Biomedical subjects

R L Faull

Publications and source records attributed to R L Faull.

At least 55 records · Page 3Linked to original sources

PubMed1998

Connexin expression in Huntington's diseased human brain.

In Huntington's diseased human brain, it is in the caudate nucleus (CN) and globus pallidus (GP) of the basal ganglia where nerve cell death is seen most dramatically. The distribution of five gap junction proteins (connexins 26, 32, 40, 43 and 50) has been examined in these areas in normal and Huntington's diseased human brain using immunohistochemical techniques. There was no Cx50 expression observed and Cx40 was localized in the endothelial cells of blood vessels, with the Huntington's diseased brains having more numerous and smaller blood vessels than normal tissue. Cx26 and Cx32 revealed a similar distribution pattern to each other in both normal and diseased brains with little labelling in the CN but clear labelling in the GP. Cx43, expressed by astrocytes, was the most abundant connexin type of those studied. In both normal and diseased brains Cx43 in the GP was homogeneously distributed in the neuropil. In the CN, however, Cx43 density was both increased with Huntington's disease and became located in patches. Glial fibrillary acidic protein(GFAP) staining of astrocytes was also highly increased in the CN compared with normal brains. These labelling patterns indicate a reactive astrocytosis around degenerating neurons with an increased expression of astrocytic gap junctions. The enhanced coupling state between astrocytes, assuming the junctions are functional, could provide an increased spatial buffering capacity by the astrocytes in an attempt to maintain a proper environment for the neurons, helping promote neuronal survival in this neurodegenerative disorder.

Animals↗

PubMed1998

Trinucleotide (CAG) repeat length is positively correlated with the degree of DNA fragmentation in Huntington's disease striatum.

Recent studies using DNA fragmentation assays suggest a role for apoptosis in cell death in Huntington's disease. In this study, we investigated the relationship between the degree of DNA fragmentation and the number of trinucleotide (CAG) repeats of the Huntington's disease gene in striatal tissue from Huntington's disease brains. We used frozen striatal tissue from 27 post mortem Huntington's disease brains (graded 0-4 on the Vonsattel classification, post mortem delay ranging from 4 to 41 h), plus control sections which were age, sex and post mortem delay matched from neurologically normal and Alzheimer's diseased striatal tissue. Our results show a significant positive correlation between the number of CAG repeats in the Huntington's disease gene and the degree of DNA fragmentation in Huntington's disease striatum. These results suggest that expanded CAG repeats in the Huntington's disease gene may lead to neuronal degeneration in Huntington's disease through an apoptotic mechanism.

Adult↗

PubMed1998

Felbamate increases [3H]glycine binding in rat brain and sections of human postmortem brain.

The anticonvulsant compound felbamate (2-phenyl-1,3-propanediol dicarbamate; FBM) appears to inhibit the function of the N-methyl-D-aspartate (NMDA) receptor complex through an interaction with the strychnine-insensitive glycine recognition site. Since we have demonstrated previously that FBM inhibits the binding of [3H]5, 7-dichlorokynurenic acid (DCKA), a competitive antagonist at the glycine site, we assessed the ability of FBM to modulate the binding of an agonist, [3H]glycine, to rat forebrain membranes and human brain sections. In contrast to its ability to inhibit [3H]5,7-DCKA binding, FBM increased [3H]glycine binding (20 nM; EC50 = 485 microM; Emax = 211% of control; nH = 1.8). FBM, but not carbamazepine, phenytoin, valproic acid or phenobarbital, also increased [3H]glycine binding (50 nM; EC50 = 142 microM; Emax = 157% of control; nH = 1.6) in human cortex sections. Autoradiographic analysis of human brain slices demonstrated that FBM produced the largest increases in [3H]glycine binding in the cortex, hippocampus and the parahippocampal gyrus. Because various ions can influence the binding of glycine-site ligands, we assessed their effects on FBM-modulation of [3H]glycine binding. FBM-enhanced [3H]glycine binding was attenuated by Zn++ and not inhibited by Mg++ in human brain. These results suggest that FBM increases [3H]glycine binding in a manner sensitive to ions which modulate the NMDA receptor. These data support the hypothesis that FBM produces anticonvulsant and neuroprotective effects by inhibiting NMDA receptor function, likely through an allosteric modulation of the glycine site.

Animals↗

PubMed1997

Brain-derived neurotrophic factor is reduced in Alzheimer's disease.

Alzheimer's disease may be due to a deficiency in neurotrophin protein or receptor expression. Consistent with this hypothesis, a reduction in BDNF mRNA expression has been observed in human post-mortem Alzheimer's disease hippocampi. To further investigate this observation, we examined whether the alteration in BDNF expression also occurred at the protein level in human post-mortem Alzheimer's disease hippocampi and temporal cortices using immunohistochemical techniques. We observed a reduction in the intensity and number of BDNF-immunoreactive cell bodies within both the Alzheimer's disease hippocampus and temporal cortex when compared to normal tissue. These results support and extend previous findings that BDNF mRNA is reduced in the human Alzheimer's disease hippocampus and temporal cortex, and suggest that a loss of BDNF may contribute to the progressive atrophy of neurons in Alzheimer's disease.

Adult↗

PubMed1997

Insulin-like growth factor-I (IGF-I) immunoreactivity in the Alzheimer's disease temporal cortex and hippocampus.

IGF-I has been shown to enhance neuronal survival and inhibit apoptosis. IGF-I immunoreactivity was examined in the Alzheimer's disease and normal post-mortem human hippocampus and temporal cortex to determine whether IGF-I protein levels are altered in response to neurodegeneration. IGF-I immunoreactivity was induced in a subpopulation of GFAP-immunopositive astroglia in the Alzheimer's disease temporal cortex. These observations raise the possibility that IGF-I has a neuroprotective role in the Alzheimer's disease brain.

Aged↗

PubMed1997

Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus.

Recent studies indicate that the proto-oncogene Bax, and other related proteins (eg Bcl-2) may play a major role in determining whether cells will undergo apoptosis under conditions which promote cell death. Increased expression of Bax has been found to promote apoptosis, while over-expression of Bcl-2 can inhibit apoptosis. To investigate the role of Bax in nerve cell death in the rat brain we examined the level of Bax expression in cells undergoing apoptosis, using a hypoxic-ischemic stroke model. We found that Bax was expressed at high levels in the nuclei of neurons in the hippocampus, cortex, cerebellum, and striatum on the control side, and that Bax levels increased in hippocampal neurons undergoing apoptosis on the stroke side, and then declined (correlating with cell loss). In the Alzheimer's disease hippocampi we found a concentrated localisation of Bax in senile plaques, which correlated with the localisation of beta-amyloid protein in adjacent sections from the same brains. beta-Amyloid positive plaques are thought to contribute to the Alzheimer's disease process, possibly via an apoptotic mechanism, and this may occur via an increase in Bax in these areas. Bax was also strongly stained in tau-positive tangles in Alzheimer's disease hippocampi, suggesting Bax may play a role in tangle formation. In addition, we observed a loss of Bax expression in the dentate granule cells of Alzheimer's disease hippocampi compared with moderate Bax expression in control hippocampi, and this loss may be related to the survival of these neurons in Alzheimer's disease. Finally, we observed substantially different staining patterns of Bax using three different commercially available antisera to Bax, indicating the need for caution when interpreting results in this area.

Adult↗

PubMed1997

Dopamine D1 and D2 receptor gene expression in the striatum in Huntington's disease.

The cellular expression of dopamine D1 and D2 receptor mRNAs was investigated in the postmortem human caudate nucleus of control cases and genetically and pathologically confirmed cases of Huntington's disease (HD) by using quantitative in situ hybridization. The HD cases were categorized (0-4) by severity of striatal neuropathology according to the Vonsattel scale. For the HD grade 0 case, a pronounced reduction in the number of D1 and D2 mRNA-positive cells was observed compared with controls; however, the abundance of both receptor mRNAs per remaining cell was within the control range. For D2 receptor mRNA, the number of detectable D2-positive medium-sized cells decreased with increasing pathology; this decrease was accompanied by a gradual reduction in the intensity of D2 signal per cell. By contrast, for D1 receptor mRNA, despite a decrease in the number of D1 mRNA-positive cells detected, the average cellular expression of D1 mRNA was markedly reduced in the HD grade 1 case and then increased (relative to the grade 1 case) with increasing pathology, presumably reflecting the relative survival of D1-expressing striatal interneurons. The implications of these findings for providing further information on the neurodegenerative process in HD are discussed.

Aged↗

PubMed1997

Expression of Fos, Jun, and Krox family proteins in Alzheimer's disease.

Apoptosis is an active process of cell death characterized by distinct morphological features and is often the end result of a genetic program of events, i.e., programmed cell death (PCD). There is growing evidence supporting a role for apoptosis and/or PCD in Alzheimer's disease (AD), based on DNA fragmentation studies and recent findings of increased levels of inducible transcription factors (ITFs) such as c-Jun in AD brains. We have characterized the expression of a large range of ITFs (c-Fos, Fos B, Fos-related antigens, c-Jun, Jun B, Jun D, Krox20, and Krox24) using multiple antisera in AD postmortem hippocampi and compared this with human control hippocampi as well as Huntington's disease hippocampi and human epilepsy biopsy tissue. We found little evidence of nuclear expression of any ITF except c-Jun in the human postmortem tissue, compared with nuclear staining in biopsy tissue. We found some evidence for increased levels of c-Jun and Krox24 protein and krox24 mRNA in the CA1 region of AD hippocampi, suggesting that PCD may be involved in the pathogenesis of AD. In general, staining characteristics of ITFs varied with different antisera directed against the same protein, indicating the need for caution when interpreting results.

Adult↗

PubMed1997

Calcium homeostasis in ageing: studies on the calcium binding protein calbindin D28K.

Calbindin D28K is a neuronal calcium binding protein which may act as a buffer of neuronal calcium. Evidence suggests that disturbance of calcium homeostasis is important in neurodegeneration, possibly via changes in calbindin D28K. Immunoreactivity of calbindin D28K is compared in Alzheimer's disease and age-matched controls. The size and number of calbindin D28K positive neurons in Alzheimer's disease tissue is reduced. There is also shrinkage of the dendritic tree. Continuing work examines the function of calbindin D28K using transgenic mice.

Aged↗

PubMed1997

Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain.

The anatomical distribution and density of cannabinoid receptors in the human brain was studied in one fetal (33 weeks gestation), two neonatal (aged three to six months) and eight adult (aged 21-81 years) human cases using quantitative receptor autoradiography following in vitro labelling of sections with the synthetic cannabinoid agonist [3H]CP55,940. Cannabinoid receptors were distributed in a heterogeneous fashion throughout the adult human brain and spinal cord. The allocortex contained very high concentrations of cannabinoid receptor binding sites in the dentate gyrus, Ammons's horn and subiculum of the hippocampal formation; high concentrations of receptors were also present in the entorhinal cortex and amygdaloid complex. Cannabinoid receptor binding sites were also present throughout all regions of the neocortex, where they showed a marked variation in density between the primary, secondary and associational cortical regions: the greatest densities of receptors were present in the associational cortical regions of the frontal and limbic lobes, with moderate densities in the secondary sensory and motor cortical regions, and with the lowest densities of receptors in the primary sensory and motor cortical regions. Relatively high concentrations of cannabinoid receptors were consistently seen in cortical regions of the left (dominant) hemisphere, known to be associated with verbal language functions. In all of the cortical regions, the pattern and density of receptor labelling followed the neocortical laminar organization, with the greatest density of receptors localized in two discrete bands--a clearly delineated narrow superficial band which coincided with lamina I and a deeper broader, conspicuous band of labelling which corresponded to laminae V and VI. Labelling in the intervening cortical laminae (II-IV) showed lower densities, with a well delineated narrow band of label in the middle of laminae IV in the associational cortical regions. The thalamus showed a distinctive heterogeneous distribution of cannabinoid receptors, with the highest concentration of receptors localized in the mediodorsal nucleus, anterior nuclear complex, and in the midline and intralaminar complex of nuclei, i.e. in thalamic nuclei which have connectional affiliations with the associational cortical areas. The basal ganglia showed a distinctive heterogeneous pattern of receptor binding, with the very highest concentrations in the globus pallidus internus, moderate concentrations in the globus pallidus externus and ventral pallidum, and moderately low levels of binding throughout the striatal complex. In the midbrain, some of the highest levels of cannabinoid receptor binding sites in the human brain were present in the substantia nigra pars reticulata, with very low levels of labelling in all other midbrain areas. The highest densities of cannabinoid receptor binding in the hindbrain were localized in the molecular layer of the cerebellar cortex and the dorsal motor nucleus of the vagus, with moderate densities of receptors in the nucleus of the solitary tract. The spinal cord showed very low levels of receptor binding. Studies on the distribution of cannabinoid receptors in the fetal and neonatal human brain showed similar patterns of receptor distribution to that observed in the adult human brain, except that the density of receptor binding was generally markedly higher, especially in the basal ganglia and substantia nigra. The pattern of cannabinoid receptor labelling in the striatum showed a striking patchy pattern of organization which was especially conspicuous in the fetal brain. These results show that cannabinoid receptor binding sites in the human brain are localized mainly in: forebrain areas associated with higher cognitive functions; forebrain, midbrain and hindbrain areas associated with the control of movement; and in hindbrain areas associated with the control of motor and sensory functions of the autonomic nervous system. (AB

Adult↗

PubMed1997

The morphological and chemical characteristics of striatal neurons immunoreactive for the alpha1-subunit of the GABA(A) receptor in the rat.

The distribution, morphology and chemical characteristics of neurons immunoreactive for the alpha1-subunit of the GABA(A) receptor in the striatum of the basal ganglia in the rat brain were investigated at the light, confocal and electron microscope levels using single, double and triple immunohistochemical labelling techniques. The results showed that alpha1-subunit immunoreactive neurons were sparsely distributed throughout the rat striatum. Double and triple labelling results showed that all the alpha1-subunit-immunoreactive neurons were positive for glutamate decarboxylase and immunoreactive for the beta2,3 and gamma2 subunits of the GABA(A) receptor. Three types of alpha1-subunit-immunoreactive neurons were identified in the striatum on the basis of cellular morphology and chemical characteristics. The most numerous alpha1-subunit-immunoreactive neurons were medium-sized, aspiny neurons with a widely branching dendritic tree. They were parvalbumin-negative and were located mainly in the dorsolateral regions of the striatum. Electron microscopy showed that these neurons had an indented nuclear membrane, typical of striatal interneurons, and were surrounded by small numbers of axon terminals which established alpha1-subunit-immunoreactive synaptic contacts with the soma and dendrites. These cells were classified as type 1 alpha1-subunit-immunoreactive neurons and comprised 75% of the total population of alpha1-subunit-immunoreactive neurons in the striatum. The remaining alpha1-subunit-immunoreactive neurons comprised of a heterogeneous population of large-sized neurons localized in the ventral and medial regions of the striatum. The most numerous large-sized cells were parvalbumin-negative, had two to three relatively short branching dendrites and were designated type 2 alpha1-subunit-immunoreactive neurons. Electron microscopy showed that the type 2 neurons were characterized by a highly convoluted nuclear membrane and were sparsely covered with small axon terminals. The type 2 neurons comprised 20% of the total population of alpha1-subunit-immunoreactive neurons. The remaining large-sized alpha1-immunoreactive cells were designated type 3 cells; they were positive for parvalbumin and were distinguished by long branching dendrites extending dorsally for 600-800 microm into the striatum. These neurons comprised 5% of the total population of alpha1-subunit-immunoreactive neurons and were surrounded by enkephalin-immunoreactive terminals. Electron microscopy showed that the alpha1-subunit type 3 neurons had an indented nuclear membrane and were densely covered with small axon terminals which established alpha1-subunit-immunoreactive symmetrical synaptic contacts with the soma and dendrites. These results provide a detailed characterization of the distribution, morphology and chemical characteristics of the alpha1-subunit-immunoreactive neurons in the rat striatum and suggest that the type 1 and type 2 neurons comprise of separate populations of striatal interneurons while the type 3 neurons may represent the large striatonigral projection neurons described by Bolam et al. [Bolam J. P., Somogyi P., Totterdell S. and Smith A. D. (1981) Neuroscience 6, 2141-2157.].

Animals↗

PubMed1996

Neuronal nitric oxide synthase (nNOS) mRNA expression and NADPH-diaphorase staining in the frontal cortex, visual cortex and hippocampus of control and Alzheimer's disease brains.

Neuronal nitric oxide synthase (nNOS) mRNA levels and NADPH diaphorase (NADPH-d) staining were compared in the frontal cortex, visual cortex and hippocampus (dentate gyrus and CA subfields of Ammon's horn) of five Alzheimer's disease (AD) and six control brains. The cellular abundance of nNOS mRNA was quantified by in-situ hybridisation using 35S-labelled antisense oligonucleotides complementary to the human nNOS sequence. Although the mean level of nNOS expression was decreased in all three regions in AD cases as compared to controls, it did not reach significance. Neurones positively labelled for nNOS mRNA and neurones positive for NADPH-d histochemistry displayed similar distribution in control and AD cases. In AD brains the density of neurones having detectable levels of nNOS mRNA was significantly decreased in the white matter underlying the frontal cortex (P < 0.05) but not in the frontal cortex gray matter; no change was observed in the gray or white matter of the visual cortex in AD. The number of cells expressing detectable levels of nNOS mRNA in the hippocampus was also significantly decreased (P < 0.05) in AD. The density of NADPH-d-positive cells was not significantly decreased in the gray or white matter of the frontal or visual cortices in AD compared to controls; however, the number of NADPH-d-positive cells was significantly decreased in the hippocampus (P < 0.01). These data indicate that although the cellular abundance of nNOS mRNA is not significantly decreased in these three regions in AD, there is a significant decrease in the number of cells expressing detectable levels of nNOS mRNA in the white matter underlying the frontal cortex and in the dentate gyrus and CA subfields of the hippocampus in AD. Furthermore, there was also a significant decrease in the number of NADPH-d-positive cells in the dentate gyrus and CA subfields of the hippocampus in AD as compared to controls. These results suggest specific populations of nNOS/NADPH-d cells in the white matter underlying the frontal cortex and in the hippocampus are vulnerable in AD. The implications of these findings are discussed.

Adult↗

PubMed1996

Loss of A1 adenosine receptors in human temporal lobe epilepsy.

Using quantitative receptor autoradiographic methods we have examined A1 adenosine receptors, adenosine uptake sites, benzodiazepine receptors, NMDA, AMPA, and kainic acid receptors in temporal lobes removed from patients suffering from complex partial seizures and in normal control post-mortem temporal cortex. Binding to A1 adenosine receptors and NMDA receptors was reduced in epileptic temporal cortex, while the other neurochemical parameters were unchanged. The reason for this A1 receptor loss is unclear as it occurred in both idiopathic and symptomatic cases and thus may be a consequence rather than an initial cause of seizures. However, because adenosine is a powerful anticonvulsant substance, loss of anticonvulsant A1 receptors may contribute to the human epileptic condition. It is also possible that the observed differences in A1 binding are due to autopsy vs. biopsy changes in the levels of A1 adenosine receptors.

Adolescent↗

PubMed1996

Localisation of the adenosine uptake site in the human brain: a comparison with the distribution of adenosine A1 receptors.

Using quantitative receptor autoradiography we investigated the distribution of the adenosine uptake site labelled with [3H]NBTI in post-mortem human brain and compared its distribution with that of the A1 adenosine receptor labelled with [3H]CHA. The highest levels of [3H]NBTI binding were found in the cortex and striatum, with moderate levels in the hippocampus, globus pallidus, cerebellum and some midbrain and spinal cord nuclei. The distribution of A1 receptors and this adenosine uptake site differed in the hippocampus where A1 receptors were highest in CA1 but the uptake site was low in CA1 and higher in the molecular layer of the dentate gyrus. These results define the anatomical distribution of the high affinity NBTI sensitive adenosine uptake site in the normal human brain.

Adenosine↗

PubMed1996

Reduction in enkephalin and substance P messenger RNA in the striatum of early grade Huntington's disease: a detailed cellular in situ hybridization study.

The expression of enkephalin and substance P messenger RNAs was examined in the caudate-putamen of human post mortem tissue from control and Huntington's disease tissue using in situ hybridization techniques and human specific enkephalin and substance P [35S] oligonucleotides. Macroscopic and microscopic quantification of enkephalin and substance P gene expression was carried out using computer-assisted image analysis. Tissue was collected from six control cases with no sign of neurological disease and six Huntington's disease cases ranging from grades 0 to 3 as determined by neuropathological evaluation. The clinical and pathological diagnosis of Huntington's disease was confirmed unequivocally by genetic analysis of the CAG repeat length in both copies of IT15, the Huntington's disease gene. A marked reduction in both enkephalin and substance P messenger RNAs was detected in all regions of the caudate nucleus and putamen in Huntington's disease grades 2/3 when compared to controls; in the dorsal caudate few enkephalin or substance P messenger RNA-positive cells were detected. For the early grade (0/1) Huntington's disease cases, a heterogeneous reduction in both enkephalin and substance P messenger RNAs were noted; for enkephalin messenger RNA the striatal autoradiograms displayed a conspicuous patchy appearance. Detailed cellular analysis of the dorsal caudate revealed a striking reduction in the number of enkephalin and substance P messenger RNA-positive cells detected and in the intensity of hybridization signal/cell. These data suggest that both the "indirect" GABA/enkephalin and "direct" GABA/substance P pathways are perturbed very early in the course of the disease and that these early changes in chemical signalling may possibly underlie the onset of clinical symptoms.

Aged↗

PubMed1996

Decreased neuronal nitric oxide synthase messenger RNA and somatostatin messenger RNA in the striatum of Huntington's disease.

The cellular abundance of neuronal nitric oxide synthase and somatostatin messenger RNAs was compared in the caudate nucleus, putamen and sensorimotor cortex of Huntington's disease and control cases. Neuronal nitric oxide synthase messenger RNA was significantly decreased in the caudate nucleus and putamen, but not in the sensorimotor cortex in Huntington's disease; the decrease in neuronal nitric oxide synthase messenger RNA became more pronounced with the severity of the disease. Somatostatin gene expression was significantly decreased in the dorsal putamen in Huntington's disease, but was essentially unchanged in all other regions examined. The density of neurons expressing detectable levels of neuronal nitric oxide synthase messenger RNA was reduced in the striata of Huntington's disease cases with advanced pathology; the density of neurons expressing detectable levels of somatostatin messenger RNA was similar in control and Huntington's disease cases. Neuropeptide Y-, somatostatin- and NADPH-diaphorase-positive neurons were consistently present throughout the striatum across all the grades of the disease. Neuronal nitric oxide synthase and NADPH-diaphorase activity (a histochemical marker for nitric oxide synthase-containing neurons) co-localize with somatostatin and neuropeptide Y in interneurons in the human striatum and cerebral cortex. Although the neurodegeneration associated with Huntington's disease is most evident in the striatum (particularly the dorsal regions), neuronal nitric oxide synthase/neuropeptide Y/somatostatin interneurons are relatively spared. Nitric oxide released by neuronal nitric oxide synthase-containing neurons may mediate glutamate-induced excitotoxic cell death, a mechanism proposed to be instrumental in causing the neurodegeneration seen in Huntington's disease. The results described here suggest that although the population of interneurons containing somatostatin, neuropeptide Y and neuronal nitric oxide synthase do survive in the striatum in Huntington's disease they are damaged during the course of the disease. The results also show that the reduction in neuronal nitric oxide synthase and somatostatin messenger RNAs is most pronounced in the more severely affected dorsal regions of the striatum. Furthermore, the loss of neuronal nitric oxide messenger RNA becomes more pronounced with the severity of the disease; thus implying a down-regulation in neuronal nitric oxide synthase messenger RNA synthesis, and potentially neuronal nitric oxide synthase protein levels, in Huntington's disease.

Aged↗

PubMed1996

GABAA receptor subtype changes in the substantia nigra of the rat following quinolinate lesions in the striatum: a correlative in situ hybridization and immunohistochemical study.

This study investigates the pattern of distribution of GABAA receptor subunit subtypes in the substantia nigra of the rat using in situ hybridization techniques and immunohistochemistry at the light microscopic level following unilateral quinolinate lesions in the striatum. The main purpose of this study was to first identify the variety and regional distribution of GABAA receptor subtype messenger RNAs in the normal substantia nigra and, second, to determine if this pattern and level of expression of GABAA receptor subtypes in the substantia nigra is affected following quinolinate-induced degeneration of the GABAergic striatonigral projection neurons. The study is based on a comparison of adjacent sections using: (i) in situ hybridization and oligonucleotide probes selective for 13 of the GABAA receptor subunits; and (ii) immunohistochemistry and antibodies specific to three protein subunits of the GABAA receptor complex. The results show that the GABAA receptor in the normal substantia nigra pars reticulata has a molecular configuration comprising of the alpha 1, beta 2, and gamma 2 subtypes and that following quinolinate lesions of the striatum the subtype configuration of the GABAA receptors remains unaltered, but that there is a marked increase in the level of expression of the alpha 1, beta 2 and gamma 2 subtypes. In confirmation of these findings, the immunohistochemical results show increased immunoreactivity for the alpha 1, beta 2,3 and gamma 2 GABAA receptor subtypes in the substantia nigra following degeneration of GABAergic striatonigral neurons. The details of these findings are discussed with reference to previous studies and with regard to the implications that these results may have for specific GABAergic neurodegenerative diseases of the human basal ganglia, such as Huntington's disease.

Animals↗

PubMed1996

Trk receptor alterations in Alzheimer's disease.

The expression of trk receptors in postmortem normal, Huntington's disease and Alzheimer's disease human brains was investigated using immunohistochemistry, in-situ hybridisation and Western blotting. Alzheimer's disease hippocampi displayed an increase in trkA receptor levels in astrocytes in the CA1 region, some of which were associated with beta-amyloid-positive plaques. Truncated trkB receptors were found in high levels in senile plaques, while the full-length receptor was expressed in glial-like cells in the hippocampus of Alzheimer's disease brains. In-situ hybridisation studies indicated that trk receptor mRNA was also elevated in Alzheimer's. The appearance of trkA and trkB receptors in astrocytes and plaques in Alzheimer's disease might be related to beta-amyloid deposition and could be implicated in the development of Alzheimer's disease.

Adult↗