for wild-type PS1 and that cannot be attributed to differences in protein expression levels. Our findings support a role for PS1 in modulating IP3-mediated Ca2+ liberation and suggest that one pathophysiological mechanism by which PS1 mutations contribute to AD neurodegeneration may involve perturbations of this function.

Alzheimer Disease↗
PubMed1999

Pathogenic amyloid beta-protein induces apoptosis in cultured human cerebrovascular smooth muscle cells.

The amyloid beta-protein (A beta) pathologically accumulates in cerebral vascular and senile plaque deposits in the brains of patients with Alzheimer's disease (AD) and related disorders including hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D). The cerebrovascular deposits are accompanied by degeneration and eventual loss of smooth muscle cells in cerebral vessel wall. Similarly, we have shown that pathogenic forms of A beta cause cell death in cultured human cerebrovascular smooth muscle (HCSM) cells in vitro. Here we show that pathogenic A beta induces a number of structural changes in HCSM cells including shrinkage of cell bodies, retraction of processes, disruption of the intracellular actin network, and nuclear condensation and fragmentation. These changes were accompanied by a number of biochemical alterations in the cells shown by in situ end labeling of nuclear DNA, proteolytic breakdown of smooth muscle cell a actin, and proteolytic activation of the proteinase caspase 3. Together, these characteristics are consistent with an apoptotic mechanism of cell death in HCSM cells in response to pathogenic A beta.

Actins↗
PubMed1998

Exercise-induced regulation of brain-derived neurotrophic factor (BDNF) transcripts in the rat hippocampus.

Previous results from our laboratory indicate that two nights of voluntary wheel running upregulates brain-derived neurotrophic factor (BDNF) mRNA expression in the hippocampus. In order to investigate the time-course of the BDNF response and to examine how physical activity preferentially activates particular transcriptional pathways, the effects of 6 and 12 h of voluntary wheel running on BDNF and exons I-IV mRNA expression were investigated in rats. Hippocampal full-length BDNF mRNA expression was rapidly influenced by physical activity, showing significant increases in expression levels as soon as 6 h of voluntary wheel running. Moreover, there was a strong positive correlation between distance run and BDNF mRNA expression. Exon I mRNA expression was significantly upregulated after 6 h of running and was maintained or enhanced by 12 h of voluntary running. Exon II had a slower time-course and was significantly upregulated after 12 h, selectively in the CA1 hippocampal region. Exon III and Exon IV showed no significant increase in expression level after 6 or 12 h of running in the paradigm studied. It is significant that the rapid neurotrophin response is demonstrated for a physiologically relevant stimulus, as opposed to the extreme conditions of seizure paradigms. Furthermore, exercise-induced upregulation of BDNF may help increase the brain's resistance to damage and neurodegeneration that occurs with aging.

Animals↗
PubMed1998

Enhanced vulnerability to apoptotic cell death in sporadic Alzheimer's disease.

All important neuropathological features like neurodegeneration and amyloid deposition occur similarly in familial and in sporadic Alzheimer's disease (AD) patients, suggesting a common pathogenetic mechanism. We investigated whether defective vulnerabilty to the induction of the apoptotic cell death pathway might be one of the underlying mechanisms leading to progressive cell death in sporadic AD. Our test could prove useful in supporting the diagnosis of AD and in predicting individuals predisposed to AD.

Aged↗
PubMed1998

Microlithographic determination of axonal/dendritic polarity in cultured hippocampal neurons.

High resolution substrates, created using patterned self-assembled monolayers, are shown to direct axonal and dendritic process extension at the level of a single hippocampal neuron. Axons and dendrites were identified using morphological characteristics and immunocytochemical markers. Patterns were formed on glass coverslips from a co-planar monolayer of cell adhesive aminosilanes and non-adhesive fluorinated silanes. On patterned surfaces, the percentage of the total number of cells attached to the 0.71 mm2 substrate field with compliance to the 25-micron diameter 'somal adhesion site' reached 41 +/- 7% (mean +/- S.D., 428 cells counted). A total of 76 +/- 11% of cells that adhered to a somal attachment site developed a lone process > or = 100 microns oriented in the direction of the continuous aminosilane pathway which was shown to express axonal markers. Cells on either the fluorinated silane, which is non-permissive for neurite outgrowth, or localized on an aminosilane region only 5 microns wide failed to extend major processes. This approach is amenable to a variety of industry standard fabrication techniques and may be used to study the role of fine scale spatial cues in neuronal development and synapse formation.

Animals↗