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P Delaère

Publications and source records attributed to P Delaère.

At least 19 recordsLinked to original sources
PubMed2001

Electrotransfer of naked DNA in the skeletal muscles of animal models of muscular dystrophies.

The electrotransfer of naked DNA has recently been adapted to the transduction of skeletal muscle fibers. We investigated the short- and long-term efficacy of this methodology in wild-type animals and in mouse models of congenital muscular dystrophy (dy/dy, dy(2J)/dy(2J)), or Duchenne muscular dystrophy (mdx/mdx). Using a reporter construct, the short-term efficacy of fiber transduction reached 40% and was similar in wild-type, dy/dy and dy(2J)/dy(2J) animals, indicating that ongoing muscle fibrosis was not a major obstacle to the electrotransfer-mediated gene transfer. Although the complete rejection of transduced fibers was observed within 3 weeks in the absence of immunosuppression, the persistency was prolonged over 10 weeks when transient or continuous immunosuppressive regimens were used. Using therapeutic plasmids, we demonstrated that electrotransfer also allowed the transduction of large constructs encoding the laminin alpha2 chain in dy/dy mouse, or a chimeric dystrophin-EGFP protein in mdx/mdx mouse. The correct sarcolemmal localization of these structural proteins demonstrated the functional relevance of their expression in vivo, with a diffusion domain estimated to be 300 to 500 microm. However, degeneration-regeneration events hampered the long-term stability of transduced fibers. Given its efficacy for naked DNA transfer in these models of muscular dystrophies, and despite some limitations, gene electrotransfer methodology should be further explored as a potential avenue for treatment of muscular dystrophies.

Animals↗
PubMed1999

Minicircle: an improved DNA molecule for in vitro and in vivo gene transfer.

Minicircles are a new form of supercoiled DNA molecule for nonviral gene transfer which have neither bacterial origin of replication nor antibiotic resistance marker. They are thus smaller and potentially safer than the standard plasmids currently used in gene therapy. They were obtained in E. coli by att site-specific recombination mediated by the phage lambda integrase, which was used to excise the expression cassette from the unwanted plasmid sequences. We produced two minicircles containing the luciferase or beta-galactosidase gene under the control of the strong human cytomegalovirus immediate-early enhancer/promoter. Comparing maximal differences, these minicircles gave 2.5 to 5.5 times more reporter gene activity than the unrecombined plasmid in the NIH3T3 cell line and rabbit smooth muscle cells. Moreover, injection in vivo into mouse cranial tibial muscle, or human head and neck carcinoma grafted in nude mice resulted in 13 to 50 times more reporter gene expression with minicircles than with the unrecombined plasmid or larger plasmids. Histological analysis in muscle showed there were more transfected myofibers with minicircles than with unrecombined plasmid.

3T3 Cells↗
PubMed1997

Quantitative analysis of tau protein-immunoreactive accumulations and beta amyloid protein deposits in the cerebral cortex of the mouse lemur, Microcebus murinus.

Recent studies have revealed the presence of tau protein-immunoreactive accumulations and beta amyloid protein (A beta) deposits in the cerebral cortex of the aged mouse lemur, Microcebus murinus. To examine the age-related evolution of these changes and compare their regional distribution to that reported for humans and nonhuman primates with Alzheimer's disease lesions, we performed a quantitative analysis of a large series of mouse lemurs aged from 1 to 13 years. The prevalence and density of tau protein-immunoreactive accumulations in the neocortex of this prosimian increased steadily with age. Neocortical areas were frequently affected even in young mouse lemurs, whereas the subiculum and entorhinal cortex were only involved occasionally in animals older than 8 years. As in anthropoid primates, diffuse A beta deposits were often observed in the cerebral cortex and amygdala of old mouse lemurs. Although all animals with diffuse A beta deposits had tau protein-immunoreactive accumulations in the neocortex, no correlation was found between the densities of these lesions in each area and among the areas studied. The age-dependent progression of tau protein-immunoreactive accumulations indicates that this prosimian may represent a valuable model for the study of the biochemical mechanisms of brain aging, while the relative sparing of hippocampus in mouse lemurs contrasts sharply with previous reports on neurofibrillary tangle formation in humans, and suggests that this animal may also be useful to investigate the biological characteristics of neuroprotection in this area. Furthermore, the present data indicate that A beta deposition in mouse lemurs is not age dependent, but occurs in a few vulnerable old animals.

Age Factors↗
PubMed1997

Proteolytical processing of mutated human amyloid precursor protein in transgenic mice.

The evidence that betaA4 is central to the pathology of Alzheimer's disease (AD) came from the identification of several missense mutations in the amyloid precursor protein (APP) gene co-segregating with familial AD (FAD). In an attempt to study the proteolytical processing of mutated human APP in vivo, we have created transgenic mice expressing the human APP695 isoform with four FAD-linked mutations. Expression of the transgene was controlled by the promoter of the HMG-CR gene. Human APP is expressed in the brain of transgenic mice as shown by Western blot and immunohistology. The proteolytic processing of human APP in the transgenic mice leads to the generation of C-terminal APP fragments as well as to the release of betaA4. Despite substantial amounts of betaA4 detected in the brain of the transgenic mice, neither signs of Alzheimer's disease-related pathology nor related behavioural deficits could be demonstrated.

Amyloid beta-Protein Precursor↗
PubMed1996

Regional and cellular presenilin 2 (STM2) gene expression in the human brain.

Presenilin 2 (STM2) is a recently cloned gene involved in some forms of early onset Alzheimer's disease with autosomal dominant inheritance. Here we report the regional and cellular distribution of STM2 mRNA in the normal human central nervous system. Using in situ hybridization. STM2 gene expression was shown to be confined exclusively to neurones in the central nervous system. A high level of STM2 mRNA expression was observed in the cerebral cortex and the hippocampus, more particularly on pyramidal neurones of Ammon's horn and granular neurones of the dentate gyrus. STM2 mRNA was also detected in Purkinje cells and granular cells of the cerebellum, and in neurones of the striatum and the nucleus basalis of Meynert. Taken together, these results suggest that the expression of STM2 mRNA is not restricted to the neuronal populations that are known to degenerate in Alzheimer's disease.

Aged↗
PubMed1994

Direct intracerebral gene transfer of an adenoviral vector expressing tyrosine hydroxylase in a rat model of Parkinson's disease.

Direct intracerebral gene transfer to neural cells has been demonstrated with recombinant adenovirus encoding beta-galactosidase. To explore the potential of recombinant adenovirus for the therapy of neurological disease we constructed a recombinant adenovirus encoding tyrosine hydroxylase and optimized intracerebral injection to express the gene in the striatum of unilaterally denervated rats. These animals have dopamine depletion in their lesioned striatum, causing a rotation asymmetry induced by apomorphine. One and two weeks after intracerebral injection this sensorimotor asymmetry was decreased by the adenovirus encoding tyrosine hydroxylase and not by a control adenovirus encoding beta-galactosidase. Histological analysis showed that tyrosine hydroxylase was preferentially expressed in astrocytes.

Adenoviridae↗
PubMed1994

Apolipoprotein E allele epsilon 4 is linked to increased deposition of the amyloid beta-peptide (A-beta) in cases with or without Alzheimer's disease.

To assess the significance of the association between apolipoprotein E (APOE) epsilon 4 allele and amyloid beta-peptide (A-beta) deposits in the brain, we performed APOE-genotyping and measured the density of A-beta deposits, neuritic plaques and neurofibrillary tangles in 27 cases from the Charles Foix clinico-pathological prospective study. We found an increased density of A-beta deposits in the three cases with the epsilon 3/epsilon 4 genotype as compared-with epsilon 3/epsilon 3 subjects. Surprisingly, one of the epsilon 3/epsilon 4 genotypes was a 88-year-old woman, with normal intellectual functions and very low densities of neuritic plaques and neurofibrillary tangles but very high densities of preamyloid diffuse deposits of A-beta. This observation contrasted with the expected association between Alzheimer's disease and APOE epsilon 4 allele.

Aged↗
PubMed1994

[Alzheimer disease. Role of beta A4 peptide and cerebral amyloid substance].

Deposition of large quantities of amyloid substance in the walls of the cerebral vessels and in the core of the senile plaques is characteristic of Alzheimer's disease. beta A4 peptide, the main component of the amyloid substance, is a product of a larger amyloid precursor protein which has the structure of a transmembrane receptor and is widely distributed throughout the body. The pathway leading to beta A4 is not yet fully established but could involve lysosomal degradation. It has been suggested that the beta A4 peptide is of neuronal or vascular origin. The beta A4 peptide is found in diffuse deposits in the cortex and cerebellum as well as in the basal ganglia before the classic senile plaques appear, mainly in layer III of the cerebral cortex. These diffuse deposits are devoid of degenerating neurites (i.e. containing abnormally phosphorylated tau protein). The classical senile plaques contain numerous degenerating neurites linking them to the connective network of the cortex. The intellectual deficit is correlated significantly to the density of the classical senile plaques but not to the density of the diffuse deposits. Although a mutation of the gene coding for the beta A4 peptide appears to be sufficient to induce (or accelerate) Alzheimer's disease, this is undoubtedly an exceptional mechanism. Certain mutations involving the beta A4 precursor protein gene increase in vitro the production of beta A4. The molecular and morphological steps leading, from the accumulation of the peptide (which in itself has no clinical expression) to the neurofibrillary pathology of the senile plaques and of the neurones (which are strongly correlated with clinical dementia), remain hypothetical.

Aged↗
PubMed1994

Cortical tangles in progressive supranuclear palsy.

Ten cases of PSP were examined for the presence of neocortical and hippocampal lesions. Samples from 10 cortical areas were stained by Bodian's method and by tau, ubiquitin and beta A4 immunocytochemistry. For the sake of comparison, 5 Alzheimer's cases were studied with the same techniques. Neocortical tangles, star-like tufts of fibers, and neuropil threads were seen in all the cases of PSP. They were stained by Bodian's technique and labelled by an anti-tau, but not by a polyclonal anti-ubiquitin antibody. Senile plaques (Bodian's technique), diffuse or focal amyloid deposits (beta-A4 immunohistochemistry) were rare or absent. The density of tangles was the highest in area 4 and the lowest in area 17. In area 4, the tangles were mainly located in layers V-VI. By contrast, the Alzheimer's tangles had a bimodal distribution (layers III and V-VI). These results favor the specificity of cortical alterations in PSP.

Aged↗
PubMed1994

[Neuropathology of 20 centenarians. I. Clinical data].

We report a clinical study of 20 patients aged more than 100 years, and deceased in Charles Foix Hospital, Ivry/Seine, France, where they had stayed for 10 days to 16 years (mean: 3.3 years, median: 4 years). Each of them was studied neuropathologically (the results of this study will be published later on). The case selection excluded only those patients whose neuropathological study could not be complete. The prevalence of sensorial deficits was high: 15/20 patients had deterioration of hearing, 8 of them were deaf; 14/20 patients had deterioration of sight, 4 of them were blind. Motor deficits were numerous: 15 patients were not ambulatory. The patients were classified as demented or not, according to the criteria of the DSMIII R (American Psychiatric Association 1987), on the basis of a retrospective evaluation of clinical records, and of an inquiry among the caring staff. Their mental status was also evaluated by the Global Deterioration Scale of Reisberg et al (1985). Five patients had been demented, four had been intellectually normal, and 11 had suffered from mild disturbances of memory or cognitive functions. This series was not representative of the general population of centenarians, but probably of those institutionalized in France. We observed a low proportion of demented patients despite the prevalence expected from epidemiological studies. This is difficult to interpret. The low proportion of dementia in this small sample is not due to the short duration of the course of diseases responsible for dementia.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Two distinct ubiquitin immunoreactive senile plaques in Alzheimer's disease: relationship with the intellectual status in 29 cases.

The aim of this study was the analysis of the development of neurofibrillary tangles (NFT) and senile plaques (SP) during aging and senile dementia of the Alzheimer type. The lesions stained by ubiquitin, tau and beta A4 antibodies were studied in Brodmann's area 22 (superior temporal gyrus) in 29 cases. Samples were from a group of women over 75 years of age, psychometrically assessed and either normal or affected by Alzheimer's disease at various degrees of severity. NFT were less numerous when revealed by ubiquitin than by tau antibodies, suggesting that ubiquitin immunoreactivity appeared later in the course of the disease. Ubiquitin immunoreactive (IR) SP were made of clusters of IR neurites usually organized around a central amyloid core. Two types of ubiquitin-IR SP were designated. "Globular neurite SP" contained weakly immunostained globular neurites. They were densest in the least affected cases. However, they were not seen in every normal or lightly affected case, and were always present in the most affected ones. The density of these globular neurite SP was not significantly correlated with the severity of dementia, nor with the density of the lesions stained by tau antibodies (neuritic component of SP, NFT and neuropil threads) or by beta A4 antibodies (diffuse or dense deposits). The "curly neurite" type of SP contained curly neurites strongly immunostained by ubiquitin antibodies. They exhibited the highest density in the most affected cases, where they were always present. They were lacking in the least affected cases. They were always found together with the globular neurite SP.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Alzheimer's lesions labelled by anti-ubiquitin antibodies: comparison with other staining techniques. A study of 15 cases with graded intellectual status in ageing and Alzheimer's disease.

We compared the densities of lesions immunolabeled with ubiquitin, tau and beta A4 antibodies and stained by various silver impregnations, with the intellectual status. The densities of senile plaques and neurofibrillary tangles labelled by anti-ubiquitin antibody were correlated with the Blessed test score. Ubiquitin-positive neurofibrillary tangles were less numerous than those labelled by Gallyas, anti-tau, Bodian's and Bielschowsky's methods. There were five times more beta A4 deposits than ubiquitin positive plaques. beta A4 deposits could be numerous in cases in which ubiquitin immunolabelling was entirely negative. Bielschowsky's method, silver methenamine and thioflavin S revealed more senile plaques than anti-ubiquitin, whereas anti-tau, Gallyas', Bodian's and Cross' techniques revealed similar numbers. Anti-ubiquitin positive lesions were correlated with the severity of dementia. Compared with other staining methods, sensitivity of anti-ubiquitin was weaker for neurofibrillary tangles than for senile plaques. These findings suggest that ubiquitin epitopes are linked to the neurofibrillary changes (in the perikaryon or within the senile plaques), and are absent from beta A4 deposits, either diffuse or compact.

Aged↗
PubMed1993

A brain bank in a neuropathology laboratory (with some emphasis on diagnostic criteria).

The Brain Bank of La Salpêtrière Hospital (Paris) is implanted in a neuropathology laboratory. It is multipurpose, prospective, and "free of charge" for the users. Protocols are prospectively established, in collaboration with the neuroscientists. One of our major difficulties in the collection of cases concerns presently the controls: the neurological status of patients coming from Neurology departments has usually been correctly assessed but those patients are bad controls. The normality of the neurological status of patients dying in other departments is difficult to assess retrospectively. A general autopsy is performed in each case. Several systematic sampling and fixation procedures are currently in use; their pros and cons are discussed. The main safety problem we are confronted with is the risk of HIV and Jakob-Creutzfeldt transmission. We try to standardize our diagnostic procedures; criteria used in Alzheimer's disease, Parkinson's disease, Huntington's chorea are briefly reviewed. We plan, in the future, to standardize our procedures for control cases. The Brain Bank has had a very positive impact on the way this neuropathology laboratory works: it introduced new techniques; on the other hand, the adequate processing and diagnosis of the samples was, in many aspects, simplified by the collaboration with the neuropathology department. The demand for human brain samples is steadily increasing in Neuroscience, for at least 2 reasons: 1. some diseases are specifically human and lack adequate animal models (Alzheimer's disease, multisystem atrophy), or animal models may appear irrelevant in some aspects (multiple sclerosis) or finally, results obtained in animal models may have to be confronted with human pathology (AIDS ...) 2. many aspects of human neuroanatomy can not be extrapolated from animal data There are many ways of organizing a brain bank and no golden standard (Swaab et al., 1989): the neuroscientist himself may collect the samples in a given pathology or the neuropathologists may modify their practice to provide adequate samples to the neuroscientists. When the neuroscientist himself collects his own samples, he obviously proceeds more rapidly. However, he is confronted with the difficult problem of the controls, which require both a clinical follow-up and a pathological check up of the tissues, both of which may be difficult to obtain in a research unit. In our opinion, the neuropathologists are the natural "brain bankers": they are indeed naturally "rich", their job being precisely to collect human samples, in connection with the clinicians.(ABSTRACT TRUNCATED AT 400 WORDS)

Brain↗
PubMed1992

Morphology of demyelination in the human central nervous system.

The principles of the neuropathological classification of disorders of central nervous system myelin are recalled. They are illustrated by a few selected examples. Dysmyelination is characterized by the production of an abnormal and unstable myelin sheath; it is often associated with hypomyelination (paucity of myelin formation) and is due to metabolic disorders. It is the main process in leukodystrophies. Storage of different lipids (e.g. sulfatides, long-chain fatty acids) or associated pathology of various cell types (in Alexander's disease, for example) are used for classifying these disorders. Biochemical and genetic characterizations are presently ongoing. Demyelination is the destruction of apparently normal myelin. It is often followed by remyelination. Our present knowledge on the neuropathology of multiple sclerosis, the most common demyelinating disease, is summarized. Cell-mediated demyelination affects the myelin sheaths for an obscure reason. The causes of the multifocal and sharply demarcated plaques, and of the fading of the remyelination process at the edge of some plaques, are not clear. A few examples of demyelinating diseases of known etiology and of various mechanisms are given. The similarities between acute disseminated leukoencephalitis and experimental autoimmune encephalitis are stressed. In progressive multifocal leukoencephalopathy, chronic infection of oligodendrocytes by JC virus induces poorly defined areas of demyelination. In AIDS, the pathogenesis of the myelin change is unclear. Macrophages may be responsible. Toxic and vascular disorders provide also good models for the understanding of mechanisms of demyelination.

Central Nervous System Diseases↗
PubMed1992

Glial cell localization of acidic fibroblast growth factor-like immunoreactivity in the optic nerve of young adult and aged mammals.

The number of axons in the optic nerve decreases with age and this degeneration is greater in patients suffering from Alzheimer's disease. Alterations in the role of neurotrophic factors could lead to this degeneration. Acidic fibroblast growth factor (aFGF)-like immunoreactivity was examined by indirect immunofluorescence on cryostat sections incubated with a rabbit polyclonal antiserum specific for aFGF. Staining was observed by photonic microscopy on optic nerves of Wistar rats (1- to 25-month-old), bovine animals (0.5- to 7-year-old) and normal human adults (24-, 34-, 54- and 84-year-old). In the three species studied, the results show that (1) glial cells were stained in the nuclear region and (2) aFGF-like immuno-reactivity was present over a large age span in adult subjects. Endogenous aFGF may have trophic effects on retinal ganglion cells and their axons throughout the adult life span.

Adult↗
PubMed1991

[Anatomy and memory].

Bilateral lesions involving the medial aspect of the hemisphere may induce pure amnestic syndromes. Which neural elements have to be destroyed remains open to question: hippocampus, mamillary body, dorso-medial nucleus of the thalamus play probably a role at one point or another of the memory process. Lesions of the dorso-lateral part of the frontal lobe disturb the chronological order of memories. Il has been suggested that 2 systems were involved: the first one is hippocampo-mamillo-thalamic (Papez circuit), the second one is amygdalo-thalamo-frontal. The respective role of each of these circuits remain controversial.

Brain↗
PubMed1991

Subtypes and differential laminar distributions of beta A4 deposits in Alzheimer's disease: relationship with the intellectual status of 26 cases.

beta A4 immunoreactivity was studied in temporal neocortex, area 22, of 26 cases with graded intellectual status. Sampling was performed in psychometrically assessed women over 75 years, either intellectually normal or affected by senile dementia of Alzheimer type of various degrees of severity. beta A4 antibodies labelled various types of beta A4 deposits in 22/26 cases: (1) small, stellate deposits; (2) diffuse deposits, (3) primitive, (4) classic and (5) compact, or burn-out, plaques. The densities of the stellate deposits, primitive and classic plaques were always positively linked with the severity of the intellectual status, whereas those of the diffuse deposits were not. This was due to a single case with normal mental status and numerous beta A4 deposits. Densities of stellate and diffuse deposits were higher in layers I, III and IV, whereas densities of primitive, classic, and neuritic plaques observed with Bodian's technique were higher in layers II and III. Topographical distribution of each subtype did not vary as a function of the severity of the intellectual status. These data suggest that deposits of beta A4 protein appear a necessary but not a sufficient condition for inducing neuritic plaque formation, in the neocortex as in other brain areas. beta A4 proteins could accumulate either as diffuse deposits, which do not cause an intellectual deficit, or as dense deposits, associated with argyrophilic neurites, i.e., classic neuritic plaques, highly correlated to the intellectual impairment. This evolution could depend on factors which are laminarily distributed in the neocortex.

Aged↗