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J W Geddes

Publications and source records attributed to J W Geddes.

At least 55 records · Page 3Linked to original sources
PubMed1990

Long-term survival of neural transplants to senescence in rats.

A critical issue for clinical and research applications of transplant techniques is the long-term survival of transplanted tissue and its effect on the host brain. In this study, entorhinal cortices from donor embryos were transplanted into the lesioned angular bundle of juvenile male Sprague-Dawley rats. Animals were maintained for 2 years and then sacrificed for histological and histochemical examinations. The results indicate that entorhinal transplants survive to old age and that both the host and transplant tissues maintain morphological features consistent with those of short-term neural grafts. An unexpected finding of this experiment was the persistence in the transplanted tissue and adjacent host cortex of a pattern of AChE staining which is typical of early postnatal development.

Acetylcholinesterase↗
PubMed1990

Altered distribution of excitatory amino acid receptors in temporal lobe epilepsy.

In temporal lobe epilepsy, excitatory amino acid receptors in the hippocampus and temporal lobe may contribute to both increased excitability and vulnerability to excitotoxic damage. We used receptor autoradiography to examine the density of N-methyl-D-aspartate (NMDA) and kainic acid (KA) receptors in the hippocampus and parahippocampal gyrus obtained from five patients who had undergone anterior temporal lobectomy for the treatment of intractable seizures and from six control individuals, in which the hippocampus was obtained postmortem. Within the hippocampal formation, loss of [3H]KA and NMDA-sensitive L-[3H]glutamate binding was apparent in the sclerotic regions CA3, hilus, and CA1. In the subiculum and molecular layer of the denate gyrus, binding densities were maintained or even increased in some of the epileptic patients. A two-fold increase in L-[3H]glutamate binding, along with an increase in [3H]KA binding, was observed in the parahippocampal gyrus obtained from the epileptic patients. The results suggest that the vulnerability of the hippocampus in temporal lobe epilepsy may result, at least in part, from the presence of aberrant excitatory circuits in the parahippocampal gyrus.

Adult↗
PubMed1990

Lesions of hippocampal circuitry define synaptosomal-associated protein-25 (SNAP-25) as a novel presynaptic marker.

Synaptosomal-associated protein, 25 kD, (SNAP-25) is a novel protein containing a possible transition metal binding site and encoded by a neuronal-specific mRNA. We examined the distribution of SNAP-25 mRNA and protein in the hippocampal formation of the adult rat following kainic acid, colchicine, and entorhinal lesions. The results show that destruction of granule cells of the dentate gyrus and CA3 pyramidal cells did not diminish SNAP-25 immunoreactivity in the dendritic fields of these cells. In contrast, lesioned neurons exhibited an extensive loss of immunoreactivity at the site of their axonal projections. These results support the identification of SNAP-25 as a novel presynaptic protein. In addition, SNAP-25 immunoreactivity was increased in afferent fibers which project to areas adjacent to the deafferented region, and expression of SNAP-25 mRNA was increased in neurons deafferented by the lesion. Examination of SNAP-25 immunoreactivity and mRNA expression may provide a useful marker of major hippocampal pathways and of axonal plasticity in neurological disorders such as Alzheimer's disease and temporal lobe epilepsy.

Animals↗
PubMed1990

Axon sprouting in the rodent and Alzheimer's disease brain: a reactivation of developmental mechanisms?

Research over the past 15 years has led to a comprehensive description of the processes of axonal sprouting and synaptic reorganization in the hippocampus. Previous studies on axonal sprouting have now been supplemented with recent studies on excitatory amino acid receptor plasticity. These and related studies pave the way to research strategies which detail the molecular mechanisms of the sprouting response. The re-expression of the fetal form of alpha-tubulin mRNA in rat after entorhinal lesions was found to be similar to the re-expression of the human fetal form of alpha-tubulin in Alzheimer's brain. This result suggests that the sprouting process may involve a reactivation of certain developmental mechanisms and that this may possibly contribute to the etiology of Alzheimer's disease.

Alzheimer Disease↗
PubMed1990

Excitotoxic amino acid receptors in human complex partial epilepsy.

It has long been recognized that mesial temporal sclerosis is the most common pathologic finding in temporal lobes removed for the treatment of medically refractory complex partial epilepsy. The regions of the hippocampus most vulnerable contain the highest densities of excitatory amino acid receptors in the brain. We used receptor autoradiography to determine the density of N-methyl-D-aspartate (NMDA) and kainic acid (KA) receptors from 5 patients undergoing such surgery and compared the findings with 6 specimens obtained at postmortem. A 2-fold increase in the density of NMDA receptors and an increased density of KA receptors was found in entorhinal cortex in epileptic specimens. Loss of NMDA and KA receptor density was apparent in the sclerotic regions CA3 and CA1, but not in other areas of the hippocampus or dentate gyrus. These findings suggest that damage in the hippocampus may result, at least in part, from the presence of aberrant excitatory circuits in the entorhinal cortex.

Autoradiography↗
PubMed1989

Protease nexin-II, a potent antichymotrypsin, shows identity to amyloid beta-protein precursor.

Protease nexin-II (PN-II) is a protease inhibitor that forms SDS-resistant inhibitory complexes with the epidermal growth factor (EGF)-binding protein, the gamma-subunit of nerve growth factor, and trypsin. The properties of PN-II indicate that it has a role in the regulation of certain proteases in the extracellular environment. Here we describe more of the amino-acid sequence of PN-II and its identity to the deduced sequence of the amyloid beta-protein precursor (APP). Amyloid beta-protein is present in neuritic plaques and cerebrovascular deposits in individuals with Alzheimer's disease and Down's syndrome. A monoclonal antibody against PN-II (designated mAbP2-1) recognized PN-II in immunoblots of serum-free culture medium from human glioblastoma cells and neuroblastoma cells, as well as in homogenates of normal and Alzheimer's disease brains. In addition, mAbP2-1 stained neuritic plaques in Alzheimer's disease brain. PN-II was a potent inhibitor of chymotrypsin with an inhibition constant Ki of 6 x 10(-10)M. Together, these data demonstrate that PN-II and APP are probably the same protein. The regulation of extracellular proteolysis by PN-II and the deposition of at least parts of the molecule in senile plaques is consistent with previous reports that implicate altered proteolysis in the pathogenesis of Alzheimer's disease.

Alzheimer Disease↗
PubMed1989

N-methyl-D-aspartate receptors in the cortex and hippocampus of baboon (Papio anubis and Papio papio).

In vitro autoradiography was used to examine the N-methyl-D-aspartate receptor in the brain of a baboon species, Papio anubis, and compared to that of Papio papio which exhibits a photosensitive epilepsy. The epilepsy originates in the frontal cortex and is accompanied by an enhanced sensitivity to N-methyl-D-aspartate. In both Papio anubis and Papio papio, the density of N-methyl-D-aspartate receptors was greatest in the hippocampus, followed by associational areas including frontal cortex, and low in primary sensory areas such as the visual cortex. The receptors were concentrated in the outer cortical layers I-III, very low in layer IV except in primary visual cortex, and of intermediate density in layer V. The density of binding sites was approximately two-fold lower than previously observed in the rodent brain, whereas the affinity of the receptor for [3H]L-glutamate was greater in the primate versus the rodent brain. Glycine potentiated the binding of [3H]L-glutamate in both cortex and hippocampus. No significant differences in the properties of N-methyl-D-aspartate receptors were observed between the two baboon species, suggesting that the photosensitivity of Papio papio is not due to alterations in the binding of L-glutamate to the N-methyl-D-aspartate receptor complex.

Animals↗
PubMed1989

Protease nexin-1, an antithrombin with neurite outgrowth activity, is reduced in Alzheimer disease.

Protease nexin-1 (PN-1) is a cell-secreted protein that inhibits certain proteases, particularly thrombin, by forming SDS-stable complexes with the catalytic site serine of the protease. PN-1 was recently shown to be identical to a glial-derived neurite-promoting factor/glial-derived nexin present in rat brain. Its neurite outgrowth activity depends on inhibition of thrombin, presumably because thrombin brings about neurite retraction. Here we show that human brain contains PN-1 and that PN-1 activity in brains of individuals with Alzheimer disease (AD) was only 14% of control values (total of 14 AD patients and 7 control individuals). PN-1 activity in the hippocampus, a region with marked neuropathology in AD, was 15% of control values (10 AD patients and 4 control individuals). Western blot analysis indicated a large decrease in free PN-1 protein and an increase in PN-1-containing complexes that comigrated with PN-1-thrombin complexes. Northern blot analysis indicated that PN-1 mRNA levels were about equal in brains from AD patients and control individuals. Thus these results suggest that the decreases in PN-1 activity and free PN-1 protein are due to formation of PN-1-protease complexes.

Alzheimer Disease↗
PubMed1987

[3H]TCP binding sites in Alzheimer's disease.

Quantitative autoradiography was used to determine the density and distribution of [3H]1-[1-(2-thienyl)-cyclohexyl]piperidine ([3H]TCP) binding sites in human hippocampal tissue sections from control and Alzheimer's disease patients. Some Alzheimer's cases showed no changes in binding site density while other cases showed substantial declines in the CA1 region. [3H]TCP binding in the CA1 region from Alzheimer's patients was reduced an average of 40% while the other hippocampal regions were unaffected. It is proposed that the loss of [3H]TCP sites in the hippocampal CA1 region of certain Alzheimer's cases is associated with the greater cell loss observed in cases of severe Alzheimer's disease.

Alzheimer Disease↗
PubMed1986

Density and distribution of NMDA receptors in the human hippocampus in Alzheimer's disease.

We examined the distribution and density of N-methyl-D-aspartate (NMDA) displaceable L-[3H]glutamate binding sites in human hippocampal samples obtained postmortem from Alzheimer's disease (AD) patients and from age-matched controls. Binding to NMDA receptors was stable for at least 72 h postmortem, and the pharmacological profile corresponded to that described using electrophysiology. NMDA receptors were concentrated in the terminal fields of major hippocampal pathways including the perforant path, Schaffer collaterals and the hippocampal output to the subiculum, all of which are proposed to use an excitatory amino acid transmitter. Little if any change in hippocampal receptor density was observed in AD patients compared to age-matched controls except in one case where major hippocampal cell loss occurred. The distribution of NMDA receptors did, however, correspond to the predilection for neuritic plaques and neurofibrillary tangles in hippocampal subfields.

Aged↗
PubMed1986

Senile plaques as aberrant sprout-stimulating structures.

In Alzheimer's disease, the cholinergic septal input to the dentate gyrus molecular layer appears to sprout, presumably in response to the loss of entorhinal input to this region. Neuritic plaques accumulated in regions of septal sprouting and were present in these regions to a much greater degree than in areas of no apparent sprouting. We suggest that the reactive sprouts participate in the pathogenesis of plaque formation. The stimulus for plaque formation may be sprouting induced by a focal accumulation of injury-induced trophic factors. The demonstration of sprouting in Alzheimer's disease indicates that the appropriate mechanisms are intact. Eventually, however, the fibers succumb to the pathogenic processes in the disorder.

Acetylcholinesterase↗
PubMed1986

Plasticity in hippocampal excitatory amino acid receptors in Alzheimer's disease.

Entorhinal cell loss occurs in the course of Alzheimer's disease. In rodents, entorhinal lesions result in axon sprouting in the hippocampus. Quantitative autoradiography was used to examine the density and distribution of N-methyl-D-aspartate (NMDA) and kainic acid (KA) receptors in human hippocampus obtained post-mortem from Alzheimer's disease patients and from age-matched controls. In Alzheimer's disease, there was an expanded distribution of the KA receptor field in the dentate gyrus, indicative of sprouting of the commissural and associational fibers. This regenerative response is thought to facilitate transmission, but in doing so it may also enhance vulnerability to excitotoxic mediated neuronal damage. No significant change was observed in the density or distribution of NMDA receptors. The distribution of these receptors does, however, correlate with the predilection for neurofibrillary tangles and neuritic plaques in hippocampal subfields.

Aged↗
PubMed1985

Plasticity of hippocampal circuitry in Alzheimer's disease.

Two markers of neuronal plasticity were used to compare the response of the human central nervous system to neuronal loss resulting from Alzheimer's disease with the response of rats to a similar neuronal loss induced by lesions. In rats that had received lesions of the entorhinal cortex, axon sprouting of commissural and associational fibers into the denervated molecular layer of the dentate gyrus was paralleled by a spread in the distribution of tritiated kainic acid-binding sites. A similar expansion of kainic acid receptor distribution was observed in hippocampal samples obtained postmortem from patients with Alzheimer's disease. An enhancement of acetylcholinesterase activity in the dentate gyrus molecular layer, indicative of septal afferent sprouting, was also observed in those patients with a minimal loss of cholinergic neurons. These results are evidence that the central nervous system is capable of a plastic response in Alzheimer's disease. Adaptive growth responses occur along with the degenerative events.

Acetylcholinesterase↗
PubMed1985

Methionine-induced changes in glutamate, aspartate, glutamine, and gamma-aminobutyrate levels in brain tissue.

Intramuscular administration of methionine to mice resulted in changes in the levels of aspartate, glutamate, glutamine, and gamma-aminobutyrate in both nerve endings (synaptosomes) and "non-nerve-ending" tissue in the brain. However, the amino acid changes in the two locations differed considerably, not only in the time to onset of the changes, but also in the direction of the changes and in their duration. The results provide additional support for a glutamate-glutamine cycle between neurons and glia, and suggest that the decreases in amino acid levels in the nerve endings are due to an insufficient supply of glutamine from glia or other cellular structures, possibly compounded by an impairment in the uptake of glutamine into the nerve terminals. The primary cause of the glutamine deficiency is unknown because methionine did not affect the enzymes of glutamate and glutamine metabolism. Treatment of mice with methionine also resulted in an anticonvulsant action, but no correlation was observed between the latter phenomenon and the glutamate content of nerve endings.

Animals↗
PubMed1984

Changes in the amino acid content of nerve endings (synaptosomes) induced by drugs that alter the metabolism of glutamate and gamma-aminobutyric acid.

The study was centered on the changes in the amino acid content of nerve endings (synaptosomes) induced by drugs that alter the metabolism of glutamate or gamma-aminobutyric acid (GABA), and that possess convulsant or anticonvulsant properties. The onset of seizures induced by various convulsant agents was associated with a decreased content of GABA and an increased content of glutamate in synaptosomes. The concurrent administration of pyridoxine prevented both the biochemical changes and the convulsions. The administration of gabaculine to mice resulted in large increases in the GABA content of synaptosomes that were counteracted by decreases in glutamate, glutamine, and aspartate levels such that the total content of the four amino acids remained unchanged. The administration of aminooxyacetic acid (0.91 mmol/kg) resulted initially in seizure activity, but subsequently in an anticonvulsant action. No simple relationship existed between the excitable state of the brain induced by aminooxyacetic acid and the changes in the synaptosomal levels of any of the amino acid transmitters. A hypothesis was, however, formulated that explained the convulsant-cum-anticonvulsant action of aminooxyacetic acid on the basis of compartmentation of GABA within the nerve endings.

Amino Acids↗
PubMed1982

Combined effects of a metabolic inhibitor (gabaculine) and an uptake inhibitor (ketamine) on the gamma-aminobutyrate system in mouse brain.

The intramuscular administration of a gamma-aminobutyrate-alpha-oxoglutarate aminotransferase (GABA-T) inhibitor, gabaculine, to mice resulted in significant increases in GABA content and decreases in the content of aspartate, glutamate, and glutamine in the nerve endings (synaptosomes). These effects were ameliorated by the concurrent administration of the GABA uptake inhibitor ketamine. A major cause of these effects was the gabaculine-induced inhibition of GABA-T activity and the lessening of this inhibition by ketamine. The latter phenomenon was not due to a direct action of ketamine on the enzyme, nor to an interaction between gabaculine and ketamine. Rather, it appeared that ketamine might be interfering with the transport of gabaculine into the cellular structures. The anticonvulsant action of the GABA-T inhibitor and the GABA uptake inhibitor together was little different from that of the GABA-T inhibitor alone.

4-Aminobutyrate Transaminase↗