Radioligand-binding assays for study of neurotensin receptors.
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Amino Acid Sequence↗
Biomedical subjects
M Goedert
Publications and source records attributed to M Goedert.
Nerve growth factor receptor mRNA distribution in human brain: normal levels in basal forebrain in Alzheimer's disease.
Nerve growth factor (NGF) receptor mRNA was found to be widely distributed throughout the human central nervous system, with the highest levels in the basal forebrain; this suggests that NGF may function as a retrograde trophic messenger for basal forebrain magnocellular cholinergic nerve cells. The degeneration of the latter constitutes one of the main features of Alzheimer's disease and it may be responsible for some of the cognitive impairment that characterizes the disease. No evidence was obtained for an insufficient synthesis of NGF receptor mRNA in the basal forebrain in Alzheimer's disease, where NGF receptor-like immunoreactivity was confined to neuronal cell bodies. NGF could thus be therapeutically beneficial. It could be expected to induce basal forebrain cholinergic cells to hypertrophy, synthesize more choline acetyltransferase and extend neurites.
Alzheimer Disease↗
Expression and cellular localization of amyloid beta-protein precursor transcripts in normal human brain and in Alzheimer's disease.
Two classes of amyloid beta-protein precursors which differ by the presence of a serine protease inhibitor domain have been described. We have used synthetic oligonucleotide probes to investigate the tissue distribution and cellular localization of mRNAs encoding the two classes of amyloid beta-protein precursors. RNA blot analysis showed that transcripts encoding the protease inhibitor sequence are ubiquitously expressed in peripheral and central tissues. By contrast, transcripts lacking the protease inhibitor domain were only found in the central nervous system. By in situ hybridization on cerebral cortex and hippocampal formation both types of transcripts were present exclusively in nerve cells and they appeared to be produced by the same cells. A reduction in the transcript lacking the protease inhibitor domain was observed in frontal cortex from Alzheimer's disease patients. The present results indicate that there exists no correlation between the distribution of amyloid amyloid beta-protein precursor mRNAs and the tissue and cellular pathology of Alzheimer's disease; they also suggest that an overproduction of amyloid beta-protein precursor mRNA is unlikely to be responsible for amyloid beta-protein deposition in Alzheimer's disease.
Aged↗
Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease.
We have determined the sequences of isoforms of human tau protein, which differ from previously reported forms by insertions of 29 or 58 amino acids in the amino-terminal region. Complementary DNA cloning shows that the insertions occur in combination with both three and four tandem repeats. RNAase protection assays indicate that transcripts encoding isoforms with the insertions are expressed in an adult-specific manner. Transcripts encoding four tandem repeats are also expressed in an adult-specific manner, whereas mRNAs encoding three tandem repeats are expressed throughout life, including in fetal brain. The levels of transcripts encoding the 29 or 58 amino acid inserts were not significantly changed in cerebral cortex from patients with Alzheimer's disease. Antisera raised against synthetic peptides corresponding to these different human tau isoforms demonstrate that multiple tau protein isoforms are incorporated into the neurofibrillary tangles of Alzheimer's disease.
Alzheimer Disease↗
Nerve growth factor mRNA and protein increase in hypothalamus in a mouse model of aggression.
The effects of intermale aggressive behavior induced by social isolation on the level of nerve growth factor (NGF) mRNA and protein were investigated in central and peripheral mouse tissues. A large increase in NGF mRNA and protein was observed in hypothalamus, with no changes in cerebral cortex, hippocampus, and cerebellum. No change in NGF mRNA levels was found in heart, spleen, vas deferens, and submaxillary salivary gland. The cellular localization of NGF mRNA in the central nervous system was investigated by in situ hybridization. Numerous nerve cells were specifically labeled in preoptic and ventrolateral nuclei of the hypothalamus, as well as in the cornu ammonis region of the hippocampus and throughout all layers of the cerebral cortex, with the highest concentration in layer III. The present results firmly establish that nerve cells constitute the major source in NGF in the brain. They also open the way to understanding the regulation of NGF biosynthesis in the central nervous system.
Aggression↗
The repeat region of microtubule-associated protein tau forms part of the core of the paired helical filament of Alzheimer's disease.
The paired helical filament, the principal component of the neurofibrillary tangles characteristic of Alzheimer's disease, is shown to consist of two structurally distinct parts. An external fuzzy region can be removed by pronase treatment to leave a pronase-resistant morphologically recognizable core. A monoclonal antibody has been raised which both decorates the core and labels peptide fragments extracted from the core. Amino acid sequence derived from such peptides was used to design oligonucleotide probes with which cDNA libraries were screened and clones coding for the corresponding proteins were isolated. The sequences proved to code for two isoforms of human microtubule-associated protein tau, which contained respectively three or four tandem repeats of 31 or 32 amino acids each with a characteristic Pro-Gly-Gly-Gly motif. The patterns of mRNA expression for the two isoforms were found to be stage and cell-type specific but were apparently unaltered in Alzheimer's disease. The repeat region of tau is believed to be the microtubule binding domain and it is this region of the molecule which is tightly and specifically bound in the core of the paired helical filament.
Alzheimer Disease↗
The mas oncogene encodes an angiotensin receptor.
The class of receptors coupled to GTP-binding proteins share a conserved structural motif which is described as a 'seven-transmembrane segment' following the prediction that these hydrophobic segments form membrane-spanning alpha-helices. Identified examples include the mammalian opsins, alpha 1-, alpha 2-, beta 1- and beta 2-adrenergic receptors, the muscarinic receptor family, the 5-HT1C-receptor, and the substance-K receptor. In addition, two mammalian genes have been identified that code for predicted gene products with sequence similarity to these receptors, but whose ligand specificity is unknown namely, G21 and the mas oncogene. The mas oncogene shows the greatest sequence similarity to the substance-K receptor, and on this basis it was predicted that it would encode a peptide receptor with mitogenic activity which would act through the inositol lipid signalling pathways. The mas oncogene product was transiently expressed in Xenopus oocytes, and stably expressed in a transfected mammalian cell line. The results demonstrate that the mas gene product is a functional angiotensin receptor.
Angiotensins↗
An extra sequence in the lambda EMBL3 polylinker.
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Bacteriophage lambda↗
Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau.
Screening of cDNA libraries prepared from the frontal cortex of an Alzheimer disease patient and from fetal human brain has led to isolation of the cDNA for a core protein of the paired helical filament of Alzheimer disease. The partial amino acid sequence of this core protein was used to design synthetic oligonucleotide probes. The cDNA encodes a protein of 352 amino acids that contains a characteristic amino acid repeat in its carboxyl-terminal half. This protein is highly homologous to the sequence of the mouse microtubule-associated protein tau and thus constitutes the human equivalent of mouse tau. RNA blot analysis indicates the presence of two major transcripts, 6 and 2 kilobases lon g, with a wide distribution in normal human brain. Tau protein mRNAs were found in normal amounts in the frontal cortex from patients with Alzheimer disease. The proof that at least part of tau protein forms a component of the paired helical filament core opens the way to understanding the mode of formation of paired helical filaments and thus, ultimately, the pathogenesis of Alzheimer disease.
Alzheimer Disease↗
Neuronal localization of amyloid beta protein precursor mRNA in normal human brain and in Alzheimer's disease.
Clones for the amyloid beta protein precursor gene were isolated from a cDNA library prepared from the frontal cortex of a patient who had died with a histologically confirmed diagnosis of Alzheimer's disease; they were used to investigate the tissue and cellular distribution of amyloid beta protein precursor mRNA in brain tissues from control patients and from Alzheimer's disease patients. Amyloid beta protein precursor mRNA was expressed in similar amounts in all control human brain regions examined, but a reduction of the mRNA level was observed in the frontal cortex from patients with Alzheimer's disease. By in situ hybridization amyloid beta protein precursor mRNA was present in granule and pyramidal cell bodies in the hippocampal formation and in pyramidal cell bodies in the cerebral cortex. No specific labelling of glial cells or endothelial cells was found. The same qualitative distribution was observed in tissues from control patients and from patients with Alzheimer's disease. Senile plaque amyloid thus probably derives from neurones. The tissue distribution of amyloid beta protein precursor mRNA and its cellular localization demonstrate that its expression is not confined to the brain regions and cells that exhibit the selective neuronal death characteristic of Alzheimer's disease.
Alzheimer Disease↗
The cellular localization of preprotachykinin A messenger RNA in the bovine nervous system.
The cellular distribution of preprotachykinin A messenger RNA in the bovine nervous system was investigated by in situ hybridization and its tissue distribution by Northern and dot blotting. The latter results were compared with the levels of substance P-like immunoreactivity as determined by radio-immunoassay. The highest levels of preprotachykinin A messenger RNA were found in striatum and trigeminal ganglion, medium levels in retina and lower levels in hypothalamus, spinal cord, pituitary gland and adrenal medulla. The cellular localization of preprotachykinin A messenger RNA was obtained in striatum and trigeminal ganglion using either single-stranded DNA or complementary RNA probes labelled with 32P, 35S or 3H. Specific labelling of small trigeminal ganglion neurones and of medium-sized striatal nerve cells was observed with probes in the anti-messenger RNA sense orientation. Only background labelling was obtained with probes in the messenger RNA sense orientation. The technique was further validated by the demonstration that the same cells in the trigeminal ganglion were labelled by both in situ hybridization and immunohistochemistry. The present findings allow an unambiguous identification of the cellular sites of synthesis of preprotachykinin A messenger RNA; in situ hybridization should also prove a useful technique for investigating the regulation of neuropeptide biosynthesis at the cellular level.
Animals↗
The cellular localization of mRNA in neurobiology.
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Animals↗
Molecular cloning of the chicken nerve growth factor gene: mRNA distribution in developing and adult tissues.
The gene for chicken nerve growth factor was cloned by screening a chicken genomic library with a mouse nerve growth factor cDNA clone. Northern blot analysis indicated the presence of nerve growth factor mRNA throughout the central nervous system of the chick, with the highest levels in retina, midbrain/hindbrain and spinal cord. In embryonic brain, nerve growth factor mRNA was expressed at low levels at day 8, with a progressive increase up to postnatal day 2. Substantial amounts of nerve growth factor mRNA were expressed in embryonic leg tissues at a time when the dorsal root ganglia that project to the limb are maximally responsive to nerve growth factor.
Animals↗
Nerve growth factor mRNA in peripheral and central rat tissues and in the human central nervous system: lesion effects in the rat brain and levels in Alzheimer's disease.
Nerve growth factor (NGF) mRNA is widely distributed throughout peripheral and central rat tissues and throughout the human central nervous system. In the rat, high levels were found in cerebral cortex, hippocampus and thalamus/hypothalamus, medium levels in striatum and brainstem and low levels in cerebellum and spinal cord. The hippocampal levels did not change following the surgical transection of the septohippocampal pathway; similarly, the ibotenic acid-induced lesion of the nucleus basalis magnocellularis did not affect the amounts of NGF mRNA in the cerebral cortex. NGF mRNA was also present in high amounts in human cortex and hippocampus, with only low levels in septum/nucleus basalis magnocellularis, suggesting that NGF may also function as a retrograde trophic messenger in the human central nervous system. No evidence was obtained for an insufficient production of NGF mRNA in senile dementia of the Alzheimer type. In peripheral rat tissues, the highest concentrations of NGF mRNA were found in vas deferens, heart, sciatic nerve, submandibular gland and skin, with low levels in tissues such as trigeminal ganglion and pituitary gland.
Alzheimer Disease↗
Neurotensin-like immunoreactivity and neurotensin receptors in the rat hypothalamus and in the neurointermediate lobe of the pituitary gland.
In the rat hypothalamus, cell bodies containing neurotensin-like immunoreactivity were mainly found in the medial preoptic area, the periventricular nucleus, the paraventricular nucleus, the supraoptic nucleus and the arcuate nucleus. [3H]neurotensin binding sites were observed throughout the hypothalamus with a dense accumulation of silver grains over the paraventricular nucleus, the arcuate nucleus and the median eminence region. By radioimmunoassay neurotensin-like immunoreactivity was also found in the neurointermediate lobe of the pituitary gland of various mammalian species and in human postmortem posterior pituitary glands. In the rat studies involving pituitary stalk transections and the neurotoxin monosodium glutamate indicated the presence of a neurotensinergic pathway from the arcuate nucleus to the neurointermediate lobe of the pituitary gland. [3H]neurotensin binding sites were found to be concentrated over the intermediate lobe of the pituitary gland and their presence was not affected by pituitary stalk transection, indicating their localization on endocrine cells of the intermediate lobe of the pituitary gland.
Animals↗
Neurotensin in human brain: regional distribution and effects of neurological illness.
The regional distribution of neurotensin-like immunoreactivity was investigated in normal human brain and in brains of patients who had died with neurological illness. In Huntington's disease, neurotensin was increased in the pallidum, whilst in Parkinson's disease no significant changes in neurotensin content were observed. Similarly no changes were found in the telencephalic neurotensin content in senile dementia of the Alzheimer type. High levels of neurotensin-like immunoreactivity were detected in lumbar cerebrospinal fluid from patients and the characterization of the immunoreactive material by high-performance liquid chromatography showed it to be indistinguishable from synthetic neurotensin.
Aged↗
The comparative distribution of [Lys8-Asn9]-neurotensin8-13-like immunoreactivity in chicken and rat tissues.
The presence of [Lys8-Asn9]-neurotensin8-13-like immunoreactivity was studied by radioimmunoassay in chicken and rat tissues. In the chicken, [Lys8-Asn9]-neurotensin8-13-like immunoreactivity showed a wide distribution throughout the central nervous system and the gastrointestinal tract, and the immunoreactive material co-eluted with the synthetic peptide on reverse-phase high performance liquid chromatography. In the rat, [Lys8-Asn9]-neurotensin8-13-like immunoreactivity was widely distributed when 0.1 M HCl was used as the extraction procedure. However, the immunoreactive material did not co-elute with the synthetic peptide on reverse-phase high performance liquid chromatography; moreover, the addition of the aspartic proteinase inhibitor pepstatin to the extraction medium resulted in a large reduction in the levels of [Lys8-Asn9]-neurotensin8-13-like immunoreactivity and no immunoreactive material could be detected when the tissues were extracted using acetone/HCl. The present results therefore indicate that [Lys8-Asn9]-neurotensin8-13-like immunoreactivity is not present in rat tissues. That which was detected resulted from an extraction artefact.
Animals↗
The effects of chronic neuroleptic treatment on neurotensin-like immunoreactivity in the rat central nervous system.
The dopamine receptor antagonist fluphenazine decanoate, when administered for a total period of 10 months, produced a large increase in neurotensin-like immunoreactivity in dopamine-rich brain areas, such as the nucleus accumbens, the striatum and the frontal cortex. A smaller, non-significant increase was observed in the substantia nigra with no change in either the hypothalamus or the spinal cord. The present results provide further evidence in favour of a functional interaction between neurotensin and dopamine in the central nervous system.
Animals↗