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A Delacourte

Publications and source records attributed to A Delacourte.

At least 37 records · Page 2Linked to original sources
PubMed2000

Synthesis and regulation of apolipoprotein E during the differentiation of human neuronal precursor NT2/D1 cells into postmitotic neurons.

Recently, we showed expression of apolipoprotein E (apoE) in human neuronal-type cells such as neuroblastoma SK N SH-SY 5Y cells. In this model, a negative effect of neuronal differentiation on apoE synthesis was suspected. To check this hypothesis, we studied the regulation of apoE in human postmitotic neurons. The presence of apoE was investigated in undifferentiated human teratocarcinoma NT2/D1 (NT2) cells and during their differentiation into postmitotic hNT neurons induced by retinoic acid (RA) treatment. Before differentiation, apoE protein and mRNA were detected in NT2 cells by Western blotting and RT-PCR experiments. Immunofluorescence study showed that apoE was present in all cells. For longer times of RA treatment (3 weeks), the apoE labeling became heterogeneous: only some cells were immunopositive and among them were some differentiating cells in which apoE was located in both cellular body and neuritic process. Interestingly, terminally differentiated hNT cells no longer expressed apoE. These results demonstrate that neuronal precursor and differentiating cells were able to synthesize apoE while the fully neuronal differentiation exerted a negative effect on apoE neuronal expression. Our results are compatible with a weak expression of apoE in neurons of adult brains.

Antineoplastic Agents↗
PubMed2000

A double-labeling immunohistochemical study of tau exon 10 in Alzheimer's disease, progressive supranuclear palsy and Pick's disease.

Neurofibrillary tangles (NFT), one of the histopathological hallmarks of Alzheimer's disease (AD) and progressive supranuclear palsy (PSP), and Pick bodies in Pick's disease (PiD) are composed of microtubule-associated protein tau, which is the product of alternative splicing of a gene on chromosome 17. Alternative expression of exon 10 leads to formation of three- or four-repeat tau isoforms. To study the differential expression of exon 10, we performed double-labeling immunohistochemistry of the hippocampal formation in nine AD, four PSP and three PiD cases. Cryostat sections were processed with and without formic acid (FA) treatment, and double-stained with anti-tau (Alz-50 or PHF-1) or anti-amyloid P component antibodies and one of two specific anti-exon 10 antibodies (E-10). The effect of proteinase-K treatment was also evaluated. The results suggest the following. First, in AD, E-10 immunoreactivity is present in most intracellular NFT, but not in most dystrophic neurites and neuropil threads, suggesting differential expression of tau isoforms in specific cellular domains. Second, in AD, E-10 immunoreactivity is lost or blocked in most extracellular NFT, possibly due to proteolysis. Third, in PSP, E-10 immunoreactivity is hidden or blocked in NFT and tau-positive glial inclusions, but FA treatment exposes the epitope consistent with the hypothesis that PSP inclusions contain four-repeat tau. Fourth, E-10 immunoreactivity is present in dentate fascia NFT in AD and PSP, but not in Pick bodies in the dentate fascia or other areas. The results suggest that expression of exon 10 in tau is specific for cellular domains in a disease-specific manner.

Aged↗
PubMed2000

Tau protein isoforms, phosphorylation and role in neurodegenerative disorders.

Tau proteins belong to the family of microtubule-associated proteins. They are mainly expressed in neurons where they play an important role in the assembly of tubulin monomers into microtubules to constitute the neuronal microtubules network. Microtubules are involved in maintaining the cell shape and serve as tracks for axonal transport. Tau proteins also establish some links between microtubules and other cytoskeletal elements or proteins. Tau proteins are translated from a single gene located on chromosome 17. Their expression is developmentally regulated by an alternative splicing mechanism and six different isoforms exist in the human adult brain. Tau proteins are the major constituents of intraneuronal and glial fibrillar lesions described in Alzheimer's disease and numerous neurodegenerative disorders referred to as 'tauopathies'. Molecular analysis has revealed that an abnormal phosphorylation might be one of the important events in the process leading to their aggregation. Moreover, a specific set of pathological tau proteins exhibiting a typical biochemical pattern, and a different regional and laminar distribution could characterize each of these disorders. Finally, a direct correlation has been established between the progressive involvement of the neocortical areas and the increasing severity of dementia, suggesting that pathological tau proteins are reliable marker of the neurodegenerative process. The recent discovery of tau gene mutations in frontotemporal dementia with parkinsonism linked to chromosome 17 has reinforced the predominant role attributed to tau proteins in the pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronal populations could lead to different pathologies.

Animals↗
PubMed2000

Brain plasmin enhances APP alpha-cleavage and Abeta degradation and is reduced in Alzheimer's disease brains.

The proteolytic processing of amyloid precursor protein (APP) has been linked to sphingolipid-cholesterol microdomains (rafts). However, the raft proteases that may be involved in APP cleavage have not yet been identified. In this work we present evidence that the protease plasmin is restricted to rafts of cultured hippocampal neurons. We also show that plasmin increases the processing of human APP preferentially at the alpha-cleavage site, and efficiently degrades secreted amyloidogenic and non-amyloidogenic APP fragments. These results suggest that brain plasmin plays a preventive role in APP amyloidogenesis. Consistently, we show that brain tissue from Alzheimer's disease patients contains reduced levels of plasmin, implying that plasmin downregulation may cause amyloid plaque deposition accompanying sporadic Alzheimer's disease.

Adult↗
PubMed2000

Rapid tau protein dephosphorylation and differential rephosphorylation during cardiac arrest-induced cerebral ischemia and reperfusion.

The effects of cerebral ischemia/reperfusion on phosphorylation of microtubule-associated tau proteins were assessed in a canine model of cardiac arrest. As tau proteins are phosphorylated by kinases involved in different transduction signal pathways, their phosphorylation state is an excellent marker of neuronal homeostasis and microtubule dynamics. Canine brain tau proteins were characterized by immunoblotting using phosphorylation-dependent antibodies and antisera raised against different amino- and carboxy-terminal tau sequences. The present study reports a complete dephosphorylation of tau proteins during ischemia, which is shown by a higher electrophoretic mobility and the almost (if not total) disappearance of phosphorylation-dependent monoclonal antibody labeling. After 2-hour restoration of spontaneous circulation, a decrease in the electrophoretic mobility was observed, and after 24 hours of reperfusion, a full restoration of the phosphorylation was visualized using phosphorylation-dependent monoclonal antibodies directed against Ser/Thr-Pro sites. However, one particular phosphorylation site involved in tau binding to microtubules, located on Ser262/356, was never fully significantly rephosphorylated, suggesting that microtubule metabolism was still affected after 24 hours of reperfusion. Thus, the sequential and differential recovery of tau phosphorylation after ischemia followed by reperfusion is a useful marker with which to monitor neuronal integrity after brain ischemia.

Animals↗
PubMed2000

Tau pathology: a marker of neurodegenerative disorders.

Tau is not only a basic component of neurofibrillary degeneration, but is also an aetiological factor, as demonstrated by mutations on the tau gene responsible for frontotemporal dementias with parkinsonism linked to chromosome 17. Polymorphisms on the tau gene and the hierarchical invasion of neocortical areas by tau pathology in numerous sporadic neurodegenerative diseases also suggest that tau pathology is a primary pathogenic event in non-familial dementing diseases and a lead for solid diagnostic and therapeutic approaches.

Alzheimer Disease↗
PubMed2000

Pathological tau phenotypes. The weight of mutations, polymorphisms, and differential neuronal vulnerabilities.

In tauopathies, comparative biochemistry of tau aggregates shows that they differ in both phosphorylation and content of tau isoforms. Six tau isoforms are found in human brain that contain either three (3R) or four microtubule-binding domains (4R). In Alzheimer's disease, all six of the tau isoforms are phosphorylated and aggregate into paired helical filaments. They are detected by immunoblotting as a major tau triplet (tau 55, 64, and 69). In corticobasal degeneration and progressive supranuclear palsy, only phosphorylated 4R-tau isoforms aggregate and appear as a major tau doublet (tau 64 and 69). In Pick's disease, only phosphorylated 3R-tau isoforms aggregate into filaments and are characterized by another major tau doublet (tau 55 and 64). Finally, recent findings provide a direct link between a genetic defect in tau and its abnormal aggregation into filaments in frontotemporal dementia with parkinsonism linked to chromosome 17. In the present study, the question of a relationship between tau isoforms and cell morphology is raised. To answer this question, stably transfected human neuroblastoma SY5Y cell lines with either 3R- or 4R-tau isoforms are established. Cell morphology and tau phosphorylation were modified, suggesting that cells undergo profound changes in their metabolism and viability.

Alzheimer Disease↗
PubMed1999

Neurodegenerative diseases of Guam: analysis of TAU.

Mutations in the tau gene have been described in families affected by frontotemporal dementia with parkinsonism linked to chromosome 17. The authors performed a genetic and biochemical analysis of this gene and its product in the parkinsonism dementia complex of Guam, a disorder characterized by the extensive formation of neurofibrillary tangles. The tau gene is not a primary cause of the parkinsonism dementia complex of Guam.

Aged↗
PubMed1999

Synthesis of apolipoprotein E (ApoE) mRNA by human neuronal-type SK N SH-SY 5Y cells and its regulation by nerve growth factor and ApoE.

By in situ hybridization, we show the ability of human neuroblastoma SY 5Y cells to synthesize apolipoprotein E (apoE) mRNA. This synthesis varied during cell NGF-differentiation: the mRNA level decreased during the first 4 days of NGF treatment (NGF 4 days) and then increased during the 3 following days (NGF 7 days). Furthermore, a treatment of 4-day NGF differentiated cells with exogenous apoE during 3 additional days induced a clear decrease in apoE mRNA synthesis when compared with control cells. This effect was more or less pronounced according to the apoE tested variants: apoE4 was more efficient to decrease the apoE mRNA synthesis as compared with the control cells than apoE3 which was itself more efficient than apoE2. These results suggest that apoE mRNA synthesis in human neuronal-type cells could be regulated by different mechanisms such as those induced by NGF- and apoE-treatments.

Apolipoproteins E↗
PubMed1999

The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease.

OBJECTIVE: To determine the spatiotemporal mapping of neurofibrillary degeneration (NFD) in normal aging and the different stages of AD. BACKGROUND: The pathophysiologic significance of AD lesions, namely amyloid plaques and neurofibrillary tangles, is still unclear, especially their interrelationship and their link with cognitive impairment. METHODS: The study included 130 patients of various ages and different cognitive statuses, from nondemented control subjects (n = 60, prospective study) to patients with severe definite AD. Paired helical filaments (PHF)-tau and Abeta were used as biochemical and histologic markers of NFD and amyloid plaques, respectively. RESULTS: NFD with PHF-tau was systematically present in variable amounts in the hippocampal region of nondemented patients age >75 years. When NFD was found in other brain areas, it was always along a stereotyped, sequential, hierarchical pathway. The progression was categorized into 10 stages according to the brain regions affected: transentorhinal cortex (S1), entorhinal (S2), hippocampus (S3), anterior temporal cortex (S4), inferior temporal cortex (S5), medium temporal cortex (S6), polymodal association areas (prefrontal, parietal inferior, temporal superior) (S7), unimodal areas (S8), primary motor (S9a) or sensory (S9b, S9c) areas, and all neocortical areas (S10). Up to stage 6, the disease could be asymptomatic. In all cases studied here, stage 7 individuals with two polymodal association areas affected by tau pathologic states were cognitively impaired. CONCLUSIONS: The relationship between NFD and Alzheimer-type dementia, and the criteria for a biochemical diagnosis of AD, are documented, and an association between AD and the extent of NFD in defined brain areas is shown.

Aged↗
PubMed1999

A new GTP-cyclohydrolase I mutation in an unusual dopa-responsive dystonia, familial form.

We found a new mutation in the GTP cyclohydrolase gene involved in dopa-responsive dystonia. We sequenced the GTP cyclohydrolase gene in a family with four siblings affected by this disorder and identified an A-T mutation in exon 2, leading to a non conservative amino acid substitution at codon 135 of the protein (Ile135Lys), which may change the conformation of the binding site of this enzyme. The clinical evolution was heterogeneous among carriers of the same mutation, underlining the involvement of other determinants modulating the occurrence of the disease such as genetic or environmental susceptibility factors.

Adolescent↗
PubMed1999

Phosphorylated serine422 on tau proteins is a pathological epitope found in several diseases with neurofibrillary degeneration.

Neuronal inclusions with bundles of abnormal filaments made of tau polymers are found in numerous diseases with neurofibrillary degeneration. Tau proteins are the basic components of paired helical filaments (PHF) in Alzheimer's disease (AD), and are abnormally phosphorylated. A disease-specific phosphorylation site at serine422 was demonstrated on PHF, but not on tau proteins from biopsy-derived brain samples. In the present study, we report the characterization of a polyclonal antibody (988) against the serine422 phosphorylation site. By using biochemical and immunohistochemical methods, we confirmed that it is not found on tau proteins from biopsy- or autopsy-derived control samples, and we investigated the presence of this epitope on tau proteins in several neurodegenerative disorders, including AD, Down syndrome (DS), Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), postencephalitic parkinsonism (PEP) and Pick's disease (PiD). By Western blotting, antibody 988 labeled the characteristic tau triplet (tau 55, 64, 69) in AD, DS, Guamanian ALS/PDC and PEP. PSP and CBD exhibited their typical tau doublet (tau 64, 69), whereas the doublet tau 55 and 64 was detected in PiD. In all of these neurodegenerative disorders, antibody 988 clearly labeled NFT and dystrophic neurites, as well as Pick bodies in PiD cases, whereas no staining was observed in control cases. These data indicate that phosphorylation of serine422 on tau proteins is a common feature among neurodegenerative disorders and is therefore not specific of AD. Moreover, phosphorylation of this epitope permits the distinction between normal tau proteins and pathological tau proteins.

Adult↗
PubMed1999

Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration: tau pathologies with exclusively "exon 10" isoforms.

Pathological tau proteins that constitute the basic matrix of neuronal inclusions observed in numerous neurodegenerative disorders are disease specific. This is mainly the consequence of the aggregation of specific sets of tau isoforms according to the diseases, i.e., six isoforms in Alzheimer's disease (AD) and exclusively the three tau isoforms lacking the corresponding sequence of exon 10 (E10-) in Pick's disease (PiD). By using antibodies specific to the different tau isoforms and one- and two-dimensional gel electrophoresis followed by western blots, we demonstrate herein a third group of neurodegenerative disorders characterized by intraneuronal inclusions exclusively constituted of tau isoforms containing the sequence corresponding to exon 10, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Together, tau isoforms with exon 10 clearly differentiate three groups of neurodegenerative diseases: AD, PiD, and PSP/CBD. For each group, the neuropathological and clinical phenotypes are most likely related to specific sets of tau isoforms expressed by the vulnerable neuronal populations. The recently described mutations of the tau gene responsible for familial frontotemporal dementias also support this hypothesis.

Alzheimer Disease↗
PubMed1999

A novel presenilin-2 splice variant in human Alzheimer's disease brain tissue.

Mutations in the presenilin-1 (PS-1) and presenilin-2 (PS-2) genes account for the majority of cases of early-onset familial Alzheimer's disease (AD). Alternative splicing forms of the PS-1 and PS-2 gene products have previously been reported in fibroblast and brain tissue from both familial and sporadic AD patients, as well as from normal tissues and cell lines. We demonstrate here unusual alternative splicing of the PS-2 gene that leads to the generation of mRNA lacking exon 5 in human brain tissue. This product was more frequently detected in brain tissue from sporadic AD patients (70.0%; 21 of 30) than from normal age-matched controls (17.6%; three of 17). In cultured neuroblastoma cells, this splice variant was generated in hypoxia but not under other forms of cellular stress. Hypoxia-mediated induction of this splice variant was blocked by pretreatment of neuroblastoma cells with the protein synthesis inhibitor cycloheximide or antioxidants such as N-acetylcysteine and diphenyl iodonium, suggesting that hypoxia-mediated oxidant stress might, at least in part, underlie the alternative splicing of PS-2 mRNA through de novo protein synthesis. Furthermore, the stable transfectants of this splice variant produced the N-terminal part of PS-2 protein (15 kDa) and were more susceptible to cellular stresses than control transfectants. These results suggest the possibility that altered presenilin gene products in stress conditions may also participate in the pathogenesis of AD.

Aged↗
PubMed1999

Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration, FTDP-17 and Pick's disease.

Neurodegenerative disorders referred to as tauopathies have cellular hyperphosphorylated tau protein aggregates in the absence of amyloid deposits. Comparative biochemistry of tau aggregates shows that they differ in both phosphorylation and content of tau isoforms. The six tau isoforms found in human brain contain either three (3R) or four microtubule-binding domains (4R). In Alzheimer's disease, all six tau isoforms are abnormally phosphorylated and aggregate into paired helical filaments. They are detected by immunoblotting as a major tau triplet (tau55, 64 and 69). In corticobasal degeneration and progressive supranuclear palsy, only 4R-tau isoforms aggregate into twisted and straight filaments respectively. They appear as a major tau doublet (tau64 and 69). Finally, in Pick's disease, only 3R-tau isoforms aggregate into random coiled filaments. They are characterized by another major tau doublet (tau55 and 64). These differences in tau isoforms may be related to either the degeneration of particular cell populations in a given disorder or aberrant cell trafficking of particular tau isoforms. Finally, recent findings provide a direct link between a genetic defect in tau and its abnormal aggregation into filaments in fronto-temporal dementia with Parkinsonism linked to chromosome 17, demonstrating that tau aggregation is sufficient for nerve cell degeneration. Thus, tau mutations and polymorphisms may also be instrumental in many neurodegenerative disorders.

Alzheimer Disease↗
PubMed1999

Biochemical and molecular characterization of neurofibrillary degeneration in frontotemporal dementias.

Neurofibrillary degeneration (NFD) is a degenerating process characterized by the intraneuronal aggregation of abnormal tau proteins. These proteins have a biochemical signature which is disease-specific. They also have a neocortical distribution which is typical of the disease. Pathological tau proteins have been analyzed qualitatively and quantitatively in all diseases that may present the clinical symptoms of frontotemporal dementias. In Alzheimer's disease, a disease with sometimes a frontal predominance, paired helical filaments (PHF) of neurofibrillary tangles are made of hyperphosphorylated tau, named PHF-tau. Their electrophoretic profile consists of four main bands (tau 55, 64, 69, 74 kD), resulting from the presence of the six tau isoforms. In Pick's disease the phosphorylated tau from Pick bodies are made of two major components (tau 55, 64 kD) and a minor 69 kD resulting from the lack of tau isoforms with the translated exon 10 (E10-). Corticobasal degeneration (CBD) also has a different pattern of tau variants, with tau 64, 69 components and a minor tau 74. Pathological tau proteins that aggregate in CBD (and progressive supranuclear palsy) are exclusively made of E10+ tau isoforms. In frontotemporal dementias non-Alzheimer, non-Pick (Lund and Manchester criteria), we did not observe the presence of pathological tau proteins in 2 cases, but a third one presented a particular pattern of tau, with soluble pathological tau in frontotemporal areas. These data show that this group could be heterogeneous. In conclusion, the biochemical signature of tau distinguishes four classes of frontotemporal dementia. The characteristic tau phenotypes observed are linked to the specific neuronal networks that are affected in each disease.

Dementia↗
PubMed1998

Alzheimer-specific epitope of AT100 in transfected cell lines with tau: toward an efficient cell model of tau abnormal phosphorylation.

Intraneuronal aggregation of specific hyperphosphorylated tau isoforms in subsets of neurons may explain many neurodegenerative processes. Only some antibodies including AP422 and AT100 are specific to the abnormal phosphorylation of tau proteins in these processes. AT100-immunoreactivity was never observed in cell models with the exception of Sf9 cells. In the present study, we developed a way to induce AT100-immunoreactivity in different cell types including COS and SY5Y cells after tau cDNA transfection and treatment by okadaic acid. This represents a useful model to study abnormal tau phosphorylation in situ.

Alzheimer Disease↗