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Biomedical subjects

F Javoy-Agid

Publications and source records attributed to F Javoy-Agid.

At least 19 recordsLinked to original sources
PubMed1992

Decreased choline acetyltransferase mRNA expression in the nucleus basalis of Meynert in Alzheimer disease: an in situ hybridization study.

The subnormal choline acetyltransferase (ChoAcTase) activity in the cerebral cortex of patients with Alzheimer disease (AD) is thought to originate from the loss of cholinergic neurons in the nucleus basalis of Meynert (nbM). To examine possible changes in the functional activity of the remaining cholinergic neurons in the nbM of patients with AD, the level of expression of ChoAcTase mRNA was evaluated. A procedure for double-labeling cholinergic neurons to detect ChoAcTase mRNA and the corresponding protein in the same cell was developed, taking advantage of an anti-ChoAcTase antibody and the recently isolated cDNA complementary to a sequence of the human ChoAcTase mRNA. In the study of three controls and four patients with AD, the presence of both ChoAcTase mRNA and protein was observed in the same large neurons in both nbM and putamen. Specificity of in situ hybridization was further supported by the absence of neuronal staining with a sense probe. In AD patients a subnormal level of expression of ChoAcTase mRNA per cholinergic cell was detected in the nbM but not in the putamen. Our data support the hypothesis that expression of ChoAcTase mRNA might be down-regulated in the surviving cholinergic neurons in the nbM of patients with AD, raising the possibility of functional restoration by stimulating ChoAcTase synthesis.

Alzheimer Disease↗
PubMed1992

Brain muscarinic cholinergic receptors in Huntington's disease.

Muscarinic cholinergic receptors and choline acetyltransferase (ChAT) activity were studied in postmortem brain tissue from patients with Huntington's disease and matched control subjects. In comparison with controls, reductions in ChAT activity were found in the hippocampus, but not in the temporal cortex in Huntington's disease. Patients with Huntington's disease showed reduced densities of the total number of muscarinic receptors and of M-2 receptors in the hippocampus while the density of M-1 receptors was unaltered. Muscarinic receptor binding was unchanged in the temporal cortex. These results indicate a degeneration in Huntington's disease of the septo-hippocampal cholinergic pathway, but no impairment of the innominato-cortical cholinergic system.

Brain Chemistry↗
PubMed1992

Measurement of nerve growth factor-like immunoreactivity in human brain using an anti-mouse-NGF enzyme immunoassay.

Nerve growth factor (NGF) like immunoreactivity, expressed as mouse 2.5S nerve growth factor equivalents, was evaluated in three structures of the human brain post-mortem using a commercially available enzyme immunoassay. Regional differences in NGF-like immunoreactivity were observed. Highest levels were found in hippocampus (148 pg/g) compared to putamen (76 pg/g) and frontal cortex (34 pg/g). In addition, these results suggest differences in the distribution of brain NGF between human and rodent, where relatively high levels of NGF are found in the cortex.

Aged↗
PubMed1992

c-fos protein-like immunoreactivity: distribution in the human brain and over-expression in the hippocampus of patients with Alzheimer's disease.

c-fos protein-like immunoreactivity was investigated in the human brain post mortem, using a polyclonal antiserum raised against the N-terminal conserved peptide of c-fos protein. Immunostaining was found in the cerebral cortex, hippocampus, striatum, thalamus and cerebellum but not in the upper brainstem and the adrenal gland. c-fos-like immunoreactivity predominated in neuronal elements, but was also observed in neuropil and glial cells. In addition to a nuclear localization, the staining could be seen in neuronal dendrites (i.e. in the pyramidal cells of hippocampus or in some cortical areas). In order to analyse the effect of brain injury on c-fos expression, the characteristics of the immunostaining were analysed in the hippocampus of patients deceased with Alzheimer's disease known to be associated with a preferential vulnerability of the pyramidal neurons. No staining was observed in the senile plaques or in neurofibrillary tangles, the histopathological stigmata of the disease. Densitometric measurement of the intensity of c-fos-like staining revealed a significant increase in the hilus, the fimbria and the CA1 field of the pyramidal layer in brains of patients with Alzheimer's disease compared to controls. These modifications may result from a suffering stage of hippocampal cells or from a compensatory mechanism in the still surviving neurons not yet affected by the pathological process.

Aged↗
PubMed1992

Is the vulnerability of neurons in the substantia nigra of patients with Parkinson's disease related to their neuromelanin content?

The contribution of neuromelanin (NM) to the pathogenesis of Parkinson's disease (PD) has long been suspected. In particular, a correlation has been reported between the estimated cell loss in the mesencephalic dopaminergic cell groups and the percentage of NM-pigmented neurons in these cell groups. To test whether the amount of pigment per cell is a critical factor or whether the presence of NM within a neuron is sufficient to account for the degeneration of dopaminergic neurons, the NM content was measured in each neuron from representative sections throughout the ventral mesencephalon of four controls subjects and four patients with PD. Intraneuronal NM was quantified by a densitometric method, using known amounts of synthetic melanin as standards. In control brains, the distribution of melanized neurons in the nigral complex showed a high proportion of lightly melanized neurons in the ventral tegmental area and the pars alpha and gamma of the substantia nigra (SN), whereas heavily melanized neurons were mostly located in the pars beta and lateralis of the SN. An inverse relationship was observed between the percentage of surviving neurons in PD compared with controls and the amount of NM they contain, suggesting that the vulnerability of the dopaminergic neurons is related to their NM content. Factors other than NM may be involved in the differential vulnerability of catecholaminergic neurons in PD. In particular, the constant topography of the cell loss suggests that cell position within the nigral complex is a key factor.

Aged↗
PubMed1992

Does loss of nerve growth factor receptors precede loss of cholinergic neurons in Alzheimer's disease? An autoradiographic study in the human striatum and basal forebrain.

The mechanism by which cholinergic neurons degenerate in Alzheimer's disease is not known. Some of these neurons depend, however, on trophic support from NGF via a membrane receptor. We have analyzed the state of these receptors by autoradiography, with 125I-NGF as the ligand, in the caudate nucleus, putamen, ventral striatum, nucleus basalis of Meynert, and nucleus tegmenti pedunculopontinus of six patients with Alzheimer's disease and five controls, matched for age and postmortem delay. The binding characteristics were similar in the striatum (including caudate nucleus, putamen, and ventral striatum) and basal forebrain of control subjects and patients with Alzheimer's disease (Kd = 2.5-4 x 10(-11) M). In control brains, high levels of 125I-NGF binding were observed in the basal forebrain and striatum (0.32-0.49 fmol/mg tissue equivalent), but no specific binding was detected in the nucleus tegmenti pedunculopontinus. NGF binding sites were distributed heterogeneously in the striatum with patches of low density, corresponding to AChE-poor striosomes, surrounded by a matrix in which receptor density was significantly greater. In Alzheimer's disease, the density of NGF receptors was markedly decreased in the caudate nucleus, putamen, ventral striatum, and nucleus basalis of Meynert. In contrast, AChE staining decreased less in the nucleus basalis of Meynert in all Alzheimer's disease patients, and in the ventral striatum of those most severely affected. These results indicate that if NGF receptors are located on cholinergic neurons, receptor loss and the consequent decrease in trophic support may precede cell degeneration in Alzheimer's disease. The relationship between the loss of these receptors and the pathogenesis of the disease remains to be determined.

Acetylcholinesterase↗
PubMed1991

Neuronal-specific expression of human copper-zinc superoxide dismutase gene in transgenic mice: animal model of gene dosage effects in Down's syndrome.

It has been suggested that copper-zinc superoxide dismutase (CuZn SOD) increment, by accelerating hydrogen peroxide formation, might promote oxidative damage within trisomy 21 cells and might be involved in the various neurobiological abnormalities found in Down's syndrome such as premature aging and Alzheimer-type neurological lesions. In order to test this hypothesis, we have developed strains of transgenic mice carrying the human CuZn SOD gene. The human transgene expression resulted in increased CuZn SOD activity predominantly in the brain (1.93 fold). Immunohistochemical and in situ hybridization analysis of brain sections revealed that human CuZn SOD protein and mRNA was preferentially expressed in neurons, particularly in pyramidal cells of Ammon's horn and granule cells of gyrus dentate. The amount of thiobarbituric acid (TBA)-reactive material was significantly higher in transgenic brains compared to controls, strongly suggesting an increased level of peroxidation in vivo. These results support the notion that CuZn SOD gene dosage effect could play a role in the pathogenesis of rapid aging features in the brain of Down's syndrome patients.

Aging↗
PubMed1991

GABAA receptor complex function in frontal cortex membranes from control and neurological patients.

The functional integrity of the GABAA receptor-benzodiazepine (BZ) recognition site-Cl- ionophore complex was assessed by means of [35S]TBPS (t-butylbicyclophosphorothionate) binding to frontal cortex membranes prepared from frozen postmortem brain tissue taken from control (n = 4), Alzheimer (n = 7), Parkinson (n = 3) and Huntington's chorea (n = 2) patients. Specific [35S]TBPS binding was similar in control, Parkinson's disease and Huntington's chorea brains, but was significantly reduced (78% control, P less than 0.01) in frontal cortex membranes from Alzheimer's patients. The linkage between the BZ recognition sites and the GABAA receptor-linked Cl- ionophore was functionally intact in these membranes as BZ site agonists (zolpidem, alpidem, flunitrazepam and clonazepam) enhanced [35S]TBPS binding under the conditions used (well-washed membranes in the presence of 1.0 M NaCl). Zolpidem (BZ1 selective) exhibited a biphasic enhancement in control membranes whereas the other compounds induced a bell-shaped concentration-response curve. The enhancement of [35S]TBPS binding by alpidem, flunitrazepam and clonazepam was greater in frontal cortex membranes from Alzheimer's patients than in controls whereas it tended to be reduced in membranes from the brains of Huntington's chorea patients. These studies demonstrate the functional integrity of the GABAA receptor macromolecular complex and also the usefulness of [35S]TBPS binding in the study of human postmortem tissue.

Adult↗
PubMed1991

Alterations of dopaminergic and noradrenergic innervations in motor cortex in Parkinson's disease.

The motor areas of the cerebral cortex contain dense dopaminergic and noradrenergic innervation in humans. We looked for changes of these innervations in cases with Parkinson's disease (PD). The density of fibers immunolabeled with tyrosine hydroxylase or dopamine-beta-hydroxylase was evaluated in the primary motor, premotor, and prefrontal cortical regions in 6 cases with PD and 7 control cases. Reductions of both noradrenergic and dopaminergic cortical innervations were observed, with similar magnitudes of reduction found in the motor and prefrontal regions of the cortex. Depletion of noradrenergic innervation was diffuse, involving all cortical laminae. Depletion of dopaminergic innervation was laminar specific, with the most significant reductions in layers I and II; reductions in layers V and VI were either less marked (prefrontal cortex) or not detectable (primary motor). The results suggest the existence of two separate mesocortical dopaminergic systems in humans, with the one distributing to upper cortical layers being preferentially involved in PD.

Aged↗
PubMed1991

Abnormal Tau proteins in progressive supranuclear palsy. Similarities and differences with the neurofibrillary degeneration of the Alzheimer type.

We have previously shown that abnormal Tau species are produced during the neurofibrillary degeneration of the Alzheimer type. These abnormal Tau proteins consist of a characteristic triplet named Tau 55, Tau 64 and Tau 69 which are constantly found in Alzheimer's disease (AD) and Downs syndrome brain regions with tangles. To determine if abnormal Tau species are also produced in other neurodegenerative conditions where intraneuronal filamentous Tau aggregates are observed, we have undertaken an immuno-blot study of brain homogenates from patients with progressive supranuclear palsy (PSP), a neurological disorder characterized by the presence of tangles in subcortical and cortical brain areas. We show here that abnormal Tau species are produced in PSP but that they are different from those in AD. Indeed, although Tau 64 and 69 were present in PSP brain homogenates, possibly as the result of an abnormal phosphorylation as in AD, they were detected in smaller amounts (three times lower) than in AD. In addition Tau 55 was undetected by the immunological tools, such as the absorbed anti-PHF antisera, which specifically label the abnormal Tau proteins. Also the two-dimensional analysis revealed different isoelectric properties. Our results suggest that the production of abnormal Tau species is a very important event during all types of neurofibrillary degeneration. The differences in the pathological Tau-variant profile that were observed between PSP and AD possibly reflect different etiopathogenetic pathways and might explain the formation of different types of filamentous Tau aggregates.

Aged↗
PubMed1991

Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia.

Levels of iron, copper, zinc and manganese were measured by inductively coupled plasma spectroscopy in frozen postmortem brain tissue from patients with Parkinson's disease (PD), progressive supranuclear palsy (PSP), multiple system atrophy with strionigral degeneration (MSA), and Huntington's disease (HD) compared with control subjects. Total iron levels were found to be elevated in the areas of basal ganglia showing pathological change in these disorders. In particular, total iron content was increased in substantia nigra in PD, PSP and MSA, but not in HD. Total iron levels in the striatum (putamen and/or caudate nucleus) were increased in PSP, MSA and HD but not in PD. Total iron levels were decreased in the globus pallidus in PD. There were no consistent alterations of manganese levels in basal ganglia structures in any of the diseases studied. Copper levels were decreased in the substantia nigra in PD, and in the cerebellum in PSP, and were elevated in the putamen and possibly substantia nigra in HD. Zinc levels were only increased in PD, in substantia nigra and in caudate nucleus and lateral putamen. Levels of the iron binding protein ferritin were measured in the same patient groups using a radio-immunoassay technique. Increased iron levels in basal ganglia were generally associated with normal or elevated levels of ferritin immunoreactivity, for example, the substantia nigra in PSP and possibly MSA, and in putamen in MSA. The exception was PD where there was a generalized reduction in brain ferritin immunoreactivity, even in the substantia nigra. An increase in total iron content appears to be a response to neurodegeneration in affected basal ganglia regions in a number of movement disorders. However, only in PD was there an increased total iron level, decreased ferritin content, decreased copper content, and an increased zinc concentration in substantia nigra. These findings suggest an alteration of iron handling in the substantia nigra in PD. Depending on the form in which the excess iron load exists in nigra in PD, it may contribute to the neurodegenerative process.

Aging↗
PubMed1991

Iron and aluminum increase in the substantia nigra of patients with Parkinson's disease: an X-ray microanalysis.

The levels of different elements were studied by x-ray microanalysis in the substantia nigra and the central gray substance of patients with Parkinson's disease, progressive supranuclear palsy, and matched controls. In control brains, only iron, potassium, silicum, sodium, sulfur, and zinc were within the limit of detection of the technique. The abundance of each element was different, but their respective concentrations in the two brain regions were similar, except for sulfur levels which were higher on neuromelanin aggregates in the substantia nigra than in nigral regions lacking neuromelanin, and in the central gray substance. In Parkinson's disease, but not in progressive supranuclear palsy, nigral iron levels increased in regions devoid of neuromelanin and decreased on neuromelanin aggregates, but were unchanged in the central gray substance, when compared to control values. Concentrations of the other elements in the central gray substance and substantia nigra were not different from controls in brains from patients with Parkinson's disease and progressive supranuclear palsy. Analysis of Lewy bodies in the parkinsonian substantia nigra revealed high levels of iron and the presence of aluminum. Metal abundance was not affected in progressive supranuclear palsy, in spite of the nigral cell death. This suggests that the increased iron levels and the detection of aluminum observed in Parkinson's disease are not solely the consequence of the neuronal degeneration.

Aged↗
PubMed1991

Quantitative autoradiography of tyrosine hydroxylase immunoreactivity in the rat brain.

Levels of tyrosine hydroxylase (TH) were quantified in discrete areas of unfixed rat brain tissue sections using a rapid and sensitive radioimmunohistochemical method. The immunological reaction with the TH monoclonal antibody was revealed by a 35S-labelled secondary antibody and thus permitted autoradiographic detection of the enzyme. Autoradiograms were generated by apposition of tissue sections to high-sensitivity films or by dipping into autoradiographic emulsion. A detailed analysis of antibody concentration, incubation time, tissue section thickness, and exposure time of the film was undertaken to determine optimal conditions to produce a linear radiolabelling intensity with respect to the amount of antigen. Quantification of the antigen at regional levels was assessed by computer-assisted image analysis. Autoradiographic optical density of radiolabelling in brain areas was converted to enzyme concentrations by interpolation with a constructed TH calibration curve processed in parallel with tissue sections. The specificity of the labelling and the validity and reproducibility of the quantification were investigated. The distribution of TH radiolabelling was comparable to that described using immunofluorescence histochemistry or measuring TH enzymatic activity on homogenates. Using a 35S-labelled antibody, the detection of TH could be performed at the cellular level.

Animals↗
PubMed1991

Progressive supranuclear palsy: loss of choline-acetyltransferase-like immunoreactive neurons in the pontine reticular formation.

We performed a quantitative immunocytochemical study using a polyclonal antibody directed against choline acetyltransferase (ChAT) in the lower pontine reticular formation in four control subjects and three patients with progressive supranuclear palsy (PSP). In the normal brains, there was detectable ChAT-like immunoreactivity in the nucleus papillioformis, a precerebellar reticular nucleus, and in the nucleus pontis centralis caudalis. In PSP patients, the mean estimated total number of ChAT-like immunoreactive cells was 54% of controls in nucleus papillioformis and 40% of controls in nucleus pontis centralis caudalis. The demonstration of ChAT-like immunoreactivity in nucleus papillioformis is consistent with studies suggesting an extrinsic cholinergic innervation of the cerebellar cortex. Loss of cholinergic cells in nucleus pontis centralis caudalis that corresponds largely to the paramedian pontine reticular formation may be related to disturbances of horizontal saccades in PSP patients.

Aged↗
PubMed1991

Neuronal localization of copper-zinc superoxide dismutase protein and mRNA within the human hippocampus from control and Alzheimer's disease brains.

The distribution of cells containing copper-zinc superoxide dismutase (CuZn SOD) protein and mRNA was studied in hippocampi from normal humans and patients with Alzheimer's disease (AD) by using immunohistochemistry and in situ hybridization. Using antisera against native and denatured CuZn SOD protein, we have determined that immunostaining was intense in pyramidal neurons of the cornu ammonis, in granule cells of the dentate gyrus and very weak in other cells. In the hippocampus of an Alzheimer's patient, successive immunostaining of the same tissue section by antiCuZn SOD and antipaired helical filaments antisera show that both normal and degenerating cells were labeled by the antiCuZn SOD antiserum. Thus, large pyramidal neurons which are susceptible to degenerative processes in AD have the property to contain high amount of CuZn SOD protein. In situ hybridization was performed on paraformaldehyde-fixed hippocampus sections of normal human brains and AD brains with a 35 S labeled DNA probe homologous to human CuZn SOD mRNA. Our results show that CuZn SOD transcripts are present at high abundance in pyramidal neurons of the CA1-CA4 fields, subiculum, and in granule cells of the dentate gyrus. This cellular distribution is similar to that obtained with the antiCuZn SOD antiserum. This might indicate that biochemical pathways leading to superoxide radicals generation are specially active in these neurons, requiring an active transcription of CuZn-SOD gene.

Aged↗
PubMed1990

Compartmental ordering of cholinergic innervation in the mediodorsal nucleus of the thalamus in human brain.

The cholinergic innervation of the mediodorsal (MD) nucleus of the thalamus was visualized immunohistochemically in human brain postmortem, using an antibody against human choline acetyltransferase (ChAT). The ChAT staining of the MD nucleus was more intense than in the surrounding thalamic nuclei but weaker than that of the striatum. No ChAT-positive cell bodies were detected. The ChAT-positive neuropil was unevenly distributed, with patches of dense immunoreactivity contrasting with a weaker surrounding matrix. In adjoining sections stained for ChAT immunoreactivity and for acetylcholinesterase (AChE) activity, the zones enriched in ChAT-immunostained neuropil corresponded to AChE-rich regions. The three-dimensional reconstruction of the richest zone in AChE/ChAT activity evidenced a cylindrical organization throughout the rostrocaudal axis of the MD nucleus. Counts of ChAT-positive varicosities confirmed an inhomogeneous distribution; the density of varicosities was 30% higher in ChAT-rich regions than in surrounding matrix. These findings suggest that the activity of intrinsic neurons within the nucleus may be differentially regulated by cholinergic systems.

Acetylcholinesterase↗