Biomedical subjects

A Delacourte

Publications and source records attributed to A Delacourte.

At least 91 records · Page 5Linked to original sources

PubMed1995

[Demonstration of a specific profile of pathological Tau proteins in frontotemporal dementia cases].

We compared samples of different brain areas from patients with Alzheimer's disease (AD), progressive supranuclear palsy (PSP), controls subjects and from 4 patients who met the clinical and pathological criteria for frontotemporal dementia (FTD), using a Western blot analysis. We used polyclonal antibodies directed against Tau proteins and the monoclonal antibody AD2 for the immunodetection of the pathological Tau proteins which are the basic components of neurofibrillary degeneration. In the PSP and AD cases, we respectively detected the abnormal Tau proteins 64 and 69 and the Tau proteins 55, 64, and 69, systematically associated with bands and smears, corresponding to catabolic products or aggregates of these abnormal Tau proteins. In FTD cases, the abnormal Tau proteins 55, 64 and 69 were also detected in the frontal and temporal poles from the autopsied case and in the cortical biopsies. However, the profiles were different because smears and proteolytics products of Tau proteins were absent. There was no detection of abnormal Tau proteins in control brain homogenates and in biopsies from patients with other neurodegenerative disorders such as spongiform encephalopathies or primitive gliosis. These results demonstrate that pathological Tau proteins are produced during FTD degenerating process, despite the absence of neurofibrillary lesions.

Adult↗

PubMed1995

Neurofibrillary degeneration in amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam. Immunochemical characterization of tau proteins.

Neurofibrillary tangles are observed in several neurodegenerative disorders including Alzheimer's disease, progressive supranuclear palsy, and amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam. The major components of neurofibrillary tangles are hyperphosphorylated tau proteins that can be directly detected in brain homogenates, using immunoblotting with specific immunological probes. To investigate whether tau proteins differ biochemically among various neurodegenerative disorders, we analyzed a series of brain samples from Guamanian patients in comparison with Alzheimer's disease, progressive supranuclear palsy, and normal aging. In Alzheimer's disease, these hyperphosphorylated tau proteins are composed of a triplet referred to as tau 55, 64, and 69, whereas in progressive supranuclear palsy, neurofibrillary degeneration is characterized by a tau doublet (tau 64 and 69). In the present study, characterization of tau proteins was performed by immunoblotting, on different cortical and subcortical regions of postmortem brain specimens from Guamanian natives. In all of the cases, biochemical data were always consistent with neuropathological findings. In contrast to Alzheimer's disease patients where the tau triplet is found mostly in cortical regions, a similar triplet was strongly detected in both cortical and subcortical areas in Guamanian patients. The tau profile differed quantitatively from case to case demonstrating that the Alzheimer's disease-related tau triplet had a heterogeneous regional distribution. These data suggest that the tau triplet found in amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam is similar to that observed in Alzheimer's disease, and the regional distribution of tau proteins differs in these disorders.

Adult↗

PubMed1995

Immunocytochemical characterization of Tau proteins during cerebral aging of the lemurian primate Microcebus murinus.

The immunocytochemistry of Tau proteins in the cortical pyramidal neurons of the adult microcebes has been studied, using antibodies against human normal and pathological Tau proteins. Some changes related to the age and to some pathologies were observed. In fact, during the adult life, Tau proteins appeared as very thin granulations scattered in the whole neuronal cytoplasm. With age, a part of these proteins aggregated and became like thick granules at the neuron periphery; the distribution was not uniform, and numerous neurons with aggregated Tau proteins were observed in amyloid plaque-containing brains. Abnormally phosphorylated Tau proteins were also observed in some aged animals, using an absorbed anti-PHF recognizing the pathological Tau proteins characteristic of Alzheimer's disease. This present work confirms that the microcebe is a good model for studying disfunctions involved in the normal cerebral aging and in some neurodegenerative disorders which affect humans.

Amyloid beta-Peptides↗

PubMed1995

Biochemical characterization of Tau proteins during cerebral aging of the lemurian primate Microcebus murinus.

Tau proteins extracted from the brain of 12 adult microcebes ranging from 2 to 9 years old were characterized by Western blots, using immunological probes against normal and pathological human Tau proteins. In microcebes, the molecular weight of Tau proteins increases during aging, with variants of 52-54, 64, 67 kDa in the young adult and variants of 60 and 70 kDa in the oldest animal studied. The increase of the apparent molecular weight is due to a change of conformation and a stabilization in the "hyperphosphorylated" state, as revealed with phosphorylation-dependent monoclonal antibodies Tau-1 and AD2. Furthermore, AD1 specifically detected Alzheimer-type epitopes on the 60 kDa Tau isoform from a very old microcebe. These results suggest that Microcebus murinus is an interesting model for the study of the biochemical dysfunctions that occur in the human brain during aging and Alzheimer disease.

Aging↗

PubMed1994

Biochemical mapping of neurofibrillary degeneration in a case of progressive supranuclear palsy: evidence for general cortical involvement.

A biochemical study was performed to quantify and map the neurodegenerating process in cortical and subcortical brain areas from a case of progressive supranuclear palsy (PSP). Our approach was based on a Western blot analysis of pathological Tau proteins, which are the basic components of neurofibrillary lesions. We found that: (i) the abnormal Tau proteins can be detected in all cortical areas, sometimes in larger amounts than in some subcortical areas; (ii) these abnormal Tau proteins consist of a doublet called Tau 64 and 69, except for in the entorhinal cortex where we detected, as for Alzheimer brains, the triplet of Tau proteins called Tau 55, 64 and 69; (iii) the amounts of abnormal Tau proteins were higher in some neocortical regions, especially in the frontal lobe, than in the hippocampal formation. Our results show that the neocortical pathology in PSP, as revealed by the presence of pathological proteins, is more extended than thought so far. Our biochemical approach appears to be more sensitive than the immunohistochemical one and can clearly differentiates between two types of neurofibrillary pathology, the Alzheimer type with a triplet of abnormal Tau proteins (Tau 55, 64 and 69) and the PSP type with a characteristic doublet (Tau 64 and 69).

Aged↗

PubMed1994

Pathological alterations of the cerebral microvasculature in Alzheimer's disease and related dementing disorders.

Alterations of the cerebral microvasculature have been reported in aging and in neurodegenerative disorders such as Alzheimer's disease. However, the exact role of microvascular alterations in the pathogenesis of neurodegeneration remains unknown. In the present report, the cerebral cortex microvasculature was studied by immunohistochemistry using a monoclonal antibody against vascular heparan sulfate proteoglycan protein core in normal aging controls. Alzheimer's disease, Down syndrome, Guam amyotrophic lateral sclerosis/parkinsonian dementia complex, Pick's disease and dementia pugilistica. In all dementing illnesses, increased microvascular pathology was evident compared to normal controls. Decreased microvascular density and numerous atrophic vessels were the primary abnormalities observed in all dementing disorders. These microvascular abnormalities demonstrated regional and laminar selectivity, and were primarily found in layers III and V of frontal and temporal cortex. Quantitative analysis employing computer-assisted microscopy demonstrated that the decrease in microvascular density in Alzheimer's disease was statistically significant compared to age-matched controls. In addition, extracellular heparan sulfate proteoglycan deposits were observed which colocalized with thioflavine S-positive senile plaques in Alzheimer's disease, Down syndrome and selected Guam dementia cases. In some cases, heparan sulfate proteoglycan was seen in senile plaques that appeared to be diffuse or primitive plaques that stained weakly with thioflavine. Heparan sulfate proteoglycan-containing neurons were also observed in Alzheimer's disease, as well as in Down syndrome and Guam cases. Glial staining for heparan sulfate proteoglycan was never observed. Our data support previous observations that microvascular pathology is found in aging and in Alzheimer's disease. The changes in Alzheimer's disease exceed those found in normal aging controls. We also found microvascular pathology in all other dementing disorders studied. Our studies further demonstrated that the microvascular pathology displays regional and laminar patterns which parallel patterns of neuronal loss. Finally, we also found that heparan sulfate proteoglycan is present in senile plaques and neurons not only as previously reported in Alzheimer's disease, but also in Down syndrome and Guam cases. Heparan sulfate proteoglycan in senile plaques may be derived from either the degenerating microvasculature or from degenerating neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗

PubMed1994

Amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam: quantitative neuropathology, immunohistochemical analysis of neuronal vulnerability, and comparison with related neurodegenerative disorders.

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (lytico-bodig) is a chronic neurodegenerative disorder with high prevalence among the native Chamorro population of Guam. Neuropathological, biochemical, and immunohistochemical analyses were performed on a relatively large series of Guamanian cases and compared to Alzheimer's disease cases. Thioflavin S and antibodies to amyloid beta A4 and tau proteins were used for analysis of pathological changes, and antibodies to the calcium-binding proteins parvalbumin and calretinin, and to a nonphosphorylated epitope on neurofilament protein to study select neuronal populations. A differential distribution of neurofibrillary tangles was observed in the neocortex of Guamanian cases compared to Alzheimer's disease cases, with much higher lesion counts in supragranular than in infragranular layers. Also, Guamanian cases with predominant parkinsonism had generally higher neurofibrillary tangle densities than cases with predominant amyotrophic lateral sclerosis. In addition, there was a certain degree of heterogeneity, qualitatively and quantitatively, in the biochemical distribution of tau proteins among Guamanian and Alzheimer's disease cases as revealed by Western blot analysis. Previous studies have suggested that the clinical symptomatology observed in patients suffering from Alzheimer's disease is related to the dramatic loss of specific corticocortically projecting neurons in the neocortex. Interestingly, a subset of neurofilament-rich pyramidal neurons known to be dramatically affected in Alzheimer's disease appears to be resistant in lytico-bodig. Finally, as in Alzheimer's disease, calcium-binding protein-containing interneurons are not affected. These data suggest that the set of projection neurons affected in Guamanian cases may not correspond to those involved in Alzheimer's disease, and that both disorders are characterized by specific patterns of neuronal vulnerability.

Adult↗

PubMed1994

Alterations in neurofilament protein immunoreactivity in human hippocampal neurons related to normal aging and Alzheimer's disease.

The distribution of immunoreactivity for the neurofilament triplet class of intermediate filament proteins was examined in the hippocampus of young, adult and elderly control cases and compared to that of Alzheimer's disease cases. In a similar fashion to non-human mammalian species, pyramidal neurons in the CA1 region showed a very low degree of neurofilament triplet immunoreactivity in the three younger control cases examined. However, in the other control cases of 49 years of age and older, many CA1 pyramidal neurons showed elevated neurofilament immunoreactivity. In the Alzheimer's disease cases, most of the surviving CA1 neurons showed intense labeling for the neurofilament triplet proteins, with many of these neurons giving off abnormal "sprouting" processes. Double labeling demonstrated that many of these neurons contained tangle-like or granular material that was immunoreactive for abnormal forms of tau and stained with thioflavine S, indicating that these neurons are in a transitional degenerative stage. An antibody to phosphorylated neurofilament proteins labeled a subset of neurofibrillary tangles in the Alzheimer's disease cases. However, following formic acid pre-treatment, the number of neurofibrillary tangles showing phosphorylated neurofilament protein immunoreactivity increased, with double labeling confirming that all of the tau-immunoreactive neurofibrillary tangles were also immunoreactive for phosphorylated neurofilament proteins. Immunoblotting demonstrated that there was a proportionately greater amount of the neurofilament triplet subunit proteins in hippocampal tissue from Alzheimer's disease cases as compared to controls. These results indicate that there are changes in the cytoskeleton of CA1 neurons associated with age which are likely to involve an increase in the level of neurofilament proteins and may be a predisposing factor contributing towards their high degree of vulnerability in degenerative conditions such as Alzheimer's disease. The cellular factors affecting hippocampal neurons during aging may be potentiated in Alzheimer's disease to result in even higher levels of intracellular neurofilament proteins and the progressive alterations of neurofilaments and other cytoskeletal proteins that finally results in neurofibrillary tangle formation and cellular degeneration.

Adolescent↗

PubMed1994

Pathological Tau proteins of Alzheimer's disease as a biochemical marker of neurofibrillary degeneration.

Paired Helical Filaments (PHF) accumulate in the degenerating neurons from the associative cortical brain areas during Alzheimer's disease. They are composed of a triplet of hyperphosphorylated microtubule-associated protein Tau, called Tau 55, 64, 69 or PHF-Tau. The distribution of PHF-Tau in the different brain areas corroborates neuropathological observations and specifies that: the entorhinal cortex and hippocampus are vulnerable regions specifically affected by Alzheimer-type neurofibrillary degeneration during aging, the temporal cortex is already affected at the very first stage of clinical manifestations, almost the whole brain is concerned by neurofibrillary degeneration at the end-stages of the disease. Tau-PHF are also observed in the cortical areas from Parkinson patients with dementia, and more especially in the prefrontal cortex. Tau pathology for Progressive Supranuclear Palsy is significantly different, with a doublet of pathological Tau, namely Tau 64 and 69, in almost all cortical and subcortical areas. Therefore, the presence of pathological Tau proteins in several associative cortical areas is always associated with severe intellectual impairment. Finally, PHF-Tau are powerful biochemical markers of the degenerating process which could be used for setting up an early biological diagnosis test of Alzheimer's disease based upon the immunodetection of PHF antigens in the CSF, as well as for developing experimental models of neurodegeneration.

Alzheimer Disease↗

PubMed1994

[Subcortical dementia of the Neumann type. Contribution of diagnostic imaging].

A 36 year-old patient presented with a dementia of frontal type, gait disturbances, incontinence and a pseudo-bulbar palsy, which caused death at age 40. Brain biopsy of the frontal lobe showed an extensive deep subcortical gliosis. A high level of GFAP was detected by immunoblotting in the biopsy. Clinical and neuropathological observations are similar to cases described as Neumann Progressive Subcortical Gliosis. Single Photon Emission Computer Tomography showed a bilateral frontotemporal hypoperfusion, and Magnetic Resonance Imaging large periventricular and subcortical hyperintensities in both hemispheres, the brainstem and the cerebellum. The hyperintensities on T2-weighted MR images might be related to the intense gliosis. The contribution of such imaging data to diagnosis must be confirmed by other clinico-pathological cases.

Adult↗

PubMed1994

[Normal cerebral aging: study of glial reaction].

Glial fibrillary acidic protein (GFAP), a biochemical marker of astrocytes and glial reaction, was quantified in different brain areas from 16 non-demented patients with a mini mental state score > 25/30 and aged from 21 to 95 years. For each brain, we analyzed the hippocampus (H), the parahippocampus gyrus (GPH) and the neocortical Brodmann areas 9, 22, 39, 44. The quantification of GFAP was performed on the different brain homogenates treated with SDS, using a Western blot method and an immunodetection with a monoclonal antibody against human GFAP. The quantity of GFAP found in the hippocampus and the parahippocampal region were significantly increased as a function of age (p < 0.001). This was not observed for neocortical areas. It has been shown that hippocampal and parahippocampal regions are specifically affected by the Alzheimer-type degenerating process during aging. Glial reaction, as visualized by immunoblotting, could be directly linked to this phenomenon.

Adult↗

PubMed1993

Binding of vascular heparan sulfate proteoglycan to Alzheimer's amyloid precursor protein is mediated in part by the N-terminal region of A4 peptide.

The exact mechanisms of deposition and accumulation of amyloid in senile plaques and in blood vessels in Alzheimer's disease remain unknown. Heparan sulfate proteoglycans may play an important role in amyloid deposition in Alzheimer's disease. Previous investigations have demonstrated high affinity binding between heparan sulfate proteoglycans and the amyloid precursor, as well as with the A4 peptide. In the current studies, a specific vascular heparan sulfate proteoglycan found in senile plaques bound with high affinity to two amyloid protein precursors (APP695 and APP770). Vascular heparan sulfate proteoglycan also bound the Alzheimer's amyloid A4 peptide, and not other amyloid protein precursor regions studied, with high affinity. Both heparan sulfate glycosaminoglycan chains and chemically deglycosylated vascular heparan sulfate proteoglycan protein core bound to A4. High affinity interactions between vascular heparan sulfate proteoglycan and the A4 peptide may play a role in the process of amyloidogenesis in Alzheimer's disease, by localizing the site of deposition of A4, protecting A4 from further proteolysis, or by promoting aggregation and fibril formation.

Alzheimer Disease↗

PubMed1993

Electrophysiological effects of 25-35 amyloid-beta-protein on guinea-pig lateral septal neurons.

The amyloid-beta-protein (A beta P) is the major component of the amyloid deposition which characterizes Alzheimer's disease. We have investigated the effects of 25-35 A beta P, the biologically active part of A beta P, on 35 lateral septal neurons in slices of guinea-pig brain during intracellular recording. Bath application of 25-35 A beta P (10(-6) M) caused transient or long-lasting membrane depolarizations in 15 neurons. These effects were not obtained with a 25-35 A beta P peptide synthetized at random. In 7 other neurons, in control medium or in presence of tetrodotoxin, 25-35 A beta P increased the amplitude of excitatory responses produced by local iontophoretic applications of glutamate and NMDA. The data demonstrate for the first time the excitatory effects of 25-35 A beta P on central neurons, effects which may be involved in the mechanisms of neuronal death in Alzheimer's disease.

Amyloid beta-Peptides↗

PubMed1993

Binding of secreted human neuroblastoma proteoglycans to the Alzheimer's amyloid A4 peptide.

Proteoglycans (PGs) may play a fundamental role in all forms of amyloidosis. In Alzheimer's disease, proteoglycans are found deposited in senile plaques and in neurofibrillary tangles. However, the cellular source of these deposited PGs and their role in amyloidosis in Alzheimer's disease is unknown. Proteoglycans were purified from conditioned medium of human neuroblastoma cells (SKNSH-SY 5Y). Two species of proteoglycans were identified by enzyme susceptibility including a heparan sulfate proteoglycan and a dermatan sulfate proteoglycan. A monoclonal antibody to the protein core of a vascular basement membrane heparan sulfate proteoglycan found in senile plaques in Alzheimer's disease cross-reacted with the proteoglycans secreted by human neuroblastoma cells. Binding between 35SO4-labelled neuroblastoma proteoglycans and the Alzheimer amyloid (A4) peptide was demonstrated by affinity chromatography. Specificity studies demonstrated that binding of human neuroblastoma proteoglycans to the amyloid peptide was specific for a heparan sulfate glycosaminoglycan, with some binding to a dermatan sulfate proteoglycan. Binding to A4 was also demonstrated by a chemically deglycosylated protein core preparation. No significant binding of neuroblastoma proteoglycans was found to two other basic peptides derived from the extracellular domain of the beta-amyloid precursor, demonstrating the specificity of proteoglycan binding to the A4 peptide. Human neuroblastoma proteoglycans may bind to the-Alzheimer amyloid A4 peptide in a region with a heparin binding consensus sequence [VHHQKL] which also contains the cleavage site of the beta-amyloid precursor protein. Neuronal proteoglycans may either regulate the secretion of the amyloid protein precursor or modify the binding of the amyloid protein precursor to other cellular adhesion molecules. Alterations in this binding may be related to the pathogenesis of amyloid deposition in Alzheimer's disease.

Alzheimer Disease↗

PubMed1993

Dementia in Parkinson's disease: biochemical evidence for cortical involvement using the immunodetection of abnormal Tau proteins.

In order to elucidate the neurochemical basis of the dementia of Parkinson's disease, we compared samples of cerebral cortex from 24 nondemented parkinsonian patients and parkinsonian patients with various degrees of dementia, with those from patients with Alzheimer's disease and control subjects, using a quantitative Western blot analysis. An anti-paired helical filaments antibody was used for the immunodetection of the abnormally phosphorylated Tau proteins 55, 64, and 69, which are known to be specific and reliable biochemical markers of Alzheimer-type neurofibrillary degeneration. The frequency and intensity of immunodetection of the abnormal Tau triplet were higher in the demented parkinsonian subgroups than in the nondemented parkinsonian subgroup in the prefrontal area, temporal cortex, and entorhinal cortex but not in either the occipital or the cingular cortex. A quantification of abnormal Tau triplet by densitometry showed that unlike the results obtained in Alzheimer patients, the intensity of lesions in the cerebral cortex of the most demented parkinsonian patients was more severe in the prefrontal area versus the temporal area. This study (1) gives biochemical evidence for Alzheimer-type changes in the cortex of demented parkinsonian patients and (2) suggests that lesions of the prefrontal cortex may significantly contribute to the occurrence of cognitive changes at least in some patients with Parkinson's disease.

Adult↗

PubMed1993

General cortical involvement in a late-onset case of Alzheimer disease. A biochemical approach by quantitation of abnormal tau proteins.

We have performed a biochemical mapping of the neurofibrillary degeneration in all cortical areas of Alzheimer patients, using the immunological quantification of pathological tau 55, 64, and 69. These abnormally phosphorylated proteins, which are the basic components of PHF, are reliable markers of the degenerating process in Alzheimer disease. Here, we report our biochemical findings on a brain from a 90-yr-old woman with an 8-yr history of Alzheimer disease who exhibited dramatic and general cortical involvement. The detection of these markers was very high in all Brodmann areas, even in primary motor, somatosensory, or visual cortex. This case report contrasts with other studies, which suggested that a more virulent disease process is generally associated with an early onset and argues for the heterogeneity of the disease. Moreover, we show here that the immunodetection of abnormal tau proteins using the western blot method is a precise, reliable, and reproducible way to quantify the degenerating process in AD.

Adult↗

PubMed1993

[Detection of Alzheimer type pathological epitopes on Tau proteins of neuroblastoma cells after treatment with okadaic acid].

In Alzheimer's disease, Tau proteins are abnormally phosphorylated. In this paper, we describe a cellular model producing such pathological Tau proteins. After differentiation by NGF and treatment with okadaic acid (an inhibitor of phosphatases 1 and 2 A), neuroblastoma SKNSH-SY 5Y cells produced Tau proteins with an increased apparent molecular weight and a more acidic isoelectric point when compared to Tau proteins from control cells. These modified tau proteins bore Alzheimer-type epitopes detectable by antibodies specific to phosphorylated Alzheimer epitopes. This model is the first step toward a pharmacological approach of neuroprotection.

Alzheimer Disease↗

PubMed1993

[Antigenic changes of Tau protein induced by glutamate on primary cultures of neurons: immunocytochemistry study].

Degenerating neurons in Alzheimer's disease are characterized by the presence of neurofibrillary tangles constituted by paired helical filaments (PHF). Abnormally phosphorylated Tau protein, a microtubule associated protein is one of the major component of PHF. Abnormal phosphorylation seems to be located in the C-terminal domain but also in the N-terminal region of Tau proteins. Previous studies demonstrated that calcium-mediated glutamate toxicity produces a dose-dependent increase of Tau immunolabellings in neuronal cultures. Biochemical results revealed that these changes could be associated with abnormal Tau migrations on immunoblots. Using three anti-Tau antibodies the present study shows that glutamate toxicity induces in neuronal cultures, Tau modifications localized in the N- and C-terminal domains of the protein. These findings suggest the possibility that glutamate toxicity can induce Tau antigenic changes involving probably the whole molecule.

Animals↗