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C W Cotman

Publications and source records attributed to C W Cotman.

At least 37 records · Page 2Linked to original sources
PubMed2001

Complement association with neurons and beta-amyloid deposition in the brains of aged individuals with Down Syndrome.

To study the link between beta-amyloid (Abeta) and neuroinflammation, we examined the levels of complement as a function of age and extent of Abeta deposition in Down Syndrome (DS) brain. C1q, the first component of the complement cascade, was visualized using immunohistochemistry in the frontal, entorhinal cortex, and hippocampus of 12 DS ranging from 31 to 69 years of age. C1q was consistently associated with thioflavine-S positive Abeta plaques in DS brain and increased with more extensive age-dependent Abeta deposition. In contrast, little or no C1q labeling was associated with diffuse or thioflavine-S negative Abeta deposits. Neurons in the hippocampus and entorhinal cortex, but less frequently in frontal cortex, were C1q positive in DS cases with sufficient neuropathology to have a diagnosis of Alzheimer's disease. C1q-positive neurons were associated with activated microglia. These results provide evidence for Abeta-mediated inflammatory factors contributing to the rapid accumulation of neuropathology in DS brain.

Adult↗
PubMed2001

Effects of exercise on gene-expression profile in the rat hippocampus.

Exercise has beneficial effects on brain function, including the promotion of plasticity and the enhancement of learning and memory performance. Previously we found that exercise increases the expression of certain neurotrophic factors including brain derived neurotrophic factor in the rat hippocampus. To further explore the molecular mechanisms underlying these changes, we used high-density oligonucleotide microarrays containing probe sets representing approximately 5000 genes to analyze the level of gene transcripts in the hippocampus of rats voluntary running for 3 weeks in comparison with sedentary animals. An improved statistical approach for the analysis of DNA microarray data, Cyber-T, was utilized in data analysis. Here we show that exercise leads to changes in the level of a large number of gene transcripts, many of which are known to be associated with neuronal activity, synaptic structure, and neuronal plasticity. Our data indicate that exercise elicits a differential gene expression pattern with significant changes in genes of relevance for brain function.

Aging↗
PubMed2001

Oxidation of Abeta and plaque biogenesis in Alzheimer's disease and Down syndrome.

The processes involved with beta-amyloid (Abeta) degradation and clearance in human brain are not well understood. We hypothesized that the distribution of oxidatively modified Abeta, as determined by an affinity-purified antibody in the entorhinal and frontal cortices of Alzheimer's disease (AD), Down syndrome (DS), nondemented elderly control cases, and canine brain, would provide insight into the mechanisms of Abeta accumulation. Based upon plaque counts, oxidized Abeta was present within 46-48% of diffuse and primitive plaques and 98% of cored plaques. Dense punctate deposits of oxidized Abeta were distributed throughout the neuropil in AD and DS brains but were also present within controls with mild neuropathology and isolated cognitive impairments. Confocal studies indicate that punctate oxidized Abeta deposits were within activated microglia. Oxidatively modified Abeta may reflect the efforts of microglial cells to take up and degrade Abeta. Oxidative modification of Abeta may be an early event in Abeta pathogenesis and may be important for plaque biogenesis.

Alzheimer Disease↗
PubMed2001

Activation of caspase-8 in the Alzheimer's disease brain.

Recent studies support the activation of apoptotic pathways in the Alzheimer's disease (AD) brain. Neurons committed to apoptosis may do so by either activation of a receptor-mediated pathway employing caspase-8 or through an alternative mitochondrial pathway involving oxidative stress. In the present study, the role of caspase-8 in the AD brain was examined by designing a caspase-cleavage site-directed antibody to one of the active fragments of caspase-8. In vitro analysis with this antibody, termed CASP-8p18, demonstrated that it recognized the active 18-kDa fragment of caspase-8 but not the precursor protein. In vivo immunohistochemical analysis using hippocampal tissue sections from AD or aged-matched control brains demonstrated CASP-8p18 immunolabeling of neurons in all AD cases, whereas little staining was observed in controls. These results were confirmed using a commercially available antibody that, like the CASP-8p18 antibody reacts only with the 18-kDa fragment of caspase-8 and not full-length caspase-8. As with CASP-8p18 antibody, the commercial antibody-labeled neurons in all AD cases, while showing a relative paucity of staining in representative control cases. Labeling of CASP-8p18 within tangle-bearing neurons was observed in double-labeling studies with AT8 or PHF-1, both markers for neurofibrillary tangles (NFTs). In addition, using a caspase-cleavage site-directed antibody that recognizes cleavage products of caspase-3 showed colocalization of this antibody with the CASP-8p18 antibody within NFTs. These results suggest a role for caspase-8 and the receptor-mediated apoptotic pathway as a mechanism leading to the activation of caspase-3 within neurons of the AD brain.

Aged↗
PubMed2001

Correlation between caspase activation and neurofibrillary tangle formation in Alzheimer's disease.

Although evidence suggests that neurofibrillary tangles (NFTs) and neuronal cell loss are prominent features of Alzheimer's disease (AD), the relationship between the two remains unknown. In the present study, the relationship between the activation of apoptotic mechanisms and NFT formation in AD was investigated using a caspase-cleavage site-directed antibody to fodrin, an abundant neuronal cytoskeleton protein. This antibody recognized cleavage products of fodrin after digestion by caspase-3, but did not recognize full-length fodrin. In vitro analysis of this fodrin caspase-cleavage product (CCP) antibody demonstrates that it is a specific probe for the detection of apoptotic but not necrotic pathways in cultured neurons. To determine whether caspases cleave fodrin in vivo, tissue sections from controls and AD were immunostained for fodrin (CCPs). Although no staining was observed in control cases, labeling of neurons was observed in the hippocampus of all AD cases, which increased as a function of disease progression. To determine a possible relationship between caspase activation and NFT formation, double-labeling experiments with fodrin CCP and PHF-1 were performed. Co-localization of these markers was observed in many neurons, and quantitative analysis showed that as the extent of NFT formation increased, there was a significant corresponding increase in fodrin CCP immunolabeling (r = 0.84). Taken together, these results provide evidence for the activation of apoptotic mechanisms in neurons in the AD brain and suggest that there is an association between NFT formation and the activation of apoptotic pathways in AD.

Adult↗
PubMed2001

Physical activity elicits sustained activation of the cyclic AMP response element-binding protein and mitogen-activated protein kinase in the rat hippocampus.

To elucidate molecular mechanisms involved in physical activity-induced beneficial effects on brain function, we studied in rats the influence of voluntary running on the activation in the hippocampus of cyclic AMP response element-binding protein (CREB) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (ERK). These are signaling molecules that play critical roles in synaptic plasticity, including learning and memory. Exercise resulted in an increase in the level of the activated transcription factor, CREB phosphorylated at Ser-133. The amount of the activated transcription factor about doubled already after 1 night of running and remained elevated for at least a week, although control levels were restored after 1 month of exercise. In addition, binding activity in nuclear extracts to cyclic AMP response element (CRE) motif containing oligonucleotides increased significantly in the hippocampus after 3 nights of exercise, although the total amount of the immunochemically identified CREB remained unaltered. Electrophoretic mobility supershift assays indicated that the increased binding was due to the recruitment of members of this transcription factor family, in addition to the CREB proper. Voluntary running also resulted in an increase in the level of phosphorylated MAPK (both p42 and p44). The time-courses of the increases in the level of the phosphorylated protein kinase and the activated transcription factor were different. In comparison with the activated CREB, the increase in the phosphorylated MAPK was delayed, but lasted longer, being detectable even after 1 month of exercise. These observations are consistent with the view that the relatively long-lasting activation of these signaling molecules participates in the regulation of genes, such as the neurotrophin genes, and contributes to the beneficial effects of physical exercise on brain function.

Animals↗
PubMed2001

Estrogen and exercise interact to regulate brain-derived neurotrophic factor mRNA and protein expression in the hippocampus.

We investigated the possibility that estrogen and exercise interact in the hippocampus and regulate brain-derived neurotrophic factor (BDNF), a molecule increasingly recognized for its role in plasticity and neuron function. An important aspect of this study is to examine the effect of different time intervals between estrogen loss and estrogen replacement intervention. We demonstrate that in the intact female rat, physical activity increases hippocampal BDNF mRNA and protein levels. However, the exercise effect on BDNF up-regulation is reduced in the absence of estrogen, in a time-dependent manner. In addition, voluntary activity itself is stimulated by the presence of estrogen. In exercising animals, estrogen deprivation reduced voluntary activity levels, while estrogen replacement restored activity to normal levels. In sedentary animals, estrogen deprivation (ovariectomy) decreased baseline BDNF mRNA and protein, which were restored by estrogen replacement. Despite reduced activity levels in the ovariectomized condition, exercise increased BDNF mRNA levels in the hippocampus after short-term (3 weeks) estrogen deprivation. However, long-term estrogen-deprivation blunted the exercise effect. After 7 weeks of estrogen deprivation, exercise alone no longer affected either BDNF mRNA or protein levels. However, exercise in combination with long-term estrogen replacement increased BDNF protein above the effects of estrogen replacement alone. Interestingly, protein levels across all conditions correlated most closely with mRNA levels in the dentate gyrus, suggesting that expression of mRNA in this hippocampal region may be the major contributor to the hippocampal BDNF protein pool. The interaction of estrogen, physical activity and hippocampal BDNF is likely to be an important issue for maintenance of brain health, plasticity and general well-being, particularly in women.

Aging↗
PubMed2001

Bcl-2 family protein behavior in frontotemporal dementia implies vascular involvement.

Frontotemporal dementia (FTD) is a neurodegenerative disease associated with aging for which the etiology is unclear. Relatively little is known about the pathology of this disease, which has only recently been a topic of investigation for dementia researchers. Though the known pathology of FTD includes neuron loss, the mechanism of neuronal death is not known. In this study, the authors investigated apoptotic pathways as a possible mechanism of neuronal cell death in FTD. They evaluated immunoreactivity for Bcl-2 family protein members Bcl-x and Bax in postmortem frontal cortex from FTD, AD, and control cases. Bcl-x(L), Bcl-x(S), and Bax all exhibited altered immunoreactivity in FTD cases as compared with control cases. Bcl-x immunoreactivity varied widely among both controls and FTD cases. However, Bcl-x(L) showed strong white matter immunoreactivity in all FTD cases, whereas white matter immunoreactivity was absent in controls. These trends in Bcl-x immunoreactivity suggest a strong white matter involvement in the pathology of FTD. Bax immunoreactivity also varied across all cases. Bax immunoreactivity was observed in terminal transferase dUTP nick ending labeling (TUNEL) positive neurons in both FTD and AD cases. However, one notable finding was immunoreactivity to Bax in astrocytes of FTD cases, as well as endothelial cells of the cerebrovasculature. Neither astrocytic nor endothelial cell immunoreactivity to Bax was exhibited in control or AD cases. Because Bax is a pro-apoptotic protein, this finding suggests the presence of a cerebrovascular component in the pathology of FTD. These findings, coupled with the proposed functions of the Bcl-2 family proteins, suggest that an apoptotic pathway may be responsible for neuron, and possibly astrocyte, death in FTD.

Aged↗
PubMed2000

Fibril formation and neurotoxicity by a herpes simplex virus glycoprotein B fragment with homology to the Alzheimer's A beta peptide.

Despite significant progress in the elucidation of the genetic basis of early-onset familial Alzheimer's disease (AD), the etiology of sporadic cases remains elusive. Although certain genetic loci play a role in conferring susceptibility in some sporadic AD cases, it is likely that the etiology is multifactorial; hence, the majority of cases cannot be attributed to genetic factors alone, indicating that environmental factors may modulate the onset and/or progression of the disease. Head injury and infectious agents are environmental factors that have been periodically implicated, but no plausible mechanisms have been clearly identified. With regard to infectious agents, speculation has often centered on the neurotropic herpes viruses, with herpes simplex virus 1 (HSV1) considered a likely candidate. We report that an internal sequence of HSV1 glycoprotein B (gB) is homologous to the carboxyl-terminal region of the A beta peptide that accumulates in diffuse and neuritic plaques in AD. Synthetic peptides were generated and the biophysical and biological properties of the viral peptide compared to those of A beta. Here we show that this gB fragment forms beta-pleated sheets, self-assembles into fibrils that are thioflavin-positive and ultrastructurally indistinguishable from A beta, accelerates the formation of A beta fibrils in vitro, and is toxic to primary cortical neurons at doses comparable to those of A beta. These findings suggest a possible role for this infectious agent in the pathophysiology of sporadic cases of AD.

Amino Acid Sequence↗
PubMed2000

Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study.

CONTEXT: Several reports from small clinical trials have suggested that estrogen replacement therapy may be useful for the treatment of Alzheimer disease (AD) in women. OBJECTIVE: To determine whether estrogen replacement therapy affects global, cognitive, or functional decline in women with mild to moderate AD. DESIGN: The Alzheimer's Disease Cooperative Study, a randomized, double-blind, placebo-controlled clinical trial conducted between October 1995 and January 1999. SETTING: Thirty-two study sites in the United States. PARTICIPANTS: A total of 120 women with mild to moderate AD and a Mini-Mental State Examination score between 12 and 28 who had had a hysterectomy. INTERVENTIONS: Participants were randomized to estrogen, 0.625 mg/d (n = 42), or 1.25 mg/d (n = 39), or to identically appearing placebo (n = 39). One subject withdrew after randomization but before receiving medication; 97 subjects completed the trial. MAIN OUTCOME MEASURES: The primary outcome measure was change on the Clinical Global Impression of Change (CGIC) 7-point scale, analyzed by intent to treat; secondary outcome measures included other global measures as well as measures of mood, specific cognitive domains (memory, attention, and language), motor function, and activities of daily living; compared by the combined estrogen groups vs the placebo group at 2, 6, 12, and 15 months of follow-up. RESULTS: The CGIC score for estrogen vs placebo was 5.1 vs 5.0 (P = .43); 80% of participants taking estrogen vs 74% of participants taking placebo worsened (P = .48). Secondary outcome measures also showed no significant differences, with the exception of the Clinical Dementia Rating Scale, which suggested worsening among patients taking estrogen (mean posttreatment change in score for estrogen, 0.5 vs 0.2 for placebo; P = .01). CONCLUSIONS: Estrogen replacement therapy for 1 year did not slow disease progression nor did it improve global, cognitive, or functional outcomes in women with mild to moderate AD. The study does not support the role of estrogen for the treatment of this disease. The potential role of estrogen in the prevention of AD, however, requires further research.

Aged↗
PubMed2000

The variability of practice hypothesis in motor learning: does it apply to Alzheimer's disease?

Based on Schmidt's (1975) variability of practice hypothesis, this study examined acquisition and transfer of a gross motor skill, namely tossing, in 58 patients with Alzheimer's disease (AD) and 58 healthy older adults under constant, blocked, and random practice conditions. While healthy older adults were able to learn the tossing task equally well under the three practice conditions, only AD patients receiving constant practice showed significant improvements. Tests of intermediate transfer yielded the expected random practice advantage in healthy controls but not AD patients. None of the practice conditions facilitated intermediate transfer in AD patients; however, constant practice did benefit these impaired individuals on tests of near transfer. These results indicate that the variability of practice hypothesis does not extend to AD patients. As motor learning and transfer were clearly a function of constant practice, future attempts to retrain basic activities of daily living in AD patients should emphasize consistency in training.

Aged↗
PubMed2000

DNA damage and activated caspase-3 expression in neurons and astrocytes: evidence for apoptosis in frontotemporal dementia.

Frontotemporal dementia (FTD) is a neurodegenerative disease which affects mainly the frontal and anterior temporal cortex. It is associated with neuronal loss, gliosis, and microvacuolation of lamina I to III in these brain regions. In previous studies we have described neurons with DNA damage in the absence of tangle formation and suggested this may result in tangle-independent mechanisms of neurodegeneration in the AD brain. In the present study, we sought to examine DNA fragmentation and activated caspase-3 expression in FTD brain where tangle formation is largely absent. The results demonstrate that numerous nuclei were TdT positive in all FTD brains examined. Activated caspase-3 immunoreactivity was detected in both neurons and astrocytes and was elevated in FTD cases as compared to control cases. A subset of activated caspase-3-positive cells were also TdT positive. In addition, the cell bodies of a subset of astrocytes showed enlarged, irregular shapes, and vacuolation and their processes appeared fragmented. These degenerating astrocytes were positive for activated caspase-3 and colocalized with robust TdT-labeled nuclei. These findings suggest that a subset of astrocytes exhibit degeneration and that DNA damage and activated caspase-3 may contribute to neuronal cell death and astrocyte degeneration in the FTD brain. Our results suggest that apoptosis may be a mechanism of neuronal cell death in FTD as well as in AD (228).

Aged↗
PubMed2000

Molecular dating of senile plaques in the brains of individuals with Down syndrome and in aged dogs.

beta-Amyloid (Abeta) is a constituent of senile plaques found with increasing age in individuals with Down syndrome (DS) and in the canine model of aging. Sections of DS and dog brain were immunostained using an affinity-purified polyclonal antibody for a posttranslationally modified Abeta with a racemized aspartate at position 7 (d7C16). The immunostaining characteristics of d7C16 Abeta in DS and dog brain indicate that it is present in all plaque subtypes, including the thioflavin-S-negative diffuse plaques that develop with age in dogs. The youngest DS case exhibited weak immunolabeling for d7C16 but the extent of d7C16-positive plaques increased with age. In addition, d7C16-positive plaques were initially found in clusters in the superficial layers of the frontal and entorhinal cortex but, with advancing age, increasing numbers appeared in deeper layers, suggesting a progression of Abeta deposition from superficial to deeper cortical layers. Ultrastructural studies in DS brain were confirmed using perfused dog brain and provided consistent results; thioflavin-S-negative diffuse plaques consist of fibrillar Abeta and racemized Abeta is associated with thicker and more highly interwoven fibrils than nonracemized Abeta. The use of antibodies to modified forms of the Abeta protein should provide insight into the progression of plaque pathology in DS and Alzheimer's disease brain.

Adult↗
PubMed2000

Use of a delayed non-matching to position task to model age-dependent cognitive decline in the dog.

Spatial learning and memory in young and old dogs was studied in a series of experiments using a delayed non-matching to position (DNMP) paradigm. Past research from our laboratory has suggested that aged dogs perform more poorly on a version of the DNMP task compared to young dogs [Head et al., Spatial learning and memory as a function of age in the dog, Behav. Neurosci. 1995;109(5):851-585]. We have now extended these findings by testing a large number of dogs on three different variations of the DNMP paradigm to evaluate different aspects of spatial learning and memory. Our results indicate that: (1) aged dogs show impaired spatial learning compared to young dogs, (2) aged dogs display spatial working memory deficits compared to young dogs, (3) young dogs have a greater maximum working spatial memory capacity than old dogs and (4) we can use the DNMP paradigm to cognitively categorize different subsets of aged dogs. These data indicate that the DNMP paradigm can serve as a valuable tool to evaluate age-dependent cognitive dysfunction in the canine.

Age Factors↗
PubMed2000

Development of a protocol for studying object recognition memory in the dog.

1. Dogs had considerable difficulty learning a delayed-non-matching-to sample task at a short delay (approximately 5 seconds) for an extended period (900 trials). Only 3 of 19 dogs met the learning criterion. 2. Acquisition on the DNMS task was markedly improved when a pause was introduced on presentation of the stimulus objects, when the objects were approximately 30 cm from the dog; eleven of 16 dogs learned the task within 600 trials. 3. Dogs learned the task more rapidly at 20 and 30 second delays than at 10-second delays. This indicates a transfer of learning. 4. Dogs that did learn the task were able to perform at accuracy greater than 85% at delays of 150 and 200 seconds. At a 5-minute delay, performance was at 75%. 5. When the animals were switched to a repeated object paradigm, accuracy markedly declined. 6. The improved performance produced by introduction of the pause is attributable to: (1) presenting the object at a distance longer than the dogs' near point, and (2) allowing increased processing time.

Animals↗
PubMed2000

Initiation and propagation of molecular cascades in human brain aging: insight from the canine model to promote successful aging.

1. Normal aging is thought to proceed through two stages: initiation and propagation. Each of these phases is associated with different neuroanatomical events, vulnerabilities to injury and responsiveness to interventions. 2. The role of beta-amyloid (Abeta) in neuron dysfunction in the initiation stage may be mediated through alterations in signal transduction pathways involving cyclic AMP response element binding protein (CREB). CREB phosphorylation is associated with the expression of brain derived neurotrophic factor (BDNF), which promotes neuron health and survival. In primary neuronal cultures, Abeta decreases the phosphorylation of CREB, which results in up to a 31% decrease in BDNF levels. 3. In vivo studies also support a role for Abeta in neuron dysfunction since soluble Abeta levels correlate with the loss of synapses in brains of non-demented humans with high pathology. 4. The authors hypothesize that interventions during the initiation stage, when neuron dysfunction, but not overt pathology, is present, have the most promise to promote successful aging. The dog can serve as a useful model for interventions during the initiation stage since dogs develop neuropathology that closely resembles that observed in high pathology human brains.

Aging↗
PubMed2000

Ultrastructural analyses of beta-amyloid in the aged dog brain: neuronal beta-amyloid is localized to the plasma membrane.

1. An electron microscopic study was undertaken to study beta-amyloid (Abeta) deposition and neuropathology in aged dogs. 2. A positive correlation between Abeta deposits and neuropathology was found in some dogs. Massive Abeta deposition was correlated to advanced lesions. 3. By use of immunocytochemistry Abeta fibers were identified within plaques, around vessels and in association with cell membranes.

Aging↗