Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mesencephalic cell suspensions were prepared from E12 wild-type (+/+) mouse embryos and stereotaxically implanted into the dorsal neostriatum of weaver mutant mice (wv/wv), which have a genetic mesostriatal dopamine (DA) deficiency. Survival of DA neurons in the grafts was documented by tyrosine hydroxylase (TH) immunocytochemistry. Axon growth was monitored by immunocytochemistry using a battery of antibody markers, and the cellular localization of structural protein and receptor RNA transcripts was studied by in situ hybridization histochemistry using [32P]oligonucleotide probes. The cell suspension grafts exhibited strong immunoreactivity for neural cell adhesion molecule (N-CAM), growth-associated phosphoprotein GAP-43, microtubule-associated protein 2 (MAP2), beta-amyloid protein precursor (beta APP), and phosphorylated neurofilament epitopes (clone SMI-31); intermediate-to-high levels of immunoreactivity were seen for synaptophysin. High levels of hybridization were found in the grafts for the RNA transcripts of GAP-43, MAP2, and isoforms beta APP695, beta APP714 and beta APP751 of the beta APP. No hybridization signal was detected in the grafts for DA D2 or neurotensin receptor mRNAs, both of which are normally expressed by nigral DA neurons. DA receptor autoradiography using the D2/D3 agonist [3H]CV 205-502 as a ligand showed no binding in the transplants, indicating an apparent abnormality of grafted cells; neurotensin binding sites, labeled with [125I]neurotensin, were visualized in the suspensions, indicating the possibility that receptors could be present but that RNA message levels might be too low to allow detection. These findings offer a molecular correlate of axonal, dendritic and structural protein expression by transplanted mesencephalic neurons; further, they suggest that specific functional properties of grafted nigral cells are maintained after transplantation, while other aspects of their cellular biology may be compromised.
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PMID:Ventral mesencephalic grafts in the neostriatum of the weaver mutant mouse: structural molecule and receptor studies. 772 32

The effects of intrahippocampally injected beta-amyloid protein (beta-AP) on glutamate- (Glu) and tyrosine hydroxylase (TH)-like immunoreactivities in the neurons of the locus coeruleus (LC) were studied in rats. A synthetic peptide or the vehicle alone was injected into the hippocampus as controls. All injections were made once a week (two or three injections; 3 nmol in 2 microliters of distilled water). Fluorescent microspheres (either alone or with one of the peptides) were also injected into the hippocampus to identify coeruleo-hippocampal neurons. The results revealed cell loss in the hippocampus at the site near beta-AP or control peptide deposition. Furthermore, in beta-AP/microsphere injected animals, only 22.4% and 49.6% of hippocampal projection neurons contained Glu and TH, respectively, compared to 88.4% and 85.3% in the animals that received control peptide with microspheres. Our results suggest that beta-AP has an effect on noradrenergic cells whose axons project to the hippocampus. These effects may contribute to the TH cell loss in the LC of Alzheimer's brains.
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PMID:Hippocampal beta-amyloid reduces locus coeruleus glutamate and tyrosine hydroxylase. 785 6

Linkage studies were performed in three families (A, B, and C) with autosomal dominantly inherited parkinsonism affecting multiple members in three generations. Affected individuals exhibited the cardinal signs and symptoms of Parkinson's disease, with a mean age of onset of 51, 62, and 61 years in Families A, B, and C, respectively. Parkinsonian symptoms responded to L-dopa treatment, and an [18F]6-fluoro-L-dopa positron emission tomography scan in 1 affected member of Family B showed decreased striatal uptake typical of Parkinson's disease. Ancestors of all three families were traced to a small region in northern Germany and southern Denmark, suggesting the possibility of a common mutation. Linkage studies were performed with polymorphic markers associated with the following candidate genes: the genes for glutathione peroxidase (GPX1, 3q11), tyrosine hydroxylase (TH, 11p15.5), brain-derived neurotrophic factor (BDNF, 11p14), catalase (CAT, 11p13), amyloid precursor protein (APP, 21q21), copper-zinc superoxide dismutase (SOD1, 21q21), and debrisoquin 4-hydroxylase (CYP2D6, 22q13.1). Summed lod scores for all families excluded linkage to the genes GPX1, TH, APP, SOD1, and CYP2D6, as well as to the chromosomal region containing the genes CAT and BDNF. If families were analyzed individually, exclusion was possible for two (Family A), six (Family B), and five (Family C) of the seven candidate genes. There was strong evidence against linkage for the remaining loci in all families analyzed individually, except for TH, which was uninformative in Families A and B, and CYP2D6, which gave slightly positive pairwise lod scores in Family A. Our results indicate that the candidate genes investigated are not involved in the etiology of parkinsonism in these families.
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PMID:Genetic linkage studies in autosomal dominant parkinsonism: evaluation of seven candidate genes. 791 97

Swollen, bulbous-shaped (dystrophic) neurites are a common pathologic feature of Alzheimer's disease (AD) and represent one of the most abundant neuritic abnormalities within the brains of patients with this disease. In the present study, we sought to determine whether the dystrophic neurites which are observed in association with senile plaques are unique to AD or whether they are characteristic of a more generalized process of neuritic and/or neuronal degeneration which can be observed in other neurodegenerative diseases. To accomplish this, we examined post-mortem brain material from patients with AD, Parkinson's disease (PD), Parkinson's disease with associated AD, Parkinson's disease with dementia yet without AD pathology, Huntington's disease (HD), Pick's disease and normal age-matched controls (NC). Using a battery of antibodies to amyloid beta-protein (A beta P), paired-helical filaments (PHF), tyrosine hydroxylase, substance P, neurotensin, and somatostatin we found that immunolabeled dystrophic neurites of the type characteristically observed in AD, were seen only in cases and in brain regions where A beta P deposition was present. More specifically, brain areas known to display severe afferent and/or local degenerative changes such as the caudate and putamen in all three PD groups, the caudate in the HD cases, and the temporal cortex in the HD and Pick's cases were conspicuously free of these swollen neurites unless A beta P deposition was also present.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alzheimer's disease-like dystrophic neurites characteristically associated with senile plaques are not found within other neurodegenerative diseases unless amyloid beta-protein deposition is present. 809 26

Using in situ hybridization histochemistry with [32P]oligonucleotide probes, we studied the cellular localization of RNA transcripts for amyloid beta-protein precursor (beta APP), growth-associated phosphoprotein-43 (GAP-43) and microtubule-associated protein 2 (MAP2) in the mesostriatal system of normal (+/+) and weaver (wv/wv) mutant mice, which lose mesencephalic dopamine neurons. In addition, expression of the same messages was studied in ventral mesencephalic cell suspensions transplanted to the weaver striatum. Transcripts encoding GAP-43, MAP2 and isoforms beta APP695, beta APP714 and beta APP751 were present in normal substantia nigra and progressively reduced in weaver substantia nigra; such a reduction was correlated with dopamine neuron loss. The survival of dopamine neurons in unilateral intrastriatal grafts was documented by methamphetamine-induced rotational asymmetry tests and by tyrosine hydroxylase immunocytochemistry. High hybridization signals were obtained for GAP-43, MAP2, beta APP695, beta APP714 and beta APP751 RNA transcripts in the grafted tissue; the beta APP770 species--normally seen in striatum and not substantia nigra--was not expressed in the grafts, but it was present in the recipient striatum. Following immunocytochemical labelling with antibodies, GAP-43 and MAP2 immunoreactivities were seen in cell processes in the grafts and surrounding tissue, whereas beta APP immunoreactivity was mainly found in grafted cell bodies. These results suggest that the transplanted mesencephalic cells mature very similarly to those in the normal substantia nigra, expressing different mRNAs that are normally present in the ventral midbrain and which are reduced in the weaver mutant as a consequence of dopamine neuron loss.
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PMID:Regional distribution of amyloid beta-protein precursor, growth-associated phosphoprotein-43 and microtubule-associated protein 2 messenger RNAs in the nigrostriatal system of normal and Weaver mutant mice and effects of ventral mesencephalic grafts. 828 93

Postmortem investigations of Alzheimer's patients reveal senile plaques that contain, among other molecules, deposits of beta-amyloid protein. The role of the beta-amyloid deposits remains unclear but identification of mutations in the amyloid precursor protein (APP) gene within the beta-amyloid portion in hereditary forms of the disease provide evidence that these deposits are involved in the pathological state. To more fully investigate this hypothesis attempts have been made to create transgenic mice to overexpress the beta-amyloid protein but these models have not been successful in modeling the disease. We have chosen to utilize the HSV-1 defective vector system which allows the expression of experimental genes in neuronal cells to overexpress APPC100. We have cloned the rat tyrosine hydroxylase (TH) promoter into a defective HSV plasmid. Cloning the firefly luciferase gene under the control of the TH promoter (demonstrates that the promoter is active after infection of human SY5Y cells or rat PC12 cells. A synthetic APP cDNA which represents the last 100 amino acids of the carboxy terminus of APP including the beta-amyloid protein was synthesized and inserted under the control of the TH promoter. Infection and subsequent nuclease protection assays demonstrate expression of the synthetic gene in the infected cells. Current research focuses on detection of the expressed protein within the infected cells and determination of the time period for continued expression.
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PMID:Expression of human amyloid precursor proteins in cultured neuronal cells through the use of HSV-1 defective vectors. 854 29

Considerable evidence exists demonstrating that beta-amyloid protein and its fragments 1-40 and 25-35 (beta (25-35)) are neurotoxic to cells in the rat hippocampus both in culture and in vivo. This neurotoxicity has been correlated to the aggregational state of the peptides. Previously we have shown that beta (25-35) produces a cavitational lesion in rat hippocampus and also reduces the enzyme or transmitter expressions in two subcortical structures whose axons project to the hippocampus: the locus coeruleus (LC) and the medial septum. In the present study, we further investigated the amino acid sequence that might be responsible for these effects. A series of synthetic peptide analogs of beta (25-35) with glycine substituted for serine, asparagine, lysine and methionine at positions 26, 27, 28 and 35, respectively, were injected at a 3 nmol dosage into the rat hippocampus once a week for 2 weeks. The damage to the hippocampus and immunohistochemistry of the LC and medial septum were examined 1 week following the second treatment. All of the synthetic peptides with glycine substitution produced damage to the hippocampal tissue. This damage was similar to that seen with beta (25-35). However, the reduction of enzyme expressions in the LC and medial septum was less from these substituted peptides than from that of beta (25-35). While beta (25-35) application resulted in a similar reduction of tyrosine hydroxylase (TH) and glutamate (Glu) immunoreactivities in the LC, only TH was significantly reduced in the substituted peptide groups. The least reduction of TH and Glu immunoreactivities in the LC was observed in rats treated with peptides in which glycine replaced either lysine or methionine. In the basal forebrain medial septum, the application of beta (25-35) resulted in a marked decrease in choline acetyltransferase (ChAT) immunoreactivity. This reduction was found to be less by each of the synthetic peptides. These results suggest that the biological activity of beta (25-35) is sensitive to changes in the primary structure of the peptide. Among the 4 amino acid residues examined, lysine and methionine at positions 28 and 35 appear to play more important roles in determining the action of beta (25-35).
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PMID:Neuropathology of synthetic beta-amyloid peptide analogs in vivo. 873 21

Beta-amyloid protein (A beta) fragments have been shown to be neurotoxic and/or enhance neuronal vulnerability when injected into the hippocampus. We investigated alterations in monoamine contents, including norepinephrine (NE), 5-HT and dopamine (DA) in the rat locus coeruleus (LC) one week following the injection of beta-amyloid peptide fragment 25-35 (beta (25-35)) into the left dorsal hippocampal areas CA1-3. A single treatment of beta (25-35) had no effect on any monoamine levels. Rats that received two treatments (separated by 7 days) revealed significant elevations in NE, 5-HT, and 5-HIAA as compared with the control group injected with ddH2O. However, these changes were observed in the LC on the contralateral side, whereas the injected side exhibited no significant change. These effects may result from an enhanced synthesis of NE by the contralateral LC neurons to compensate for the loss of tyrosine hydroxylase and accompanying recurrent inhibition in a small number of their population. In a second experiment, the influence of beta (25-35) on spatial learning was evaluated using a Morris water maze task. Rats received bilateral injections of beta (25-35) into hippocampal areas CA1-3. The results indicate that beta (25-35)-treated rats exhibited significantly longer latencies and swim distances to locate the submerged platform than did members of the control group.
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PMID:The neurochemical and behavioral effects of beta-amyloid peptide(25-35). 878 96

During development in vivo and in vitro, estrogens: a) increase brain excitability, particularly in limbic structures; b) are responsible for the maturation and cyclicity of limbic-hypothalamic interrelations; c) enhance myelinogenesis; and d) may act with NGF to stimulate neurite formation. In senescence, estrogen administration would improve memory in postmenopausal women. The absence or low levels of estrogens after menopause would increase prevalence of Alzheimer's dementia (AD) more in women than men, irrespective of age or ethnicity. In the present study, addition of 17-beta estradiol to cultured human neuroblastoma cells affected growth slightly, but stimulated cell maturation as shown by increased tyrosine hydroxylase activity. The extracellular deposition in brain tissue and around blood vessels of the amyloid beta-peptide (A beta), a 4.3 kD fragment of the larger integral membrane protein, beta-amyloid precursor protein (beta-APP), is considered an important characteristic of AD. We investigated whether 17-beta estradiol may influence the formation of the A beta (thus the abnormal accumulation of amyloid proteins) in neuroblastoma cells and in a beta-APP transfected human kidney 293 cell line. Two doses of 17 beta-estradiol were added to the cultures of both cell lines. Cells were grown until confluence, metabolically labeled with 35S-methionine, immunoprecipitated with the rabbit antiserum R1282, gel electrophoresed and autoradiographed in order to compare levels of A beta under the different estradiol concentrations. While in neuroblastoma cells, levels of A beta were only slightly reduced after estradiol and a dose-effect relationship with the hormone could not be demonstrated, in the 293 cells, A beta band intensity decreased as concentration of estradiol increased. These data support the role of estrogen in normal and abnormal brain metabolism and suggest potential hormonal interventions which may reduce or prevent the formation of amyloid deposits occur in AD.
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PMID:Estrogens influence growth, maturation, and amyloid beta-peptide production in neuroblastoma cells and in a beta-APP transfected kidney 293 cell line. 941 80

Immunohistochemistry was used to analyse 18- and 26-month-old transgenic mice overexpressing the human beta-amyloid precursor protein under the platelet-derived growth factor-beta promoter with regard to presence and distribution of neuropeptides. In addition, antisera/antibodies to tyrosine hydroxylase, acetylcholinesterase, amyloid peptide, glial fibrillary acidic protein and microglial marker OX42 were used. These mice have been reported to exhibit extensive amyloid plaques in the hippocampus and cortex [Masliah et al. (1996) J. Neurosci. 16, 5795-5811]. The most pronounced changes were related to neuropeptides, whereas differences between wild-type and transgenic mice were less prominent with regard to tyrosine hydroxylase and acetylcholinesterase. The main findings were of two types; (i) involvement of peptide-containing neurites in amyloid beta-peptide positive plaques, and (ii) more generalized changes in peptide levels in specific layers, neuron populations and/or subregions in the hippocampal formation and ventral cortices. In contrast, the parietal and auditory cortices were comparatively less affected. The peptide immunoreactivities most strongly involved, both in plaques and in the generalized changes, were galanin, neuropeptide Y, cholecystokinin and enkephalin. This study shows that there is considerable variation both with regard to plaque load and peptide expression even among homozygotes of the same age. The most pronounced changes, predominantly increased peptide levels, were observed in two 26-month-old homozygous mice, for example, galanin-, enkephalin- and cholecystokinin-like immunoreactivities in stratum lacunosum moleculare, and galanin, neuropeptide Y, enkephalin and dynorphin in mossy fibers. Many peptides also showed elevated levels in the ventral cortices. However, decreases were also observed. Thus, galanin-like immunoreactivity could not any longer be detected in the diffusely distributed (presumably noradrenergic) fiber network in all hippocampal and cortical layers, and dynorphin-like immunoreactivity was decreased in stratum moleculare, cholecystokinin-like immunoreactivity in mossy fibers and substance P-like immunoreactivity in fibers around granule cells. The significance of generalized peptide changes is at present unclear. For example, the increase in the mainly inhibitory peptides galanin, neuropeptide Y, enkephalin and dynorphin and the decrease in the mainly excitatory peptide cholecystokinin in mossy fibers (and of substance P fibers around granule cells) indicate a shift in balance towards inhibition of the input to the CA3 pyramidal cell layer. Moreover, it may be speculated that the increase in levels of some of the peptides represents a reaction to nerve injury with the aim to counteract, in different ways, the consequences of injury, for example by exerting trophic actions. Further studies will be needed to establish to what extent these changes are typical for Alzheimer mouse models in general or are associated with the V717F mutation and/or the platelet-derived growth factor-beta promoter.
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PMID:Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein--initial observations. 1100 66


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