Biomedical subjects

C W Cotman

Publications and source records attributed to C W Cotman.

At least 73 records · Page 4Linked to original sources

PubMed1998

Initiation and propagation stages of beta-amyloid are associated with distinctive apolipoprotein E, age, and gender profiles.

Several recent studies have defined a relationship between apo-lipoprotein E (apoE) genotype and the risk of various neurodegenerative disorders. However, few studies have examined the influence of apoE on quantitative measures of beta-amyloid (Abeta) accumulation in a large population of autopsy cases. Using a multi-level analysis model, the interrelationships among apoE genotype, gender, age, and Abeta accumulation were investigated. In the population of these cases, there was a strong relationship between the presence of an epsilon4 allele and extent of Abeta in the frontal and entorhinal cortex. That is, when evaluating the presence or absence of significant Abeta (>1% Abeta load), subjects with one and two epsilon4 alleles were 1.9 and 3.5 times more likely to have significant Abeta accumulation than those with no epsilon4 alleles. These risks increased by a multiplicative factor of 1.014 for each year of age (at the time of death). In the subset of cases with significant Abeta (>1% Abeta load), the degree of Abeta load was best predicted by the presence of an epsilon2 allele and gender; females with no epsilon2 alleles had the highest Abeta loads (mean=12.3%), while males with one epsilon2 allele had the lowest amount of Abeta accumulation (mean=8.6%). Our results suggest that the presence of an epsilon4 allele predicts an earlier onset of Abeta deposition that is independent of gender. In contrast, once Abeta deposition has been initiated, the presence of an epsilon2 allele is associated with slower rates of accumulation, with males benefiting from the protective effect more than females.

Adult↗

PubMed1998

Cross-linking of NCAM receptors on neurons induces programmed cell death.

Programmed cell death has been implicated in the loss of neurons that occurs in many neurodegenerative diseases. This has led to an increased interest in the types of stimuli that can initiate neurons to undergo programmed cell death. Previously, we have shown that cross-linking of membrane receptors with the lectin concanavalin A can trigger programmed cell death in neurons [D.H. Cribbs, V.M. Kreng, A.J. Anderson, C.W. Cotman, Cross-linking of Concanavalin A receptors on cortical neurons induces programmed cell death, Neuroscience 75 (1996) 173-185]. Concanavalin A, however, binds to many surface glycoproteins and therefore, it is important to determine whether certain specific receptors can initiate the program. We found that surface immobilized anti-neural cell adhesion molecules (NCAM) monoclonal antibodies provide a good substrate for adhesion and neurite outgrowth for cortical neurons. However, neurons treated directly with soluble anti-NCAM monoclonal antibodies show significant cell death after 24 h and exhibit the morphological and biochemical features indicative of apoptosis, including membrane blebbing, cell shrinkage, condensation of nuclear chromatin and internucleosomal DNA cleavage.

Animals↗

PubMed1998

Receptor-coupled phospholipase C and adenylyl cyclase function with different calcium pools in astrocytes.

Astrocytes express phospholipase C (PLC)-coupled metabotropic glutamate receptors (only mGluR5 is detectable) and adenylyl cyclase (AC)-linked beta-adrenergic receptors. Calcium-sensitive effector enzymes are associated with these signal transduction pathways, but the relevant calcium compartments involved were found to be different. mGluR5-linked PLC responded primarily to extracellular Ca2+, suggesting a close spatial relation between the enzyme and Ca2+ entry channels. On the other hand, the calcium-inhibited AC associated with beta-adrenergic receptors was sensitive to intracellular Ca2+ selectively accessible to intracellular Ca2+ chelation. Furthermore, cAMP formation induced by direct activation of AC by forskolin was less responsive to intracellular Ca2+ chelation than that evoked by the receptor-activated AC, raising the possibility of selective access of the receptor to a pool of calcium-inhibited AC and/or the calcium modulation of some components of the coupling pathway.

Adenylyl Cyclases↗

PubMed1998

GADD45 is induced in Alzheimer's disease, and protects against apoptosis in vitro.

Expression of the growth arrest DNA damage-inducible protein, GADD45, has recently been reported to be induced by a wide range of stimuli, especially those that produce a high level of base pair damage. We have investigated the expression of GADD45 in brain tissue obtained from patients suffering from Alzheimer's disease (AD). Our results demonstrate that many neurons express the GADD45 protein, and that expression of this protein in neurons is associated with expression of the anti-apoptotic protein Bcl-2, and the presence of DNA damage, but not closely associated with tangle-bearing neurons. Additionally, cell lines overexpressing this protein confer resistance to apoptosis induced by DNA damage agent, suggesting that this protein may participate in cell survival mechanisms.

Alzheimer Disease↗

PubMed1998

Beta-amyloid induces local neurite degeneration in cultured hippocampal neurons: evidence for neuritic apoptosis.

Many apoptotic insults, including beta-amyloid, cause neuritic degeneration. The possibility that apoptotic insults act directly on neurites was investigated in experiments using compartmented cultures of hippocampal neurons. Neurites in modified Campenot chambers displayed morphological signs of degeneration, including beading or blebbing, when exposed to beta-amyloid. At short time points neurite degeneration was limited to the distal portions of neurites directly exposed to beta-amyloid. Furthermore, annexin V binding detected extracellular exposure of phosphatidylserine in portions of neurites directly exposed to apoptotic insults. Pretreatment of the cultures with zVAD-fmk blocked annexin V binding induced by beta-amyloid and concanavalin A, suggesting that caspase activity was required. Caspase activation was also visualized in neurites locally exposed to apoptotic insults. Together these results show that apoptotic insults cause local neurite degeneration which displays morphological and biochemical characteristics of apoptosis and suggest that neurite degeneration may use mechanisms common to apoptosis.

Amyloid beta-Peptides↗

PubMed1998

Lymphocytes as cell model to study apoptosis in Alzheimer's disease: vulnerability to programmed cell death appears to be altered.

Recent evidence indicates that programmed cell death (apoptosis) may contribute to neuronal death in Alzheimer's disease (AD). In situ data derived from post mortem brain tissue indicate that DNA fragmentation which represents an important and typical apoptotic feature is markedly increased in brain cells of AD patients compared to controls. Furthermore, in vitro studies demonstrate that the peptide beta-amyloid (A beta) and its fragments induce apoptosis in neuronal cell cultures. One possible mechanism initiating apoptosis could be free radical generation by the peptide leading to oxidative stress. In a wide range of cell types common morphological and molecular events occur during apoptosis and several genes appear to be involved. Particularly in lymphocytes, apoptosis plays an important physiological role. Our data demonstrate that similar oxidative stressors induce apoptosis in mature human lymphocytes as in neurons. In addition, first evidence indicates that susceptibility to apoptosis is altered in lymphocytes from AD patients compared to non-demented controls. Our preliminary findings suggest that changes of the individual sensitivity to undergo cellular apoptosis are already detectable in lymphocytes from AD patients, probably as a consequence of genetic as well as other risk factors. Therefore, this biochemical marker might have the potential for identifying individuals at risk of the diseases.

Aged↗

PubMed1998

Plaque biogenesis in brain aging and Alzheimer's disease. II. Progressive transformation and developmental sequence of dystrophic neurites.

Plaque-associated dystrophic neurites are a common pathological feature in the brains of patients with Alzheimer's disease (AD). In the present study, we investigated the relative abundance and progressive transformation of the amyloid precursor protein (APP), neurofilament (NF) and paired helical filament (PHF) tau-positive dystrophic neurites, within plaques in non-demented controls versus plaque-associated dystrophic neurites in mild or severe AD using double and triple immunolabeling. We also determined the argentophilia of the various sub-populations of dystrophic neurites. In aged non-demented brain, approximately half of the APP-positive plaques contained NF-immunopositive dystrophic neurites; rarely were PHF/tau-positive dystrophic neurites detectable. In contrast, in the AD brain, three-fourths of the APP-positive plaques contained NF-positive dystrophic neurites and half contained PHF/tau neurites. We also observed focal patches of hyper-phosphorylated NF and/or PHF/tau within APP-immunopositive dystrophic neurites, which appeared similar to retrograde degeneration, whereas we never observed focal accumulations of APP within NF- or PHF/tau-positive fibers. We hypothesize that plaque-associated dystrophic neurites within plaques develop in a particular sequence: APP-positive dystrophic neurites appear first and are non-argentophilic. This is followed by the appearance of NF-positive dystrophic neurites, where a subset of NF-positive dystrophic neurites are lightly argentophilic. Over time, PHF/tau-positive dystrophic neurites develop and are strongly argentophilic. These data suggest that dystrophic neurites can develop retrogradely from focal plaque damage to induce somatic and dendritic degeneration and potentially contribute to neurofibrillary tangle formation.

Aged↗

PubMed1998

Mechanisms of trafficking in axons and dendrites: implications for development and neurodegeneration.

In the area of routing and sorting of dendritic traffic, the current phenomenological data beg questions about the cellular mechanisms utilized not only to transport material but also to modulate activity in a process, even apoptosis. To aid in formulating testable hypotheses, many plausible models are developed here and linked with some of the preliminary data that supports them. We first assume that in long dendrites the sorting of membranous proteins into transport vesicles also involves the linkage of motor proteins to the vesicles. Second, we assume that the cytoskeleton in dendrites is altered from the cytoskeleton in axons and the cell body. Viral glycoproteins, MAP2 and specific mRNA sorting into dendrites provide the simplest models for analyzing vesicular, cytoskeletal and RNA sorting. In the case of viral glycoproteins, initial sorting appears to occur at the Golgi but additional routing steps involve further complexities that could best be served by an additional sorting step at the junction of the cell body and the process. Transport of the specialized cytoskeletal proteins and specific mRNAs as well as vesicular material could be controlled by a similar gatekeeper at the mouth of a process. Studies of the microtubule-organelle motor complex, regulation of microtubule-based motility by microtubule-associated proteins, and slow axonal transport all provide insights into important aspects of the routing and sorting. These processes are in turn controlled by extracellular signals such as those generated by matrix molecules or their hydrolysis products in the case of amyloid precursor protein (APP). Routing and sorting mechanisms may be central to the development of Alzheimer's disease in view of evidence that APP processing is affected, transport is disturbed, and intracellular vesicles (early endosomes) hypertrophied. Further it is possible that routing mechanisms play a role in cell-cell interactions as, for example, the possibility that pathogenic/cellular stress signals may be passed along circuits transsynaptically.

Animals↗

PubMed1998

Cell adhesion molecules in neural plasticity and pathology: similar mechanisms, distinct organizations?

Brain plasticity and the mechanisms controlling plasticity are central to learning and memory as well as the recovery of function after brain injury. While it is clear that neurotrophic factors are one of the molecular classes that continue to regulate brain plasticity in the adult central nervous system (CNS), less appreciated but equally profound is the role of cell adhesion molecules (CAMs) in plasticity mechanisms such as long term potentiation, preservation of neurons and regeneration. Ironically, however, CAMs can also reorganize the extra-cellular space and cause disturbances that drive the development of brain pathology in conditions such as Alzheimer's disease and multiple sclerosis. Candidate molecules include the amyloid precursor protein which shares many properties of a classical CAM and beta-amyloid which can masquerade as a pseudo CAM. Beta-Amyloid serves as a nidus for the formation of senile plaques in Alzheimer's disease and like CAMs provides an environment for organizing neurotrophic factors and other CAMs. Inflammatory responses evolve in this environment and can initiate a vicious cycle of perpetuated neuronal damage that is medicated by microglia, complement and other factors. Certain CAMs may converge on common signal transduction pathways involving focal adhesion kinases. Thus a breakdown in the organization of key CAMs and activation of their signal transduction mechanisms may serve as a new principle for the generation of brain pathology.

Animals↗

PubMed1998

Preserved cerebellar tyrosine hydroxylase-immunoreactive neuronal fibers in a behaviorally aggressive subgroup of Alzheimer's disease patients.

Aggression is a very problematic behavioral symptom affecting a significant proportion of Alzheimer's disease patients. Previous work in our laboratory has shown that a subgroup of Alzheimer's patients displaying aggressive behaviors had a markedly higher level of alpha2-adrenergic receptors in the cerebellar cortex (approaching or exceeding those of controls), compared to Alzheimer's patients with similar cognitive impairments, but no history of aggressive behaviors. This study has sought to assess whether noradrenergic neuronal inputs to the cerebellum reflect similar changes in this Alzheimer's subgroup. Cerebellar cortex from non-aggressive Alzheimer's subjects showed a markedly lower level of tyrosine hydroxylase-positive neuronal fibers than normal controls (approximately 75% decreased), visualized by immunohistochemistry. Cerebellar cortex from the aggressive Alzheimer's subgroup, on the other hand, had a tyrosine hydroxylase fiber concentration not significantly different than controls. These results suggest that there is a relative preservation of inhibitory noradrenergic neuronal input to the cerebellar cortex in this aggressive subgroup of Alzheimer's disease patients. Much evidence exists that the cerebellum assists in behavioral control. The possibility that this lack of noradrenergic decline in the cerebellum could lead to a system imbalance and result in a selective behavioral disturbance is discussed.

Aged↗

PubMed1998

Learning upregulates brain-derived neurotrophic factor messenger ribonucleic acid: a mechanism to facilitate encoding and circuit maintenance?

Brain-derived neurotrophic factor (BDNF) promotes neuron survival, enhances sprouting, protects neurons against insult, and may be involved in several aspects of learning and memory. In this study, rats trained to locate a submerged platform in a water maze had elevated levels of BDNF messenger ribonucleic acid (mRNA) in the hippocampus (p < .05), a structure associated with spatial memory. BDNF mRNA expression increased after 3 and 6 days but not after 1 day of training in the water maze. A yoked control group that swam without the platform present, to control for physical activity, showed a trend for elevated BDNF mRNA at an intermediate level between the learning and sedentary groups. Other cortical and subcortical areas did not show a significant increase in BDNF mRNA after learning or activity (p > .05). These findings suggest that learning can impact BDNF mRNA expression localized to the brain areas involved in the processing of spatial information. Furthermore, behaviors such as physical activity and learning may help maintain and protect neurons at risk in aging and neurodegenerative disease via increased BDNF expression.

Analysis of Variance↗

PubMed1998

Metabotropic glutamate receptor agonists potentiate cyclic AMP formation induced by forskolin or beta-adrenergic receptor activation in cerebral cortical astrocytes in culture.

The metabotropic glutamate receptor (mGluR) agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid (ACPD) potentiated the accumulation of cyclic AMP induced by either beta-adrenergic receptor stimulation (isoproterenol) or direct activation of adenylyl cyclase (AC) with forskolin in rat cerebral cortical astrocytes grown in a defined medium. In contrast, ACPD inhibits the cyclic AMP response in astrocytes cultured in a serum-containing medium. Pharmacological characterization indicated that a group I mGluR, of which only mGluR5 is detectable in these cells, is involved in the potentiation of cyclic AMP accumulation. Potentiation was elicited by mGluR I agonists [e.g., (R,S)-3,5-dihydroxyphenylglycine (DHPG)], but not by mGluR II or III agonists; it was pertussis toxin resistant and abolished by procedures suppressing mGluR5 function (phorbol ester pretreatment or DHPG-induced receptor down-regulation). Nevertheless, it appears that products generated through the mGluR5 transduction pathway, such as elevated [Ca2+]i or activated protein kinase C (PKC), are not involved in the potentiation as it was not influenced by either the intracellular calcium chelator BAPTA-AM or the PKC inhibitor Ro 31-8220. An inhibitor of phospholipase C, U-73122, markedly attenuated mGluR5-activated phosphoinositide hydrolysis but did not significantly affect the DHPG potentiation of the cyclic AMP response. A mechanism is proposed in which the potentiating effect on AC could be mediated by free betagamma complex that is liberated after the agonist-bound mGluR5 interacts with its coupled G protein.

Adenylyl Cyclases↗

PubMed1998

Enhancement of spatial-temporal reasoning after a Mozart listening condition in Alzheimer's disease: a case study.

Several recent studies have investigated the effectiveness of various behavioral interventions on the cognitive performance of subjects with Alzheimer's disease (AD). Simulations of Shaw's structured model of the cortex led to the predictions that music might enhance spatial-temporal reasoning. A subsequent behavioral study in college students documented an improvement in scores on a spatial-temporal task after listening to a Mozart piano sonata. In this study, we investigated the enhancement of scores on a spatial-temporal task after a Mozart listening condition in a set of twins who are discordant for AD. After listening to an excerpt from a Mozart piano sonata, the AD twin showed considerable improvement on the spatial-temporal task when compared with pretest scores. Furthermore, no enhancement of scores was seen following either of the control conditions (i.e., silence or 1930s popular tunes). This finding suggests that music may be used as a tool to investigate functional plasticity in Alzheimer's disease and to better understand the underlying pathophysiology.

Aged↗

PubMed1998

Magnetic resonance imaging relaxation times and gadolinium-DTPA relaxivity values in human cerebrospinal fluid.

RATIONALE AND OBJECTIVES: This study was conducted to prove the feasibility of using cerebrospinal fluid (CSF) T1 and T2 measurements to assess the blood-brain barrier integrity in disease states not noted for focal blood-brain barrier disruption, such as Alzheimer's disease. METHODS: T1 and T2 of human CSF samples were measured with and without gadolinium Gd-DTPA over a concentration range of 1.98 x 10(-3) to 6.32 mM, in a GE 1.5-T Signa scanner. RESULTS: T1 and T2 of human CSF without Gd-DTPA were measured as 2.39 and 0.23 s. K1 and K2 were calculated as 6.25 and 6.74 mM(-1) s(-1). The lowest Gd-DTPA concentration with measurable T1 and T2 was 1.98 x 10(-3) mM. There is no statistically significant difference in T2 and K2 at different repetition times. CONCLUSIONS: This work demonstrates that a single measurement of relaxation times after contrast-enhanced magnetic resonance imaging could be used to determine the Gd-DTPA concentration in CSF. It may thus be feasible, using this technique, to measure intersubject and intraregional variability in the quantity of Gd-DTPA transferred across the blood-brain barrier after intravenous injection of contrast agent.

Blood-Brain Barrier↗

PubMed1997

The progression of beta-amyloid deposition in the frontal cortex of the aged canine.

Brains from 41 aged canines (> or = 10 years of age) were examined immunohistochemically to characterize the laminar distribution and age-related progression of beta-amyloid (A beta) in frontal cortex. We classified the A beta patterns into four distinct types. Type I was characterized by small, faint deposits of A beta in deep cortical layers. Type II consisted of diffuse deposits of A beta mainly in layers V and VI. Type III had both dense plaques in superficial layers, and diffuse deposits in deep layers. Finally, Type IV had solely dense plaques throughout all layers of cortex. We compared the A beta distribution pattern between the Old canines (10-15 years, n = 22) and the Very Old canines (> 15 years, n = 19). The Old group primarily had negative staining, or Type I and Type II patterns of amyloid deposition (73%). Conversely, the Very Old group had predominantly Types II, III and IV deposits (89.5%), a difference that was significant (P < 0.05). We suggest that A beta deposition in canine frontal cortex is a progressive age-related process beginning with diffuse deposits in the deep cortical layers followed by the development of deposits in outer layers. In support of this hypothesis, the deeper layer diffuse plaques in the Very Old group of dogs also contain the largest proportion of beta-amyloid with an isomerized aspartic acid residue at position 7, indicating that these deposits had been present for some time. We also observed fiber-like A beta immunoreactivity within regions of diffuse A beta deposits. These fibers appeared to be degenerating neurites, which were negative for hyperphosphorylated tau. Therefore, these fibers may represent a very early form of neuritic change that precede tau hyperphosphorylation or develop by an alternative pathway.

Aging↗

PubMed1997

Neuronal DNA damage precedes tangle formation and is associated with up-regulation of nitrotyrosine in Alzheimer's disease brain.

The relationship of neuronal DNA damage to tangle-bearing neurons and nitrotyrosine (NT) expression, a neurochemical marker of oxidative damage mediated by peroxynitrite, was examined in visual cortex of AD patients. Many terminal deoxynucleotidyl transferase (TdT)-positive neurons were detected and the majority (93%) of these TdT-labeled neurons lacked evidence of tangle formation. NT expression was elevated in AD cases and most TdT-labeled nuclei also showed strong NT immunoreactivity. These data suggest the hypothesis that the neurons with DNA damage in the absence of tangle formation may degenerate by tangle-independent mechanisms and that oxidative damage may contribute to such mechanisms in AD.

Aged↗

PubMed1997

Amyloid deposition in cerebrovascular angiopathy.

Recent evidence suggests that AD is associated with the development of cerebral amyloid angiopathy and with significant changes in the blood-brain barrier glucose transporter and basement membrane protein alterations. It is likely that these changes significantly contribute to chronic cerebral hypoperfusion, possibly resulting in progressive neural death in AD. To investigate the etiology of these changes, we have analyzed postmortem tissue sections of frontal cortex of moderately demented AD cases, stained using both single-label and double-label immunocytochemistry to detect vessels and beta-amyloid. The resultant color images are analyzed using HSV (hue-saturation-value) color image analysis, shape analysis, and histogram analysis techniques. These analyses let us segment the tissue images for further statistical analyses.

Alzheimer Disease↗

PubMed1997

Thrombin induces apoptosis in cultured neurons and astrocytes via a pathway requiring tyrosine kinase and RhoA activities.

Thrombin activity is a factor in acute CNS trauma and may contribute to such chronic neurodegenerative diseases as Alzheimer's disease. Thrombin is a multifunctional serine protease that catalyses the final steps in blood coagulation. However, increasing evidence indicates that thrombin also elicits a variety of cellular and inflammatory responses, including responses from neural cells. Most recently, high concentrations of thrombin were shown to cause cell death in both astrocyte and hippocampal neuron cultures. The purpose of this study was to determine the mechanisms underlying thrombin-induced cell death. Our data show that thrombin appears to cause apoptosis as evidenced by cleavage of DNA into oligonucleosomal-sized fragments, fragmentation of nuclei, and prevention of death by inhibition of protein synthesis. Synthetic peptides that directly activate the thrombin receptor also induced apoptosis, indicating that thrombin-induced cell death occurred via activation of the thrombin receptor. The signal transduction cascade involves tyrosine and serine/threonine kinases and an intact actin cytoskeleton. Additional study revealed the involvement of the small GTP-binding protein RhoA. Thrombin induced RhoA activity in both astrocytes and hippocampal neurons, and inhibition of RhoA activity with exoenzyme C3 attenuated cell death, indicating that thrombin activation of RhoA was necessary for thrombin-induced cell death. Tyrosine kinase inhibitors blocked thrombin induction of RhoA, indicating that tyrosine kinase activity was required upstream of RhoA. These data suggest a sequential linkage of cellular events from which we propose a model for the second messenger cascade induced by thrombin in neural cells that can lead to apoptosis.

Animals↗