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Biomedical subjects

A Delacourte

Publications and source records attributed to A Delacourte.

At least 127 records · Page 7Linked to original sources
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↗
PubMed1991

Expression of human Cu-Zn superoxide dismutase gene in transgenic mice: model for gene dosage effect in Down syndrome.

It was suggested that increased Cu-Zn superoxide dismutase (SOD-1) might be involved in the various biological abnormalities found in Down's syndrome (DS) such as premature aging and Alzheimer-type neurological lesions. As a model system for testing this hypothesis we have developed two strains of transgenic mice carrying only one copy of the human SOD-1 gene. In the first strain (TG1), no expression has been found by northern blot analysis. The second strain (TG2) exhibited human SOD-1 mRNA and increased SOD-1 activity in the brain (1.93 fold), in the heart (1.69 fold), thymus (1.49 fold) and to a lesser extent in muscle (1.25 fold), liver (1.19 fold), kidney (1.18 fold), spleen (1.35 fold), lung (1.26 fold) and erythrocytes (1.09 fold). In this strain, increased SOD-1 activity in the brain did not induce modifications in the seleno-dependent glutathione peroxidase, glutathione reductase and glutathione S-transferase activities. In brain homogenates, we have focused our studies on Tau proteins which are known to be the major antigenic components of paired helical filaments (PHF), both in DS and Alzheimer's disease. Our results suggested that, in our experimental conditions, the overexpression of SOD-1 did not induce the modifications of Tau proteins similar to those seen during neurofibrillary degeneration.

Animals↗
PubMed1990

Tau marker?

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Alzheimer Disease↗
PubMed1990

Phosphorylation of Tau proteins: a major event during the process of neurofibrillary degeneration. A comparative study between Alzheimer's disease and Down's syndrome.

Six different brain areas from 6 patients with Down's syndrome (DS) of different ages were studied in respect of their Tau protein content using the western-blot technique. They were also studied histologically using a Palmgren (silver staining) method in order to reveal the presence of NFT and SP. The results of these studies show that Tau 64 and 69, two pathological Tau variants recently described in the brains of patients with Alzheimer's disease (AD), are also present in the brains of patients with DS. Alkaline phosphatase treatment demonstrates that their heavy molecular weight is due, as in AD, to an abnormal phosphorylation of Tau proteins. The results of this study show that the detection of Tau 64 and 69 in the brain of these patients is correlated with the presence of neurofibrillary tangles (NFT) and senile plaques (SP). These findings confirm that DS can act as a model for the study of the pathological events that occur in AD. Moreover, they suggest that the abnormal phosphorylation of Tau proteins, enhancing a shift of their electrophoretic mobility, might be an important step among the sequence of events that characterize neurofibrillary degeneration.

Adult↗
PubMed1990

[Towards the development of an in vivo study model of Alzheimer-type neurofibrillary degeneration].

Progress in the search for the cause of Alzheimer's disease is considerably hampered by the lack of animal or in vitro model. We have shown that in Alzheimer's disease two pathological variants of Tau proteins, called Tau 64 and Tau 69, are regularly present in neural tissue undergoing neurofibrillary degeneration. Beside their diagnostic value, Tau 64 and Tau 69 might enable such a model to be devised at long last. It now seems possible to investigate for biochemical disorders capable of inducing the emergence of these two Tau proteins in neuron cultures or among transgenic animals. The innumerable pathogenetic tracks of Alzheimer's disease (aluminium, zinc, superoxide dismutase and free radicals, proteases and antiproteases, beta protein A4 precursor, etc.) should then be opened to exploration.

Alzheimer Disease↗
PubMed1990

Pathological proteins Tau 64 and 69 are specifically expressed in the somatodendritic domain of the degenerating cortical neurons during Alzheimer's disease. Demonstration with a panel of antibodies against Tau proteins.

Bundles of paired helical filaments (PHF) accumulate in the pyramidal neurons that degenerate during Alzheimer's disease. This neurofibrillary degeneration is highly correlated with clinical signs of dementia. During the degenerating process, Tau proteins, which are the major antigenic components of PHF, are abnormally phosphorylated and two pathological isoforms named Tau 64 and 69 are expressed. We have studied their immunoblot distribution in the cortical gray and white matter from different regions of normal and Alzheimer brains, to determine if the degenerating process preferentially affects the somatodendritic or the axonal domain. Two categories of antibodies were used. The first category consisted of anti-human native Tau, anti-Tau proteins from different vertebrates, anti-PHF, monoclonal antibody Alz-50 and an anti-C terminal repeated region of Tau. In control brains, these antibodies strongly detected normal Tau proteins in the gray matter while Tau immunodetection was weak in the white matter. In Alzheimer brain cortices, each antibody detected Tau 64 and 69 in gray matter extracts but not at all in white matter extracts. The second category of anti-Tau consisted of the anti-PHF saturated with normal brain protein extracts. This antiserum only probed the abnormally phosphorylated Tau proteins. It detected Tau 64 and 69 exclusively in the cortical gray matter of Alzheimer brains. Moreover, a 55-kDa Tau protein was also immunolabelled, which might be an intermediary form between normal Tau and Tau 64 and 69. Our results demonstrate that Tau proteins are normal and major components of the somatodendritic domain and that Tau pathology, reflected by the presence of Tau 64 and 69, affects preferentially this domain during Alzheimer's disease.

Aged↗
PubMed1990

Correlation between microscopical changes and Tau 64 and 69 biochemical detection in senile dementia of the Alzheimer type. Tau 64 and 69 are reliable markers of the neurofibrillary degeneration.

We have recently reported that the immunoblot detection of two abnormally phosphorylated tau proteins, named Tau 64 and 69, in homogenates of cortical areas from patients with Alzheimer's disease (AD) was systematically associated with the presence of neurofibrillary tangles (NFT) and senile plaques (SP) in these areas. A blind study was performed to confirm that these proteins had a reliable diagnostic value and to study more precisely the correlation between Tau 64 and 69 and the presence of the characteristic lesions of AD. The density of NFT and of SP was evaluated on histological sections of gyrus supramarginalis from 17 patients with graded intellectual status. Immunodetection of Tau 64 and 69 was semiquantitatively evaluated by densitometry (reflectance mode) on immunoblots of homogenates of the same area on the contralateral hemisphere. The statistical analysis of results showed that Tau 64 and 69 were more strongly correlated with NFT than with SP. Moreover, semiquantitative evaluation of Tau 64 and 69 was correlated with the intellectual status (BTS score). Therefore, these pathological forms of tau proteins are reliable markers of the presence of NFT and SP in the neocortex and may be used as a diagnostic tool.

Aged↗
PubMed1990

General and dramatic glial reaction in Alzheimer brains.

We quantified glial fibrillary acidic protein (GFAP) using immunoblot techniques and anti-GFAP, in unfractionated homogenates of different brain regions from Alzheimer's disease (AD) patients. The amount of GFAP was significantly higher than in brains from controls and other neurodegenerative disorders (mean of 11 times), even in brain regions usually free of AD lesions such as caudate nucleus, thalamus, cerebellum, or brainstem. This dramatic increase of GFAP is not simply reflective of the astrocytic gliosis usually observed near the neurofibrillary tangles and senile plaques but more likely represents an astrocytic reaction in the whole brain corresponding to an overproduction or an accumulation of GFAP. The significance of such an increase is unknown, but it might be a key element in the pathogenesis of AD.

Aged↗
PubMed1990

[Alzheimer's disease: the beta amyloid protein A4 is also present in the cortical white matter].

Amyloid deposits constituted with the beta amyloid protein A4 (beta PA4) have been recently immunodetected in skin and intestine wall of Alzheimer's patients. These findings support the hypothesis of an extraneuronal origin of the beta PA4. Until now, these amyloid deposits had not been observed in the white matter of Alzheimer's brains. Using an antiserum against the 1-10 N Ter subsequence of the beta PA4, we immunodetected amyloid deposits in white matter sections of Alzheimer's brains, pretreated with periodic acid. The immunolabelled amyloid substance was associated with capillaries. These original findings are in good agreement with the vascular origin of the beta PA4.

Aged↗
PubMed1989

Alzheimer's disease: microtubule-associated proteins 2 (MAP 2) are not components of paired helical filaments.

In Alzheimer's disease, the most characteristic neuropathological changes are the formation of neurofibrillary tangles (NFT) and neuritic plaques (NP) characterized by the presence of bundles of paired helical filaments (PHF) that accumulate in the degenerating neurites and neuronal cell bodies. Although the protein composition of the PHF is ill-defined, a number of microtubule-associated proteins have been implicated in these lesions. Here we report results with an antiserum monospecific for the microtubule-associated protein MAP 2 which does not cross-react with any other microtubular protein. Immunostaining with this antibody of sections from an Alzheimer's brain show a strong reactivity with NFT but no reactivity at the level of the NP. On the other hand, immunostaining of Alzheimer's brain sections with another antibody specific for the microtubule-associated protein tau shows strong staining of PHF on both NFT and NP. These findings confirm the presence of the tau proteins in the PHF and strongly suggest that MAP 2 may not be a main structural component of the PHF. Labelling of NFT with the anti-MAP 2 antiserum suggests a non-specific binding of MAP 2 to the PHF during the process of NFT formation.

Alzheimer Disease↗
PubMed1989

Abnormal tau species are produced during Alzheimer's disease neurodegenerating process.

Tau proteins were detected in human brain using two polyclonal antibodies: anti-paired helical filaments and anti-human native tau proteins. Both antisera detected identically the normal set of tau proteins in control brains. Moreover they detected two abnormal tau variants of 64 and 69 kDa exclusively in brain areas showing neurofibrillary tangles and senile plaques. Tau 64 and 69 were abnormally phosphorylated as revealed by the decrease in their molecular mass observed after alkaline phosphatase treatment. Therefore, tau 64 and 69 are specific markers of the neurofibrillary degeneration of the Alzheimer type and might be useful tools for studying the first pathological events that lead to neuronal death.

Aged↗
PubMed1989

Dystrophic peptidergic neurites in senile plaques of Alzheimer's disease hippocampus precede formation of paired helical filaments.

The relationship between peptidergic dystrophic neurites and paired helical filament (PHF)-positive neurites in Alzheimer's disease (AD) senile plaques (SPs) was studied using combined fluorescence and bright-field optics. Cryostat sections of AD hippocampi were first stained with thioflavine-S and immunolabelled with antisera raised against different neuropeptides: somatostatin-28(1-12), somatostatin-14, neuropeptide Y, cholecystokinin (CCK) and substance P. Secondly, using the elution-restaining procedure, sections were immunolabelled with anti-tau/PHF. In immature SPs, clusters of abnormal, swollen neurites were found. The dystrophic, strongly peptidic-positive neurites contained fewer PHFs than the poorly positive ones. Cell bodies, exhibiting a peptidic content, could be found within SPs without any alteration. These results suggest the following sequence of events: an extracellular poisoning mechanism, perhaps the amyloid substance, first changes the structure of presynaptic endings and causes the formation of ballooning dystrophic neurites filled with their normal peptidic content. Subsequently, intracellular degradation occurs with formation of the PHFs. Then the other structures such as dendrites and perikarya are damaged by the same mechanism. Therefore, this phenomenon seems to precede any formation of PHFs in SPs.

Alzheimer Disease↗
PubMed1989

Characterization of two pathological tau protein, variants in Alzheimer brain cortices.

Tau proteins were detected in brain tissue homogenates from 10 patients with Alzheimer's disease versus 10 age-matched controls using the immunoblot technique and 2 polyclonal antibodies: anti-paired helical filaments (PHF) and anti-human native Tau proteins. In control brains, both antisera detected identically the normal set of Tau proteins, with molecular weight (MW) ranging from 45 to 62 kDa. Moreover, in association areas of neocortex from Alzheimer brains, the antisera detected 2 additional Tau variants of 64 and 69 kDa. Tau 64 and 69 were not found in regions of Alzheimer brains where the Alzheimer pathology was absent (caudate nucleus or cerebellum for example). The heavy MW of Tau 64 and 69 is due to their phosphorylation state as shown by the decrease of their MW after alkaline phosphatase treatment. Therefore, Tau 64 and Tau 69 are specific markers of the Alzheimer's disease neuronal degenerating process and their characterization demonstrates that an abnormal phosphorylation of Tau really occurs during the disease. Tau 64 and 69 were isolated with normal Tau proteins while the PHF were insoluble. Therefore, Tau proteins are likely to be abnormally phosphorylated prior to their incorporation in the PHF structure. Consequently, they might appear before the lesions and might be instrumental for the search of biochemical deregulations that precede the neurofibrillary degeneration.

Aged↗
PubMed1989

Immunocytochemical profile of neurofibrillary tangles in Down's syndrome patients of different ages.

Brains were obtained at autopsy from 24 patients with Down's syndrome, ranging in age from 13 to 71 years. Neurofibrillary tangle containing neurones of the hippocampus were stained using a Palmgren silver method and immunocytochemically (PAP) using antisera to paired helical filament protein, human tau protein and ubiquitin, as primary antibody. Counts of cells stained by each method were compared. In patients under 50 years of age, in whom only a limited number of tangle bearing cells were present, the number of profiles visualized with silver, anti-paired helical filament and anti-tau methods were similar. However, in patients over 50 years of age (and in certain of those under 50), in whom numerous tangles were present, the number of cell profiles visualized with silver and anti-paired helical filament methods were still similar though anti-tau detected fewer positive cells. This was because of the increased presence, in such patients, of extracellular tangles which had "lost" anti-tau immunoreactivity. Such data suggest that although tau protein forms a major antigenic determinant of neurofibrillary tangles in Down's syndrome (as it does in Alzheimer's disease) this protein may only decorate the basic paired helical filament protein skeleton, and is removed by macrophagic activity upon neuronal death. In all patients, anti-ubiquitin revealed fewer tangles than any other method. It is possible that ubiquitin may be present only transiently, within tangles perhaps following initial formation and lasting only as long as the normal protein degradation processes remain viable within the diseased neurone.

Adolescent↗