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C W Cotman

Publications and source records attributed to C W Cotman.

At least 91 records · Page 5Linked to original sources
PubMed1997

Adrenergic receptors in Alzheimer's disease brain: selective increases in the cerebella of aggressive patients.

In this study, the distribution and concentration of beta1, beta2, and alpha2 adrenergic receptors were examined in the frontal cortex, hypothalamus, and cerebellum of Alzheimer's disease (AD) and age-matched control human brains by receptor autoradiography. The purpose of this study was to detect changes in adrenergic receptor concentrations in key areas of the brain known to affect behavior. For these studies, [125I]iodopindolol ([125I]IPIN) was used to visualize total beta adrenergic sites (with ICI-89,406 and ICI-118, 551 as subtype-selective antagonists to visualize beta2 and beta1 receptors, respectively). [3H]UK-14,304 was used to localize the alpha2 sites. Essentially no significant difference in adrenergic receptor concentration was found between total AD cases taken together and control patients. It was found, however, that there were important distinctions within the AD group when cases were subdivided according to the presence or absence of aggression, agitation, and disruptive behavior. Aggressive AD patients had markedly increased (by approximately 70%) concentrations of alpha2 receptors in the cerebellar cortex compared with nonaggressive patients with similar levels of cognitive deficit. The levels of cerebellar alpha2 receptors in aggressive AD patients were slightly above the healthy elderly controls, suggesting that these receptors are preserved and perhaps increased in this subgroup of AD. beta1 And beta2 adrenergic receptors of the cerebellar cortex showed smaller but significant ( approximately 25%) increases in concentration in aggressive AD subjects versus both nonaggressive AD patients and controls. No significant differences were found in adrenergic receptor concentrations within the frontal cortex or hypothalamus. These results point out the importance of distinguishing behavioral subgroups of AD when looking for specific neurochemical changes. These autoradiographic results may reflect the importance of the cerebellum in behavioral control.

Aged↗
PubMed1997

A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study.

BACKGROUND: There is evidence that medications or vitamins that increase the levels of brain catecholamines and protect against oxidative damage may reduce the neuronal damage and slow the progression of Alzheimer's disease. METHODS: We conducted a double-blind, placebo-controlled, randomized, multicenter trial in patients with Alzheimer's disease of moderate severity. A total of 341 patients received the selective monoamine oxidase inhibitor selegiline (10 mg a day), alpha-tocopherol (vitamin E, 2000 IU a day), both selegiline and alpha-tocopherol, or placebo for two years. The primary outcome was the time to the occurrence of any of the following: death, institutionalization, loss of the ability to perform basic activities of daily living, or severe dementia (defined as a Clinical Dementia Rating of 3). RESULTS: Despite random assignment, the baseline score on the Mini-Mental State Examination was higher in the placebo group than in the other three groups, and this variable was highly predictive of the primary outcome (P<0.001). In the unadjusted analyses, there was no statistically significant difference in the outcomes among the four groups. In analyses that included the base-line score on the Mini-Mental State Examination as a covariate, there were significant delays in the time to the primary outcome for the patients treated with selegiline (median time, 655 days; P=0.012), alpha-tocopherol (670 days, P=0.001) or combination therapy (585 days, P=0.049), as compared with the placebo group (440 days). CONCLUSIONS: In patients with moderately severe impairment from Alzheimer's disease, treatment with selegiline or alpha-tocopherol slows the progression of disease.

Activities of Daily Living↗
PubMed1997

All-D-enantiomers of beta-amyloid exhibit similar biological properties to all-L-beta-amyloids.

The amyloidogenic peptide beta-amyloid has previously been shown to bind to neurons in the form of fibrillar clusters on the cell surface, which induces neurodegeneration and activates a program of cell death characteristic of apoptosis. To further investigate the mechanism of Abeta neurotoxicity, we synthesized the all-D- and all-L-stereoisomers of the neurotoxic truncated form of Abeta (Abeta25-35) and the full-length peptide (Abeta1-42) and compared their physical and biological properties. We report that the purified peptides exhibit nearly identical structural and assembly characteristics as assessed by high performance liquid chromatography, electron microscopy, circular dichroism, and sedimentation analysis. In addition, both enantiomers induce similar levels of toxicity in cultured hippocampal neurons. These data suggest that the neurotoxic actions of Abeta result not from stereoisomer-specific ligand-receptor interactions but rather from Abeta cellular interactions in which fibril features of the amyloidogenic peptide are a critical feature. The promiscuous nature of these beta-sheet-containing fibrils suggests that the accumulation of amyloidogenic peptides in vivo as extracellular deposits represents a site of bioactive peptides with the ability to provide inappropriate signals to cells leading to cellular degeneration and disease.

Amyloid beta-Peptides↗
PubMed1997

Transneuronal degeneration in the spread of Alzheimer's disease pathology: immunohistochemical evidence for the transmission of tau hyperphosphorylation.

Neurofibrillary tangles and dystrophic neurites appear to develop in a highly characteristic spatial and temporal sequence in AD. In order to examine the nature of the cellular progression we have studied the trisynaptic entorhinal, dentate gyrus, CA3/4 circuit, using an antibody to hyperphosphorylated tau which is a biochemical marker for tangle formation. In early AD cases, we found numerous ATB-stained boutons in the outer molecular layer of the dentate gyrus, the termination field of neurons from the entorhinal cortex. These AT8-stained boutons co-labeled with synaptophysin, indicating that they represent synaptic boutons in an early state of degeneration. Since the labeled boutons were apposed to or clustered around dendrites or soma that lacked or had less intense staining for AT8 or PHF-1, it appeared that presynaptic events preceded postsynaptic neurofibrillary tangle formation. Furthermore, as a function of disease progression, the pattern of degeneration moved through the circuit. In this progression tau, which is normally localized to axons, becomes redistributed into dendrites and hyperphosphorylated. These observations support the hypothesis that the presynaptic terminal changes may promote the formation of initial neurofibrillary pathology in the postsynaptic neurons via anterograde transneuronal mechanisms and that this initiates a breakdown of routing and sorting mechanisms for the cytoskeletal protein tau.

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PubMed1997

Open field activity and human interaction as a function of age and breed in dogs.

Open field (OF) activity was studied in kennel reared purebred beagles from two separate colonies (2-13 years in age) and pound source mixed breed dogs (9 months to 10 years in age). Dogs were observed for 10 min sessions and records were taken of: locomotion, urination, sniffing, grooming, rearing, vocalizing, jumping frequencies and inactivity (16). Since dogs are uniquely social towards people, we also measured human interaction (HI), which recorded the same behaviors as during OF when a person was present in the room. Measures of exploratory behavior decreased as a function of age in pound source dogs in the OF test, but not in beagles from either colony. No breed differences were found between the young dogs. In the HI test, age effects were found in beagles but not pound source dogs. OF activity correlated with tests of cognitive function, but differences were found between the three groups. These findings indicate that OF activity is age-sensitive in dogs, but that breed and test conditions are also essential factors.

Aging↗
PubMed1997

Heparan sulfate potentiates the autocrine action of basic fibroblast growth factor in astrocytes: an in vivo and in vitro study.

Increasing evidence indicates that heparan sulfate proteoglycans have a critical role in the regulation of the activity of basic fibroblast growth factor by interacting with it or its receptor. In this study we examined the possibility that heparan sulfate can modulate the basic fibroblast growth factor system at a more fundamental level than activity regulation, by influencing the synthesis of basic fibroblast growth factor and its receptor messenger RNAs. Previous studies in vitro indicate that basic fibroblast growth factor promotes proliferation and differentiation of astrocytes. Accordingly, we examined the possibility that the action of heparan sulfate on the basic fibroblast growth factor system could have a critical role in the modulation of reactivity and/or proliferation of astrocytes in vitro and in vivo. We report that basic fibroblast growth factor applied to pure astrocyte cultures or rat neocortex promoted an increase in the messenger RNA for basic fibroblast growth factor itself and for its receptor. Furthermore, basic fibroblast growth factor applied directly into the brain elicited an increase in messenger RNA for the astrocytic marker glial fibrillary acidic protein. All of these actions, both in vitro and in vivo, were highly potentiated when heparan sulfate was applied in combination with basic fibroblast growth factor. These results suggest that basic fibroblast growth factor regulates astrocytic proliferation or reactivity via an autocrine cascade that involves induction of its own receptor and that this action is modulated by heparan sulfate.

Animals↗
PubMed1997

Decreased expression of N-methyl-D-aspartate receptor 1 messenger RNA in select regions of Alzheimer brain.

An antisense oligonucleotide probe was used to examine the expression of gene encoding the obligatory NMDAR1 subunit of the N-methyl-D-aspartate receptor in the hippocampus and adjacent cortical areas (entorhinal and perirhinal cortices) of seven Alzheimer patients and in the same brain regions of seven control individuals. Both groups were matched according to age, sex, cause of death, post mortem delay, and tissue storage time. Densitometric analysis of in situ hybridization autoradiograms revealed a 34% (P<0.05) decrease in NMDAR1 messenger RNA levels in layer III of the entorhinal cortex in Alzheimer brains. Similar deficits. although statistically not significant, were observed in layers II and IV-VI of the entorhinal cortex, and in granule cells of the dentate gyrus. Reduced levels of NMDAR1 messenger RNA were also found in layers II-VI of the perirhinal cortex (41 53% decrease, P<0.02). There were no changes in NMDAR1 messenger RNA expression in the CA1, hilus, or subiculum. Both Alzheimer and control group show substantial intersubject variation in levels of NMDAR1 messenger RNA. The analysis of emulsion-dipped tissue revealed a trend toward a decrease in the number of silver grains overlying individual neurons in the CA1, entorhinal cortex, and granule cell layer of some Alzheimer patients. No significant relationship was detected between the levels of NMDAR1 messenger RNA and post mortem delay, tissue storage, age of the subjects, or mini mental state exam score either in control or Alzheimer individuals. In contrast, a strong inverse correlation between NMDAR1 expression and disease duration was found. These data suggest that reduction in expression of the NMDAR1 gene observed in certain regions of Alzheimer hippocampus and adjacent cortical regions is specific for the disease itself. We postulate that reduced transcript levels may reflect either regional cell loss or anomalies in glutamatergic input to the hippocampus and entorhinal cortex in Alzheimer's disease. When followed by changes at the receptor subunit protein level, altered expression of the NMDAR1 gene in Alzheimer brain may contribute, through the formation of N-methyl-D-aspartate receptors with different properties, to the previously reported modified N-methyl-D-aspartate receptor ligand binding, abnormal vulnerability of select neuronal populations to excitotoxic insult, and may also be involved in learning and memory deficits.

Aged↗
PubMed1997

Metabotropic glutamate receptor mGluR5 in astrocytes: pharmacological properties and agonist regulation.

Metabotropic glutamate receptor (mGluR) agonists induce extensive phosphoinositide (PI) hydrolysis in astrocytes grown in a chemically defined medium with select growth factors. These astrocytes express mGluR5 transcripts, but none of the splice variants of mGluR1, thus permitting the characterization of mGluR5 in a native CNS cell without interference from mGluR1 activity. mGluR5 activation (1) was not associated with stimulation of cyclic AMP formation, (2) showed high sensitivity to the removal of extracellular versus intracellular Ca2+, (3) displayed high coupling efficiency relative to receptor density, and (4) induced PI hydrolysis that was suppressed by phorbol esters with low potency. The rank order of agonist potency was similar to that observed in mGluR1 and mGluR5 transfected cells. The phenylglycine antagonists tested were effective in blocking responses to 1-aminocyclopentane-1S,3R-dicarboxylic acid, but not to glutamate. Prolonged exposure to agonists induced a two-phase desensitization of mGluR5 function, an initial phase (completed by 1 h and plateaus for another 3 h) and a late phase (progressive decrease to approximately 30% of control levels by 24 h). Only the latter phase was associated with receptor down-regulation. Desensitization of mGluR5 function did not involve receptor internalization or phosphorylation mediated by protein kinase C or A; it was purely homologous, and reversible. Resensitization after short agonist treatment did not require prior receptor sequestration. Recovery after prolonged agonist exposure required new protein synthesis, but the restoration of function was more rapid than normalization of receptor protein levels, indicating that regulation also involves other components of the transduction system. The protracted desensitization of mGluR5 in astrocytes suggests that the functions mediated by this receptor are maintained under a variety of conditions ranging from repetitive stimulation to injury responses.

Animals↗
PubMed1997

Beta-amyloid neurotoxicity in vitro: evidence of oxidative stress but not protection by antioxidants.

Recent data from several groups suggest that the primary mechanism of beta-amyloid neurotoxicity may be mediated by reactive oxygen species. To evaluate this hypothesis, we first compared the efficacy of antioxidant agents in preventing toxicity caused by oxidative insults (iron, hydrogen peroxide, and tert-butyl hydroperoxide) and beta-amyloid peptides in cultured rat hippocampal neurons. Tested antioxidants (propyl gallate, Trolox, probucol, and promethazine) generally provided significant protection against oxidative insults but not beta-amyloid peptides. Next, we examined whether beta-amyloid causes oxidative stress, by comparing levels of lipid peroxidation after exposure to either iron or beta-amyloid. In a cell-free system, iron but not beta-amyloid generated lipid peroxidation. In culture, both insults caused rapid increases in lipid peroxidation, with iron inducing higher levels at later time points. Pretreatment with the antioxidant probucol significantly reduced lipid peroxidation caused by both insults but only attenuated iron toxicity, suggesting that lipid peroxidation does not contribute directly to cell death induced by beta-amyloid. Finally, we observed that increasing basal levels of oxidative stress by pretreating cultures with subtoxic doses of iron significantly increased neuronal vulnerability to beta-amyloid. The ability of beta-amyloid to induce oxidative stress and the demonstration that oxidative stress potentiates beta-amyloid toxicity support the clinical use of antioxidants for AD. However, these data do not support the theory that the primary mechanism of beta-amyloid toxicity involves oxidative pathways, indicating a continued need to identify additional cellular responses to beta-amyloid that underlie its neurodegenerative actions.

Amyloid beta-Peptides↗
PubMed1997

Bax protein expression is increased in Alzheimer's brain: correlations with DNA damage, Bcl-2 expression, and brain pathology.

We have shown that many neurons in Alzheimer's disease (AD) exhibit terminal deoxynucleotidyl transferase (TdT) labeling for DNA strand breaks, and upregulation of Bcl-2 is associated with neurons exhibiting nuclear DNA fragmentation, while downregulation of Bcl-2 is associated with tangle-bearing neurons in AD brains. Consequently, we examined the expression of bcl-associated X (Bax) protein in AD brain. Immunoreactivity for Bax was seen in neurons and microglia of the hippocampal formation, and was elevated in the majority of AD cases as compared to control cases. Interestingly, 3 transitional cases, which had mild degeneration changes, exhibited relatively high levels of Bax immunoreactivity. Most Bax-positive neurons showed either TdT-labeled nuclei or Bcl-2 immunoreactivity. Although Bax immunoreactivity was detected within most early tangle-bearing neurons, many Bax-positive neurons did not colocalize with later-stage tangle-bearing neurons. In regions containing relatively few tangles in mild AD brains, many TdT-labeled neurons were immunolabeled with Bax antibody and most of them lacked evidence of neurofibrillary changes. These findings suggest that Bax may contribute to neuronal cell death in AD. Furthermore, DNA damage and the upregulation of Bax appear to precede tangle formation or may represent an alternative pathway of cell death in AD.

Aged↗
PubMed1996

Constructional apraxia in Alzheimer's disease correlates with neuritic neuropathology in occipital cortex.

A variety of measures of neuropathology in Alzheimer's disease (AD) correlate with dementia severity. However, the role of beta-amyloid protein and abnormally phosphorylated tau protein in the decline of specific cognitive abilities is unknown. "Constructional praxis' (e.g., copying, constructing) is believed to require integrity of the parietal-occipital lobes. Unlike most other cognitive tasks, some AD patients are able to perform some constructional tasks even late in the disease course. Thus, it may be an ideal task to evaluate the relationship between various measures of AD neuropathology and cognitive performance. Fixed brain tissue was obtained from 16 AD patients who were cognitively assessed shortly before death. Parietal, frontal, entorhinal, and occipital cortices were examined by immunocytochemistry for beta-amyloid protein and abnormally phosphorylated tau protein at both early and later stages of neuropil thread and tangle formation. Constructional praxis in AD was strongly related to early-stage tau hyperphosphorylation in occipital cortex. Praxis ability was specific in that it was not significantly related to pathology in other areas and non-constructive tasks were not associated with occipital cortex pathology. In contrast, global dementia severity was related to beta-amyloid deposition in entorhinal, parietal, and frontal regions. These findings suggest that occipital cortex is critical for some constructional praxis tasks and that some regionally localizable tasks may be good indices of underlying pathology in corresponding brain regions.

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PubMed1996

Plaque biogenesis in brain aging and Alzheimer's disease. I. Progressive changes in phosphorylation states of paired helical filaments and neurofilaments.

Paired helical filament (PHF)/tau immunoreactive dystrophic neurites are a common pathological feature in the brain of patients with Alzheimer's disease. Recent studies suggest that swollen neurofilament-immunoreactive neurites are also present in senile plaques. In the present study, we investigated whether PHF/tau-positive dystrophic neurites are located in all subtypes of plaques and whether swollen neurofilament-immunoreactive neurites are hyper-phosphorylated, using a battery of antibodies to PHF/tau, neurofilament, and beta-amyloid protein. PHF/tau-positive dystrophic neurites were present in and around nearly all subtypes of plaques, including small amyloid deposits, diffuse plaques, and perivascular plaques in the hippocampal formation of Alzheimer brain. The earlier changes were detectable with AT8 antibody and later changes with PHF-1 antibody. Plaque-associated PHF/tau-positive dystrophic neurites were rare or absent in the hippocampal formation of normal aged brain. Swollen neurofilament-positive neurites appeared to be hyper-phosphorylated in Alzheimer's disease and to a lesser degree in aged control brains. Neurites that contained hyper-phosphorylated tau as well as neurofilament were strongly argentophilic because both populations of dystrophic neurites stained with silver stains. Swollen neurofilament-positive plaque-associated neurites were often present in the absence of PHF/tau-positive plaque-associated dystrophic neurites. These data suggest that PHF/tau-positive dystrophic neurites are a common component of all subtypes of plaques in Alzheimer brain and neurofilament protein in swollen neurites, like tau protein, is hyper-phosphorylated. Hyper-phosphorylated neurofilaments in plaque-associated neurites may represent one of the earliest cytoskeletal changes in vulnerable neurons in Alzheimer's disease and aged control brains.

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PubMed1996

Alzheimer-associated presenilin-2 confers increased sensitivity to apoptosis in PC12 cells.

Presenilin-2 is a gene of unknown function recently identified based upon linkage with some forms of familial Alzheimer's disease. To investigate potential effects of PS-2 on cell viability, rat pheochromocytoma (PC12) cells were stably transfected with cDNA constructs encoding either full-length human PS-2 or, for comparison, mouse Bcl-X(L). Overexpression of PS-2 conferred increased sensitivity to the apoptotic stimuli staurosporine and hydrogen peroxide. In contrast, Bcl-X(L) overexpression significantly reduced cell death induced by these stimuli. These results suggest that one function of PS-2 may involve modulation of cell viability.

Alzheimer Disease↗
PubMed1996

Gene expression of Alzheimer-associated presenilin-2 in the frontal cortex of Alzheimer and aged control brain.

The presenilin-2 (PS2) gene expression pattern in Alzheimer's disease (AD) and control brains was examined using nonradioactive in situ hybridization. Message for PS2 was primarily detectable in neurons, particularly in somal cytoplasm. Intense staining signal was most commonly found in large pyramidal neurons, whereas moderate or faint staining was usually present in smaller neurons. The pattern of PS2 gene expression exhibited a laminar distribution profile in the frontal cortex. A small subset of tangle-bearing neurons exhibited PS2 hybridization signal in AD. PS2 mRNA expression appeared correlated to a high degree with lipofuscin autofluorescence in a large subset of neurons.

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PubMed1996

Injury induces presenilin-1 gene expression in mouse brain.

Information regarding the genetic factors and environmental conditions that influence presenilin-1 (PS-1) gene expression is essential for the elucidation of its pathophysiological role in Alzheimer's disease (AD). Previous in situ hybridization studies have demonstrated that neurons are the predominant cell type expressing PS-1 in the mammalian central nervous system (CNS) under physiological conditions. In this study, we examined the consequences of an experimentally induced focal injury on PS-1 gene expression in the mouse CNS. Physical lesions to white matter regions produced a robust increase in PS-1 gene expression in non-neuronal cells immediately surrounding the site of injury. These findings underscore the epidemiological evidence that implicate head injury as a risk factor for AD and suggest a possible role for PS-1 in this capacity.

Alzheimer Disease↗
PubMed1996

Dopaminergic denervation of striatum results in elevated expression of NR2A subunit.

An imbalance between glutamate and dopamine in the striatum may contribute to the pathophysiology of Parkinson's disease. We therefore studied the effect of dopaminergic denervation of the rat striatum (unilateral 6-OHDA lesions of the medial forebrain bundle) on NMDA receptors. The expression of NMDA receptor genes (NR1, NR2A-B) was examined by in situ hybridization using oligonucleotide probes, and binding to NMDA receptors assessed using L-[3H]glutamate. Three weeks after lesioning, denervated striatum exhibited a selective increase (+13%) in the level of NR2A mRNA, NMDA receptor binding was unchanged. These results demonstrate that dopaminergic denervation exerts differential effects on NMDA receptor gene expression. Because the properties of NMDA receptors depend on the subunit composition, selective changes in the expression of mRNAs encoding the subunits may lead to modified NMDA receptor function.

Animals↗
PubMed1996

Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain.

Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) support the viability and function of many types of neurons, and are likely mediators of activity-dependent changes in the CNS. We examined BDNF and NGF mRNA levels in several brain areas of adult male rats following 0, 2, 4, or 7 nights with ad libitum access to running wheels. BDNF mRNA was significantly increased in several brain areas, most notably in the hippocampus and caudal 1/3 of cerebral cortex following 2, 4, and 7 nights with exercise. Significant elevations in BDNF mRNA were localized in Ammon's horn areas 1 (CA1) and 4 (CA4) of the hippocampus, and layers II-III of the caudal neocortex and retrosplenial cortex. NGF mRNA was also significantly elevated in the hippocampus and caudal 1/3 of the cortex, affecting primarily the dentate gyrus granular layer (DG) and CA4 of the hippocampus and layers II-III in caudal neocortex.

Analysis of Variance↗