Biomedical subjects

F Boissière

Publications and source records attributed to F Boissière.

12 recordsLinked to original sources

PubMed2000

Expression of Trk isoforms in brain regions and in the striatum of patients with Alzheimer's disease.

The TrkAII tyrosine kinase receptor differs from the TrkAI isoform by an insertion of six amino acids in the extracellular domain. We used RT-PCR to determine their respective distribution in rat and human brain. Only trkAII transcripts were detected in 12 rat brain regions, while both trkAI and trkAII transcripts were detected in the cerebellum and pituitary gland. In human, both trkAI and trkAII transcripts were detected in the frontal, temporal, and occipital cortex and thalamus, while only trkAI transcripts were detected in the hippocampus and cerebellum. In the caudate and putamen, trkAII transcripts were exclusively detected. Thereafter, we studied the expression of TrkA isoforms in the striatum of five patients with Alzheimer's disease (AD), four patients with non-AD dementia, seven patients with Parkinson's disease, and six paired nondemented elderly control individuals. In controls and non-AD patients, a constant expression of trkAII transcripts was detected within all striatum parts. In AD patients, a heterogeneous decrease in trkAII expression was observed in the caudate, putamen, and ventral striatum, resulting either in a drop of trkAII transcript levels or in a weak coamplification of trkAII and trkAI transcripts. The alteration of TrkAII gene expression paralleled those of choline acetyltransferase. Together with previous data, this suggests that the alteration of trk gene expression could contribute to a decrease in NGF binding sites and its protective effects on cholinergic neurons of AD patients.

Adult↗

PubMed2000

Efficient DNA electrotransfer into tumors.

DNA transfer to tumor cells of antiproliferative genes or of genes coding for immunomodulatory or antiangiogenic products is a promising approach for cancer therapy. However, intratumoral injection of plasmid DNA either naked or associated to chemical vectors results in a low level of gene expression. Recently, electrically mediated gene transfer has been described to strongly increase foreign gene expression in various tissues. We confirm and extend these observations using long duration electric pulses for several murine and human tumor models, using a reporter gene encoding for luciferase. After plasmid intratumoral injection, eight electric pulses of 20-ms duration were delivered at a frequency of 1 Hz through two flat parallel stainless steel electrodes placed at each side of the tumor. Optimal gene transfer was obtained using a voltage-to-distance ratio comprising between 400 and 600 V/cm. Two days after electrotransfer, we obtained a 10- to 1200-fold increase in gene expression over the naked DNA injection alone, leading to the expression of 0.6 to 300 ng luciferase per tumor. Moreover, histological results using beta-Gal reporter gene injected in H1299 tumor indicate that electrotransfer leads to a substantial increase in the percentage of beta-Gal positive cells. These results confirm the wide potential of electrotransfer for gene therapy in cancer.

Animals↗

PubMed1998

Striatal expression of glutamic acid decarboxylase gene in Alzheimer's disease.

To examine potential alteration of GABAergic striatal neurons in Alzheimer's disease, we used quantitative in situ hybridization to analyze the messenger RNA coding for Mr 67,000 glutamic acid decarboxylase (GAD67 mRNA) in the striatum of five patients with Alzheimer's disease (AD) and nine matched control subjects. We found a 51-57% increase in the optical density of hybridization signal in the caudate nucleus and putamen, corresponding to a 30-42% increase in the number of neurons expressing a detectable amount of GAD67 mRNA. By contrast, no alteration was observed in the ventral striatum. The expression of GAD67 mRNA per neuron was similar in AD and control subjects both in the dorsal and ventral striatum. Taken together, our data indicate that, in AD, GABAergic neurotransmission is increased in the dorsal striatum but not in the ventral striatum. We suggest that this increased GABAergic neurotransmission may explain extrapyramidal signs often observed in AD.

Aged↗

PubMed1997

Nuclear translocation of NF-kappaB in cholinergic neurons of patients with Alzheimer's disease.

NF-kappaB is a nuclear transcription factor involved in the control of numerous cellular functions, particularly regulation of survival. Translocation from the cytoplasm to the nucleus, an event essential for NK-kappaB activation, could be mediated through the low-affinity nerve growth factor receptor, p75, which has recently been shown to mediate cell death. In the human brain, p75 is exclusively expressed in cholinergic neurons of the basal forebrain. This population degenerates in Alzheimer's disease (AD). To investigate whether p75 could play a role in the vulnerability of these neurons via NF-kappaB activation, we studied the cellular distribution of NF-kappaB in the nucleus basalis of Meynert of four AD patients and four control subjects. The immunostaining observed both in AD patients and control subjects was limited to large, probably cholinergic, neurons. In AD, the proportion of neurons with nuclear NF-kappaB staining was significantly increased, suggesting an association between NF-kappaB functions and the process of cholinergic degeneration in AD.

Acetylcholine↗

PubMed1997

Choline acetyltransferase mRNA expression in the striatal neurons of patients with Alzheimer's disease.

Besides cortical pathology, Alzheimer's disease (AD) is associated with a massive loss of cholinergic neurons in the basal forebrain. The resulting cortical cholinergic depletion is thought to contribute to the major cognitive impairment described in Ad. A selective loss of cholinergic neurons has also been observed in the ventral striatum, despite the lack of any major neurochemical dysfunction in the striatum of patients with AD. To examined possible changes in the functional activity of the neurons that remain in the striatum of AD patients, the expression level of the gene coding for choline acetyltransferase (ChAT) was evaluated using in situ hybridization in the caudate nucleus, putamen and ventral striatum. Quantitative analysis showed (i) a marked decrease in the number of ChAT mRNA-positive neurons in the ventral striatum, and (ii) significantly reduced ChAT mRNA expression in the surviving cholinergic neurons of the ventral striatum, whereas it was only slightly decreased in those of the dorsal striatum. Our data support the hypothesis of a down-regulated expression of ChAT in striatal cholinergic neurons, especially in those most vulnerable to the neurodegenerative process. The subnormal ChAT mRNA content may be the consequence of changes in the level of transcription of the ChAT gene, possibly in relation to sustained suffering still present at the late stages of this disease. Furthermore, the involvement of the ventral striatum in Alzheimer's disease may account for some of the behavioral and motor dysfunctions often observed in patients with AD.

Aged↗

PubMed1997

Expression of catalytic trkB gene in the striatum and the basal forebrain of patients with Alzheimer's disease: an in situ hybridization study.

The expression of catalytic trkB gene, encoding for the high affinity brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5) receptor, was studied post mortem in the striatum and the nucleus basalis of Meynert of patients with Alzheimer's disease (AD) and control subjects, using in situ hybridization coupled with choline acetyltransferase immunohistochemistry. Microscopic examination of tissue sections showed labelling on perikarya of neurons but no labelling on glial cells. In the striatum, cholinergic as well as non-cholinergic and, presumably GABAergic, neurons expressed detectable levels of TrkB mRNA, while in the nucleus basalis of Meynert, only cholinergic neurons were labelled. Quantitative analysis of the in situ hybridization signal in cells of these two regions failed to demonstrate any significant difference between AD patients and control subjects. Normal levels of TrkB mRNA in the surviving cholinergic neurons of the nucleus basalis of Meynert suggest that these neurons could respond to an exogenous supply of BDNF and/or NT-4/5.

Aged↗

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↗

PubMed1996

Glial cell line-derived neurotrophic factor (GDNF) gene expression in the human brain: a post mortem in situ hybridization study with special reference to Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for dopaminergic neurons. Since dopaminergic neurons degenerate in Parkinson's disease, this factor is a potential therapeutical tool that may save dopaminergic neurons during the pathological process. Moreover, a reduced GDNF expression may be involved in the pathophysiology of the disease. In this study, we tested whether altered GDNF production may participate in the mechanism of cell death in this disease. GDNF gene expression was analyzed by in situ hybridization using riboprobes corresponding to a sequence of the exon 2 human GDNF gene. Experiments were performed on tissue sections of the mesencephalon and the striatum from 8 patients with Parkinson's disease and 6 control subjects matched for age at death and for post mortem delay. No labelling was observed in either group of patients. This absence of detectable expression could not be attributed to methodological problems as a positive staining was observed using the same probes for sections of astroglioma biopsies from human adults and for sections of a newborn infant brain obtained at post-mortem. These data suggest that GDNF is probably expressed at a very low level in the adult human brain and its involvement in the pathophysiology of Parkinson's disease remains to be demonstrated. GDNF may represent a powerful new therapeutic agent for Parkinson's disease, however.

Aged↗

PubMed1996

Nitric oxide synthase and neuronal vulnerability in Parkinson's disease.

Parkinson's disease is characterized by a loss of dopaminergic neurons in the mesencephalon. Although the mechanism of this neuronal loss is still unknown, oxidative stress is very likely involved in the cascade of events leading to nerve cell death. Since nitric oxide could be involved in the production of free radicals, we analysed, using immunohistochemistry and histochemistry, the production systems of nitric oxide in the mesencephalon of four patients with idiopathic Parkinson's disease and three matched control subjects. Using specific antibodies directed against the inducible isoform of nitric oxide synthase (the enzyme involved in the synthesis of nitric oxide), we found evidence to suggest that this isoform was present solely in glial cells displaying the morphological characteristics of activated macrophages. Immunohistochemical analysis performed with antibodies against the neuronal isoform of nitric oxide synthase, however, revealed perikarya and processes of neurons but no glial cell staining. The number of nitric oxide synthase-containing cells was investigated by histoenzymology, using the NADPH-diaphorase activity of nitric oxide synthase. Histochemistry revealed (i) a significant increase in NADPH-diaphorase-positive glial cell density in the dopaminergic cell groups characterized by neuronal loss in Parkinson's disease and (ii) a neuronal loss in Parkinson's disease that was two-fold greater for pigmented NADPH-diaphorase-negative neurons than for pigmented NADPH-diaphorase-positive neurons. These data suggest a potentially deleterious role of glial cells producing excessive levels of nitric oxide in Parkinson's disease, which may be neurotoxic for a subpopulation of dopaminergic neurons, especially those not expressing NADPH-diaphorase activity. However, it cannot be excluded that the presence of glial cells expressing nitric oxide synthase in the substantia nigra of patients with Parkinson's disease represents a consequence of dopaminergic neuronal loss.

Aged↗

PubMed1994

High affinity neurotrophin receptors in cholinergic neurons in the human brain.

Tyrosine protein kinases TrkA and TrkC are signal-transducing receptors for nerve growth factor (NGF) and neurotrophin-3 (NT-3), respectively. In the human brain postmortem, using sequential immunohistochemistry, we detected the presence of TrkA and TrkC on 99% and 95% of cholinergic neurons from the basal forebrain and on some cholinergic neurons (22% and 16%, respectively) from the striatum, but not on those from the mesencephalon. These results suggest that some cholinergic neurons, particularly those of the nucleus basalis of Meynert, may be sensitive to both NGF and NT-3 in the human brain. The sensitivity of cholinergic neurons to these two neurotrophins may have a special interest in therapeutic strategies for Alzheimer's disease.

Aged↗

PubMedDate not supplied

Neurotrophin receptors and selective loss of cholinergic neurons in Alzheimer disease.

The most consistent neuropathological finding in Alzheimer disease (AD) is the loss of cholinergic neurons of the nucleus basalis of Meynert (NbM). Using immunohistochemistry, we have previously shown that cholinergic neurons located in the ventral striatum were affected, whereas those of the caudate nucleus, putamen, and mesencephalon were spared. Since cholinergic neurons that degenerate in AD are sensitive to NGF and those that are spared are not, it has been hypothesized that the loss of neurotrophins receptors may play a role in the death of cholinergic neurons in AD. Using immunohistochemistry, we have detected the presence of TrkA on most cholinergic neurons from the NbM, on some from those of the striatum, but not on those of the mesencephalon in the human brain. In AD patients, the number of neurons that expressed TrkA was markedly decreased in the NbM very likely as a consequence of cholinergic neuronal loss. In the striatum, despite the loss of high-affinity NGF binding previously reported, no loss of TrkA was observed. Taken together, these results suggest a decreased expression of NGF receptors on the striatal cholinergic neurons in AD. This loss may contribute, when it reaches a crucial threshold, to the death of cholinergic neurons occurring in AD.

Alzheimer Disease↗

PubMedDate not supplied

Trk neurotrophin receptors in cholinergic neurons of patients with Alzheimer's disease.

Besides cortical pathology, Alzheimer's disease (AD) is characterized by a loss of cholinergic neurons in the basal forebrain but not in the caudate nucleus, putamen or mesencephalon. Since cholinergic neurons which degenerate in AD are sensitive to nerve growth factor (NGF), a link between NGF sensitivity and the vulnerability of cholinergic neurons has been suspected. Levels of NGF are not altered in patients with AD, however. Thus, cholinergic nerve cell death in AD could not result from a deficiency in NGF receptors. Using sequential immunohistochemistry with antibodies that recognize preferentially TrkA, the specific receptor for NGF, and with antibodies directed against choline acetyltransferase we analyzed the expression of neurotrophin receptors in cholinergic neurons from control and AD brains. TrkA was expressed on cholinergic neurons of the striatum and nucleus basalis of Meynert but not on those of the mesencephalon. In AD patients, the number of neurons expressing TrkA was markedly decreased in the nucleus basalis of Meynert, very likely as a consequence of cholinergic neuronal loss. No loss of TrkA-positive neurons was observed in the striatum. Taken in conjunction with our previously published report of loss of high-affinity NGF binding in the striatum of AD patients, our results suggest a reduced expression of TrkA, the specific receptor for NGF, on striatal cholinergic neurons in AD. The loss of neurotrophin receptors may contribute to the alteration of cholinergic neurons occurring in AD.

Aged↗