Biomedical subjects

A Delacourte

Publications and source records attributed to A Delacourte.

At least 55 records · Page 3Linked to original sources

PubMed1998

Loss of somatostatin-like immunoreactivity in the frontal cortex of Alzheimer patients carrying the apolipoprotein epsilon 4 allele.

We measured somatostatin-like immunoreactivity, using a radioimmunoassay which does not cross react with cortistatin-like immunoreactivity, in postmortem frontal cortex (Brodmann area 9) from 32 patients, of different apolipoprotein E genotypes, and presenting with different degrees of cognitive impairment. Eleven subjects and eight patients presented with no (controls) or limited memory impairments (Borderline), respectively. Six patients with clinical criteria for possible Alzheimer's disease also presented with clinical or brain imaging of cerebrovascular disease (mixed dementia) and seven patients were classified as Alzheimer's disease (AD). In the 6 months preceeding their deaths, all subjects had been evaluated by Folstein's Mini Mental State examination (MMS). Sixty nine percent of patients with MMS >20 did not carry the epsilon 4 allele while 66% of patients with MMS <10 did. Somatostatin concentrations (ng/mg wet weight) were significantly lower in the patients carrying the epsilon 4 allele (E2/3: 0.71 +/- 0.05, n = 19 vs. E4: 0.42 +/- 0.06, n = 13; mean +/- SEM, P < 0.001). These results, which are reminiscent of those obtained on cholinergic markers, suggest that apolipoprotein E4 is involved in the somatostatinergic dysfunction early after the onset in AD.

Aged↗

PubMed1998

Phosphorylation of specific sets of tau isoforms reflects different neurofibrillary degeneration processes.

Tau proteins are the basic components of filaments that accumulate within neurons during neurofibrillary degeneration, a degenerating process with disease-specific phenotypes. This specificity is likely to be sustained by both phosphorylation state and isoform content of tau aggregates that form neuronal inclusions. In the present study, characterization of tau isoforms involved in neurofibrillary degeneration in Alzheimer's disease, Pick's disease, corticobasal degeneration and progressive supranuclear palsy was performed. Both analyses by immunoblotting using specific tau antibodies and cell transfection by tau isoform cDNAs allowed us to demonstrate the aggregation of (1) the six hyperphosphorylated tau isoforms in Alzheimer's disease, (2) tau isoforms without exon 10-encoding sequence in Pick's disease and (3) hyperphosphorylated exon 10-tau isoforms in corticobasal degeneration and progressive supranuclear palsy. Thus, neurofibrillary degeneration phenotypes are likely to be related to the phosphorylation of different combinations of tau isoforms (with and/or without exon 10-encoding sequence) in subpopulations of neurons.

Alzheimer Disease↗

PubMed1998

Apolipoprotein E and Tau phosphorylation in human neuroblastoma cells.

Phosphorylation is the major post-translational modification of Tau proteins and it plays an important role in Tau biological functions. Hyperphosphorylation of these proteins occurs during neurodegenerative disorders such as Alzheimer's disease. It was hypothesized that some variants of apolipoprotein E (apo E) may have a protective effect against the normal or pathological phosphorylation of Tau proteins. We have recently shown that apo E synthesis occurs in human SY 5Y and Kelly neuroblastoma cell lines which express different isoforms (E3 for SY 5Y; E3 and E4 for Kelly) [Dupont-Wallois, L., Soulié, C., Sergeant, N., Wavrant-de Wrieze, F., Chartier-Harlin, M.C., Delacourte, A. and Caillet-Boudin, M.L., Neurobiol. Dis., 4 (1997) 356-364]. Therefore, this cellular model makes it possible to study the differential influence, if any, of apo E3 and E4 on Tau phosphorylation. Using a large panel of Tau phosphorylation-dependent antibodies, we were not able to detect a significant difference in Tau immunoreactivity linked to the different apo E genotypes, even when the hyperphosphorylation of Tau proteins was induced by treating cells with Okadaic acid (OA), an inhibitor of phosphatase 1 and 2A proteins. Thus, a difference in apo E isoforms had no dramatic effect upon Tau phosphorylation in native or OA treated cells.

Apolipoproteins E↗

PubMed1998

Vulnerable neuronal subsets in Alzheimer's and Pick's disease are distinguished by their tau isoform distribution and phosphorylation.

Aggregated tau proteins constitute the basic matrix of neuronal inclusions specific to numerous neurodegenerative disorders. Monodimensional and two-dimensional Western blot analyses performed on cortical brain homogenates allowed discrimination between disease-specific tau protein profiles. These observations raised the issue of the physiopathological significance of such specificities. Alzheimer's disease (AD) pathological tau proteins (PTPs) (tau 74, 69, 64, 55) were compared with those of Pick's disease (PiD) (tau 64, 55) using a panel of antibodies against peptidic sequences of tau isoforms corresponding to exons 2, 3, and 10. AD and PiD could then be critically differentiated by the absence of translated tau isoforms with exon 10 in PiD PTPs, along with the absence of the phosphorylation site on Ser262. Immunohistochemical studies corroborate these findings. Indeed, Pick bodies were strongly immunostained by an anti-"exon 2" antibody but failed to reveal any anti-exon 10 reactive epitope. Tangles in AD contained exon 2, 3, and 10 epitopes. Altogether, our results demonstrated that Pick bodies develop within specific neuronal subsets that express specific patterns of 7 isoforms lacking exon 10 peptidic sequence. We conclude that neurodegenerative disorders imply attrition of selectively vulnerable neuronal subsets, a process revealed, and may be sustained by specific tau isoform patterns.

Alzheimer Disease↗

PubMed1998

Influence and optimisation of operating parameters with a new binder in wet granulation. I: use in powder form.

It is very important to know the properties of a new binder in wet granulation because it involves the good or poor quality of the grain and the tablets. To estimate the effects of various procedural parameters on the tablet properties, to evaluate the optimal quantity of binder and solvent, the consequences of excess solvent or time mixing and to limit the number of experiments, the authors use the method of design of experiments. The experiments were carried out on a classical blend of lactose and maize starch and the binder was LYCATAB DSH, a maltodextrin. In this first part the binder was used in powder form and three process factors were retained and controlled, the binder quantity, the quantity of wetting liquid and the mixing time after granulation. Different outcomes were measured and mathematical relationships between responses and operating factors were performed and discussed. A 4% binder concentration with 14-16% of solvent gives good results and an increase in mixing time improves the tablet hardness without increasing the disintegration time (the wetting liquid was water and the blender a LOEDIGE).

Chemistry, Pharmaceutical↗

PubMed1998

Pronounced impact of Th1/E47cs mutation compared with -491 AT mutation on neural APOE gene expression and risk of developing Alzheimer's disease.

Possession of the apolipoprotein E (APOE) epsilon4 allele is the most frequently associated genetic susceptibility factor for Alzheimer's disease (AD). Recently, new polymorphisms in the regulatory region of the APOE gene have been described. We analysed the effects of three of these mutations (-491 AT, -427 CT and Th1/E47cs) on disease risk in a large case-control study, and tested their impacts on APOE allelic expression in brain tissues. The Th1/E47cs T allele was associated with an increased risk of occurrence of AD, while the -491 T allele was associated with a decreased risk, independently of the APOE epsilon2/epsilon3/epsilon4 polymorphism effect. However, the impact of the Th1/E47cs mutation was the strongest. The -427 CT polymorphism was not associated with the disease. In AD subjects heterozygous for the epsilon4 allele, analysis of allelic expression showed that the relative expression levels of the epsilon4 allele were higher than those of the corresponding controls. Consistent with epidemiological data, the relative level of expression of the epsilon4 allele was modified accordingly to the presence or absence of the two main promoter polymorphisms, indicating, in vivo, the deleterious effect of the Th1/E47cs T allele and the protective effect of the -491 T allele in population. These data indicate that in addition to the qualitative effect of the APOE epsilon2/epsilon3/epsilon4 polymorphisms on the AD occurrence, the quantitative variation of expression of these alleles due to functional APOE promoter mutations, is a key determinant of AD development.

Aged↗

PubMed1998

Non-Alzheimer degenerative dementias.

Recent progress in diagnostic criteria of non-Alzheimer degenerative dementias is reviewed. These dementias comprise frontotemporal dementias (including hereditary dementias), primary progressive aphasia and anarthria, corticobasal degeneration, progressive supranuclear palsy and dementia with Lewy bodies. The approach of studying these diseases has changed considerably with genetic and biochemical analyses. A molecular classification is suggested and the clinical significance of this classification is discussed.

Dementia↗

PubMed1997

Glial reaction in the hippocampal formation is highly correlated with aging in human brain.

Glial fibrillary acidic protein (GFAP), a biochemical marker of astrocytes and glial reaction, was quantified by immunoblotting in different brain areas from 33 non-demented patients with a Mini Mental State Examination score above 26 and aged from 12 to 98 years. An increase of GFAP with age was first found in the hippocampus and then in the entorhinal cortex. In both regions, GFAP amounts were correlated with age (r = 0.768). In the isocortex, the increase of GFAP as a function of age was also significant (r = 0.672), but less than for the hippocampal region. GFAP levels increased dramatically after the age of 65 years, and more especially in the hippocampal formation. This glial reaction was observed in aged controls that do not show cognitive impairment and the neuropathological hallmarks of Alzheimer's disease.

Adolescent↗

PubMed1997

Brain microvascular changes in Alzheimer's disease and other dementias.

Vasculopathy in Alzheimer's disease (AD) may represent an important pathogenetic factor of this disorder. In the present study, microvasculature was studied by immunohistochemistry using a monoclonal antibody against a vascular heparan sulfate proteoglycan. Vascular changes were consistently observed in AD and included decrease in vascular density, presence of atrophic and coiling vessels, and glomerular loop formations. The laminar and regional distribution of these vascular alterations was correlated with the presence of neurofibrillary tangles. However, vascular changes may also follow neuronal loss. Vascular density may be related to a decrease in brain metabolism. Furthermore, one of the main features of AD is the presence of amyloid deposits within brain parenchyma and blood vessel walls. It is not yet clear whether amyloid components are derived from the blood or the central nervous system. Because AD is clearly heterogeneous, based on clinical and genetic data, evidence for either a brain or peripheral origin is discussed. Microvasculature was also analyzed in other neurodegenerative disorders devoid of amyloid deposits including amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam and Pick's disease. In conclusion, if vasculopathy in neurodegenerative disorders is not directly involved in pathogenesis, it may act synergistically with other pathogenetic mechanisms including genetic and environmental factors. This aspect of pathology is particularly interesting in view of its accessibility to therapeutic interventions.

Aged↗

PubMed1997

Different distribution of phosphorylated tau protein isoforms in Alzheimer's and Pick's diseases.

Tau proteins aggregate into different neuronal inclusions in several neurodegenerative disorders. In Alzheimer's disease (AD), hyperphosphorylated Tau from paired helical filaments (PHF) of neurofibrillary tangles, named PHF-Tau, have an electrophoretic profile with four main bands (Tau 55, 64, 69, 74 kDa). In Pick's disease, phosphorylated Tau from Pick bodies are made of two major components (Tau 55, 64 kDa) and a minor 69 kDa. Here we show, using specific antibodies against translated exon 2, 3 or 10 of Tau isoforms, that the set of Tau isoforms engaged in the most insoluble part of PHF in AD is made of Tau isoforms with exon 10 while they are lacking in phosphorylated Tau from Pick's disease. Our results suggest that specific sets of Tau isoforms distinguish between typical neuronal inclusions.

Alzheimer Disease↗

PubMed1997

Association between the low density lipoprotein receptor-related protein (LRP) and Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting elderly people. It usually occurs after 65 years old (late-onset AD). The epsilon4 allele of apolipoprotein E (APOE) gene is a risk factor which contributes about 50% of the genetic risk for this form of the disease. The low density lipoprotein receptor-related protein (LRP) is a major receptor for APOE which is found in the senile plaques of AD brains. This makes it a good candidate gene for the disease. There is a polymorphism in the region upstream of the LRP gene that has been associated with AD in an American population. We examined this polymorphism by restriction fragment length polymorphism analysis in a French population with sporadic late-onset AD. In the previous report, a significant increase of the 87 bp allele was found in the AD cases; however, in our population, we observed a significant decrease with this same allele of the LRP gene. The possible reasons for this discrepancy, linkage disequilibrium or statistical anomaly, are discussed.

Age of Onset↗

PubMed1997

Pathological tau proteins in postencephalitic parkinsonism: comparison with Alzheimer's disease and other neurodegenerative disorders.

Immunohistochemical and biochemical analyses of hyperphosphorylated tau proteins, the major component of neurofibrillary tangles, were performed in different brain regions from patients presenting with postencephalitic parkinsonism. Neurofibrillary tangles were found in hippocampus, neocortical areas (mostly in supragranular layers), and several subcortical structures. By immunoblotting, a tau protein triplet similar to the one seen in Alzheimer's disease was observed. This biochemical approach allows for the definition of postencephalitic parkinsonism from certain neurodegenerative disorders such as progressive supranuclear palsy and corticobasal degeneration.

Aged↗

PubMed1997

ApoE synthesis in human neuroblastoma cells.

Apolipoprotein E (apoE) is associated with the two hallmarks of Alzheimer's disease: A beta deposits and neurofibrillary tangles. ApoE synthesis was detected in astrocytes by in situ hybridization but was not detected in neurons. Nevertheless, different studies on apoE immunoreactivity reported the presence of apoE in neurons of Alzheimer, control, and necrosis pontisubicular brains. In this study, we addressed the question of potential synthesis of apoE in neurons and its possible involvement in or in response to pathological conditions. To this purpose, we have studied human neuronal cell lines (SY 5Y and Kelly cells) originating from neuroblastoma. Using monoclonal and polyclonal antibodies, a 32-kDa band was detected in SY 5Y and Kelly cells, before and after NGF differentiation. Two-dimensional gel electrophoresis analysis showed a typical profile of apoE spots resolved to the exact isoelectric points. By reverse transcription-polymerase chain reaction experiments, we demonstrated the presence of apoE mRNA in these cell lines. SY 5Y cells synthesized the apoE3 variant, whereas Kelly cells expressed both apoE3 and apoE4 isoforms, corroborating the two-dimensional gel results. These results suggested that apoE synthesis could occur in human neuronal cell lines under certain conditions.

Antibodies, Monoclonal↗

PubMed1997

Normal and pathological Tau proteins as factors for microtubule assembly.

Tau proteins are microtubule-associated proteins. They regulate the dynamics of the microtubule network, especially involved in the axonal transport and neuronal plasticity. Tau proteins belong to a family of developmentally regulated isoforms generated by alternative splicing and phosphorylation. This generates several Tau variants that interact with tubulin and other proteins. Therefore, Tau proteins are influenced by many physiological regulations. Tau proteins are also powerful markers of the neuronal physiological state. Their degree of phosphorylation is a good marker of cell integrity. It is heavily disturbed in numerous neurodegenerative disorders, leading to a collapse of the microtubule network and the presence of intraneuronal lesions resulting from Tau aggregation. However, different biochemical and immunological patterns of pathological Tau proteins found among neurodegenerative disorders are useful markers for the understanding of the role of Tau protein isoforms and the diagnosis of these pathological conditions.

Alzheimer Disease↗

PubMed1997

Two-dimensional characterization of paired helical filament-tau from Alzheimer's disease: demonstration of an additional 74-kDa component and age-related biochemical modifications.

PHF-tau proteins are the major components of the paired helical filament (PHF) from Alzheimer's disease (AD) neurofibrillary lesions. They differ both qualitatively and quantitatively in their degree of phosphorylation when compared with native tau proteins. However, little is known about the extent and heterogeneity of phosphorylated sites or the isoform composition and the isoelectric variants of PHF-tau. Therefore, we have characterized PHF-tau proteins from cortical brain tissue homogenates of 13 AD patients using two-dimensional gel electrophoresis. Whatever the topographical origin of brain tissue homogenates, PHF-tau proteins shared the same two-dimensional gel electrophoresis profile made of a tau triplet of 55, 64, and 69 kDa. A 74-kDa hyperphosphorylated tau component was detected particularly in the youngest and most severely affected AD patients. This additional component of hyperphosphorylated tau was shown to correspond to the longest brain tau isoform. Furthermore, the isoelectric points of PHF-tau from older AD patients were significantly more basic, indicating a lower degree of phosphorylation. These results show that the severity of neurofibrillary degeneration of AD is modulated by age.

Aged↗

PubMed1997

Distortion of allelic expression of apolipoprotein E in Alzheimer's disease.

The APOE epsilon4 allele is a strong genetic susceptibility factor for Alzheimer's disease. Interaction with other biological factors may modulate the effect of the apoE isoforms. However, previous work suggested that other genetic variability within the APOE locus, influencing the effect of the epsilon4 allele, may exist. Such variability could modify the expression of the APOE gene and, in particular, the level of expression of APOE alleles could be an important determinant of disease pathogenesis. To test this hypothesis we examined the levels of expression of APOE in heterozygotes with AD and in controls, using a new method of semi-quantitation. We report that relative epsilon4 mRNA expression is increased in AD compared with controls and suggest that genetic variability in the neural expression of APOE contributes to disease risk.

Aged↗

PubMed1997

Neurofibrillary tangles in Gerstmann-Sträussler-Scheinker syndrome with the A117V prion gene mutation.

One patient of a French family with Gerstmann-Sträussler-Scheinker syndrome with the mutation in codon 117 of the prion protein (PrP) gene displayed unexpected neuritic degeneration around PrP plaques and numerous diffuse neurofibrillary tangles, whereas other members did not. The tau profile in this patient's brain was analysed and compared with one from another member of the Gerstmann-Sträussler-Scheinker family as well as with the Alzheimer's tau profile. A panel of well characterised antibodies against both normal tau protein and paired helical filaments-tau protein was used on immunoblots of brain proteins resolved by mono and two dimensional gels. The tau profile in the patient with Gerstmann-Sträussler-Scheinker syndrome without neurofibrillary tangles was normal. The tau profile from the patient with Gerstmann-Sträussler-Scheinker syndrome and neurofibrillary tangles was characterised by a hyperaggregation state of tau protein. This case illustrates the phenotypic heterogeneity of the GSS117 mutation not only from one family to another, but also between members of the same family. In this family, the presence of neurofibrillary tangles is still unexplained, but could be correlated with either the protracted duration of the disease or the old age of the patient.

Adult↗

PubMed1996

Induction of a specific tau Alzheimer epitope in SY-5Y neuroblastoma cells.

Hyperphosphorylation of the microtubule-associated tau proteins is one of the main pathological events that leads to neurofibrillary neurodegeneration in Alzheimer's disease. A similar tau phosphorylation pattern may be obtained in SY-5Y neuroblastoma cells after okadaic acid treatment. In this paper, we clearly demonstrate phosphorylation of Ser422 in tau proteins of treated cells as well as in Alzheimer brain homogenates. By contrast, Ser422 was not phosphorylated on native tau proteins from non-treated cells or rapidly processed biopsies. These results confirm that this cell model is still relevant to study neurofibrillary neurodegeneration of the Alzheimer type.

Adult↗