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Biomedical subjects

J Poirier

Publications and source records attributed to J Poirier.

At least 55 records · Page 3Linked to original sources
PubMed2000

The Ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by beta-amyloid.

Substantial evidence suggests that the accumulation of beta-amyloid (Abeta)-derived peptides, and to a lesser extent free radicals, may contribute to the aetiology and/or progression of Alzheimer's disease (AD). Ginkgo biloba extract (EGb 761) is a well-defined plant extract containing two major groups of constituents, i.e. flavonoids and terpenoids. It is viewed as a polyvalent agent with a possible therapeutic use in the treatment of neurodegenerative diseases of multifactorial origin, e.g. AD. We have investigated here the potential effectiveness of EGb 761 against toxicity induced by (Abeta)-derived peptides (Abeta25-35, Abeta1-40 and Abeta1-42) on hippocampal primary cultured cells, this area being severely affected in AD. A co-treatment with EGb 761 concentration-dependently (10-100 microg/mL) protected hippocampal neurons against toxicity induced by Abeta fragments, with a maximal and complete protection at the highest concentration tested. Similar, albeit less potent protective effects were seen with the flavonoid fraction of the extract (CP 205), while the terpenes were ineffective. Most interestingly, EGb 761 (100 microg/mL) was even able to protect (up to 8 h) hippocampal cells from a pre-exposure to Abeta25-35 and Abeta1-40. EGb 761 was also able to both protect and rescue hippocampal cells from toxicity induced by H2O2 (50-150 microM), a major peroxide possibly involved in mediating Abeta toxicity. Moreover, EGb 761 (10-100 microg/mL), and to a lesser extent CP 205 (10-50 microg/mL), completely blocked Abeta-induced events, e.g. reactive oxygen species accumulation and apoptosis. These results suggest that the neuroprotective effects of EGb 761 are partly associated with its antioxidant properties and highlight its possible effectiveness in neurodegenerative diseases, e.g. AD via the inhibition of Abeta-induced toxicity and cell death.

Alzheimer Disease↗
PubMed2000

Apolipoprotein E and Alzheimer's disease. A role in amyloid catabolism.

It has been shown over the past few years that apolipoprotein E (apoE) plays a central role in the brain response to injury and neurodegeneration in mammalian species. The coordinated expression of apoE and its different receptors, the so-called LDL receptor family, appears to regulate the transport of cholesterol and phospholipids during the early and middle phases of the reinnervation in the adult mammalian brain. As neurons undergo dendritic remodelling and synaptogenesis using cholesterol internalization through the apoE/LDL receptor pathway, they progressively shut down 3,3-hydroxymethylglutaryl-Coenzyme A (HMG CoA) reductase activity, the rate-limiting enzyme in the synthesis of cholesterol. These results suggest that cholesterol delivery and synthesis in the brain are tightly regulated through an apoE-dependent mechanism. The discovery that the apolipoprotein e4 allele is strongly linked to both sporadic and familial late-onset Alzheimer's disease (AD) has raised the possibility that a dysfunction of lipid transport could explain the poor compensatory synaptogenesis reported by several independent research groups in the brain of AD subjects. Recently, it has been shown that alterations of cholesterol homeostasis in the brain by exogenous administration of dietary cholesterol, or through inhibition of cholesterol synthesis, markedly affect beta amyloid production (1-40 and 1-42) and deposition and significantly impair amyloid precursor protein (APP) metabolism. In vivo, it has been shown that breeding of APP-overexpressing mice with apoE knockout mice completely abolishes amyloid plaque deposition in the brain of hybrid animals, without affecting beta amyloid steady state levels. Conversely, introduction of the human apoE3 and apoE4 genes in APP-overexpressing mice drastically reduced beta amyloid deposition in the brain of hybrid mice, confirming the proposed biological role of apoE in the clearance of extracellular beta amyloid. These results indicate that lipid homeostasis is controlled in large part by the apoE lipoprotein transport system in the extracellular space, whereas alterations in intracellular lipid homeostasis markedly affect APP processing, beta amyloid production and plaque formation in vivo. The convergence of the so-called amyloid cascade hypothesis (Hardy et al., 1992) and of the apoE/lipid recycling cascade model (Poirier, 1994) is consistent with the notion that alterations in lipid homeostasis could serve as the common denominator for apoE and beta amyloid dysfunctions in Alzheimer's disease. It is also interesting to note that lipid homeostasis is also a central feature of one of the most important neurotransmitter systems in the brain: the cholinergic system. This system is unique in the CNS since it relies heavily on lipid bioavailability to locally synthesize acetylcholine. It is thus quite tempting to propose that two of the most common neuropathologic landmarks of AD--namely, cholinergic dysfunction and amyloid deposition--may in fact depend on the integrity of local lipid homeostatic processes, which in turn are strongly dependent upon proper lipid delivery by the apoE transport system.

Alzheimer Disease↗
PubMed2000

[Neurology in Paris hospitals, particularly the Salpêtrière before Charcot: Rostan on brain softening].

In the beginning of the 19th century, many studies were devoted to the diseases of the nervous system in France, long before the work of Charcot. The researches of Léon Rostan on the cerebral softening (1819, 1823) were based on the anatomoclinic method developed by the School of Paris whose most famous representatives were Corvisart and Laennec for the study of heart and lung diseases. The researches of Rostan were performed in the Salpêtrière hospital which was, at this time, an hospice for old women. Rostan was appointed Inspector of the Health service in the Salpêtrière hospital in 1812 then Head of a department in 1818. He was 28 year old when he published his book "Researches on the cerebral softening" in 1819. Rostan was the first to describe the spontaneous cerebral softening as a special anatomoclinic entity distinct from encephalitis and apoplexy. He compared this entity to the senile gangrene and stated that it was related to the ossification of cerebral arteries. He described the pathologic features of the brain softening and also its clinical symptomatology in opposition to that of apoplexy. The concept of brain softening according to Rostan was harshly fought by the followers of the Broussais's physiological medicine (from Lallemand, 1830 to Calmeil, 1859) who claimed that all brain softenings were due to the inflammation process and thus should be described as encephalitis. In opposite, the ideas of Rostan were accepted and developed by others such as Carswell in England (1835), Abercrombie in Scotland (1836) and Andral in France (1827, 1840). These authors agreed that some type of cerebral softening was related to a disease of the arterial system. Nevertheless, the modern concept of brain softening was not definitively accepted before the description of the thromboembolic mechanisms by Virchow in Germany (1856) with the help of the microscope, and the anatomoclinic studies of Proust, Laborde and Prevost and Cottard in France (1866). The book of Rostan was dedicated to the "Conseil Général des Hospices" which was created in 1801 to unify the administration of the hospitals in Paris and became the "Administration Générale de l'Assistance Publique à Paris" in 1849. One hundred and fifty years after its publication, the work of Léon Rostan was outstanding by its modernity of the form as well as the substance.

Cerebrovascular Circulation↗
PubMed1999

Bradykinin B1 receptor expression and function on T lymphocytes in active multiple sclerosis.

BACKGROUND: Lesion development in MS is initiated by migration of inflammatory cells into the central nervous system, a process dependent on endothelial cell-lymphocyte interaction. Bradykinin B1 receptor is a membrane-bound G protein-coupled receptor shown to be upregulated on the surface of various cells types during inflammation. OBJECTIVE: To assess the expression and function of the bradykinin B1 receptor on T lymphocytes from MS patients. METHODS: The authors used multiplex polymerase chain reaction amplification and Western blot techniques to demonstrate B1 receptor expression by T cells. A modified Boyden chamber assay also was used to assess the effect of B1 agonist and antagonist on T cell migration. RESULTS: The authors demonstrated that the expression of B1 receptor was upregulated on T cells derived from peripheral blood of MS patients. Expression of this receptor was upregulated on T cells from patients with secondary progressive MS and relapsing-remitting patients in active relapse. Expression was lower in relapsing remitting patients in remission and least in control subjects, including patients with epilepsy, chronic inflammatory demyelinating polyneuritis, and systemic lupus erythematosus. In vitro treatment of cells from healthy control subjects with tumor necrosis factor-alpha and interferon-gamma also induced the expression of B1 receptors. The authors also found that the significantly higher rate of migration of MS T lymphocytes, compared with control subjects in the Boyden chamber assay, could be prevented by the addition of the selective and stable B1 agonist Sar (D-Phe8) desArg9-BK. CONCLUSION: The authors demonstrate that B1 receptors are upregulated by T lymphocytes during the course of MS and that signaling through this receptor with a B1 agonist can negatively regulate T-cell migration in vitro.

Adult↗
PubMed1999

A nonpathogenic GAAGGA repeat in the Friedreich gene: implications for pathogenesis.

An individual with late-onset ataxia was found to be heterozygous for an unusual (GAAGGA)65 sequence and a normal GAA repeat in the frataxin gene. No frataxin point mutation was present, excluding a form of Friedreich ataxia. (GAAGGA)65 did not have the inhibitory effect on gene expression in transfected cells shown by pathogenic GAA repeats of similar length. GAA repeats, but not (GAAGGA)65, adopt a triple helical conformation in vitro. We suggest that such a triplex structure is essential for suppression of gene expression.

Aged↗
PubMed1999

Apolipoprotein E and beta-amyloid levels in the hippocampus and frontal cortex of Alzheimer's disease subjects are disease-related and apolipoprotein E genotype dependent.

The epsilon4 allele of apolipoprotein E (apoE) is associated with increased risk for the development of Alzheimer's disease (AD), possibly due to interactions with the beta-amyloid (Abeta) protein. The mechanism by which these two proteins are linked to AD is still unclear. To further assess their potential relationship with the disease, we have determined levels of apoE and Abeta isoforms from three brain regions of neuropathologically confirmed AD and non-AD tissue. In two brain regions affected by AD neuropathology, the hippocampus and frontal cortex, apoE levels were found to be decreased while Abeta(1-40) levels were increased. Levels of apoE were unchanged in AD cerebellum. Furthermore, levels of apoE and Abeta(1-40) were found to be apoE genotype dependent, with lowest levels of apoE and highest levels of Abeta(1-40) occurring in epsilon4 allele carriers. These results suggest that reduction in apoE levels may give rise to increased deposition of amyloid peptides in AD brain.

Aged↗
PubMed1999

Modulation of apolipoprotein D and apolipoprotein E expression in rat hippocampus after entorhinal cortex lesion.

Apolipoprotein (apo) D is a member of the lipocalin family of proteins. Although its physiological function is unknown, apoD is thought to transport one or more small hydrophobic ligands. A second apolipoprotein, apoE is known to play an important role in lipid transport, and apoE genetic polymorphism has been shown to be associated with susceptibility to Alzheimer's disease. Both apoD and apoE are expressed in the central nervous system (CNS) and both proteins accumulate at sites of peripheral nerve injury due to increased local synthesis. The two proteins may have overlapping or complementary functions within nervous tissue. In order to define the role of apoD within the CNS, we have studied the regional distribution of apoD and apoE mRNA and protein within the normal rat brain and the changes in apoD and apoE expression in the hippocampus of rats after entorhinal cortex lesion (EC lesion). Within the brains of normal rats, apoD expression in the hippocampus was as high as 180-fold that of the liver. ApoD mRNA levels in other areas of the rat brain ranged from 40 to 120 times the hepatic levels. The distribution of apoE gene expression within the brain was similar to that of apoD, but was much lower than hepatic apoE expression. When rats were subjected to EC lesion, the apoD message increased by 54% at 4 days post lesion (DPL) in the ipsilateral region of hippocampus while apoE mRNA levels (ipsilateral and contralateral) decreased by 43%. At 6 to 8 DPL apoD mRNA in the ipsilateral hippocampus remained elevated (42% above controls) whereas the apoE mRNA levels increased to about 15% above those of controls. At 14 and 31 DPL, both apoD and apoE expression was similar to controls. The increase in immunoreactive apoD in hippocampal extracts was more dramatic. At 1 DPL, immunoreactive apoD levels were already 16-fold higher than those in extracts of non-lesioned animals and, at 31 DPL, levels were still 8-fold higher than those of control animals. Finally, we have demonstrated that the levels of apoD in the brains of apoE-deficient mice are 50-fold those of wildtype control mice. ApoD clearly has an important function within the CNS in both normal and pathological situations.

Animals↗
PubMed1999

Apolipoprotein E isoform-specific reduction of extracellular amyloid in neuronal cultures.

Both apolipoprotein E (apoE) and amyloid peptides are associated with Alzheimer's disease (AD). Using primary hippocampal neurons, we demonstrate that apoE is capable of reducing potentially toxic extracellular amyloid peptides, likely through a receptor mediated mechanism. We hypothesize that isoform-specific differences in apoE-mediated amyloid clearance and intracellular accumulation may be responsible, at least in part, for the increased number of amyloid plaques observed in apoE epsilon4 allele AD individuals.

Amyloid beta-Peptides↗
PubMed1999

Dehydroepiandrosterone (DHEA) protects hippocampal cells from oxidative stress-induced damage.

It has been postulated that decreases in plasma levels of dehydroepiandrosterone (DHEA) may contribute to the development of some age-related disorders. Along with neuroprotective and memory enhancing effects, DHEA has been shown to display antioxidant properties. Moreover, oxidative stress is known to cause lipid peroxidation and degenerative changes in the hippocampus, an area involved in memory processes and especially afflicted in Alzheimer's disease (AD). Accordingly, we investigated the antioxidant effects of DHEA in models of oxidative stress using rat primary hippocampal cells and human hippocampal tissue from AD patients and age-matched controls. A pre-treatment of rat primary mixed hippocampal cell cultures with DHEA (10-100 microM) protected against the toxicity induced by H2O2 and sodium nitroprusside. Moreover, DHEA (10-100 microM) was also able to prevent H2O2/FeSO4-stimulated lipid oxidation in both control and AD hippocampal tissues. Taken together, these data suggest that DHEA may be useful in treating age-related central nervous system diseases based on its protective effects in the hippocampus.

Adjuvants, Immunologic↗
PubMed1999

The polymorphism in exon 3 of the low density lipoprotein receptor-related protein gene is weakly associated with Alzheimer's disease.

The low density lipoprotein receptor-related protein (LRP) gene is a candidate gene for Alzheimer's disease (AD) due to its role as a receptor for apolipoprotein E (apoE), a major genetic risk factor for late-onset familial and sporadic AD. Recently, several studies have reported a correlation between a polymorphism (C766T) in exon 3 of LRP and AD. We examined this polymorphism in a Caucasian population of 225 neuropathologically confirmed cases with AD and 187 elderly cases without any AD neuropathological changes. We found that the exon 3 LRP C/C genotype was slightly but not significantly higher in the AD group when compared to the control group. A meta-analysis of previous studies revealed only a weak correlation of this polymorphism with AD (odds ratio 1.34, [95% CI 1.16-1.54], P < 0.0001). These data indicate that the polymorphism in exon 3 of LRP is only a minor risk factor for AD and that another locus on chromosome 12 is likely responsible for the associations observed in other studies.

Aged↗
PubMed1999

Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes.

Friedreich's ataxia is the most common inherited ataxia. Ninety-six percent of patients are homozygous for GAA trinucleotide repeat expansions in the first intron of the frataxin gene. The remaining cases are compound heterozygotes for a GAA expansion and a frataxin point mutation. We report here the identification of 10 novel frataxin point mutations, and the detection of a previously described mutation (G130V) in two additional families. Most truncating mutations were in exon 1. All missense mutations were in the last three exons coding for the mature frataxin protein. The clinical features of 25 patients with identified frataxin point mutations were compared with those of 196 patients homozygous for the GAA expansion. A similar phenotype resulted from truncating mutations and from missense mutations in the carboxy-terminal half of mature frataxin, suggesting that they cause a comparable loss of function. In contrast, the only two missense mutations located in the amino-terminal half of mature frataxin (D122Y and G130V) cause an atypical and milder clinical presentation (early-onset spastic gait with slow disease progression, absence of dysarthria, retained or brisk tendon reflexes, and mild or no cerebellar ataxia), suggesting that they only partially affect frataxin function. The incidence of optic disk pallor was higher in compound heterozygotes than in expansion homozygotes, which might correlate with a very low residual level of normal frataxin produced from the expanded allele.

Adolescent↗
PubMed1999

Haemorrhagic acoustic neuroma with features of a vascular malformation. A case report.

A 55-year-old man with hearing loss presented with vertigo and vomiting. CT tomography and MRI demonstrated a cerebellopontine angle mass with foci of haemorrhage. An angiomatous tumour, with large abnormal veins adhering to the capsule, was completely removed. Histologically, the tumour was an acoustic neuroma with abnormal vascularisation and limited intratumoral haemorrhage.

Hearing Loss, Sensorineural↗
PubMed1999

Further evidence for a synergistic association between APOE epsilon4 and BCHE-K in confirmed Alzheimer's disease.

Recent reports on a potential association between the K-variant of the gene for butyrylcholinesterase (BCHE-K) and Alzheimer's disease (AD) are discordant. An initial finding of association through a synergistic enhancement of risk of APOE epsilon4 with late-onset AD has not been confirmed by others. We have conducted a case-control study of histopathologically confirmed AD (n=135) and non-AD (n=70) cases (age of death > or =60 years), in which we have genotyped for APOE epsilon4, BCHE-K, and BCHE-A1914G, a silent polymorphism 299 bp downstream of the BCHE-K mutation. The allelic frequency of BCHE-K was 0.13 in the controls and 0.23 in the AD cases, giving a carrier odds ratio (OR(c)) of 2.1 (95% C.I. 1.1-4.1) for BCHE-K in confirmed AD. The allelic frequency for the BCHE-1914G variant was 0.19 and 0.33 in controls and AD cases, respectively (OR(c)=2.4; 95% C.I. 1.3-4.5). In an older sub-sample of 27/70 controls and 89/135 AD patients with ages of death > or =75 years, the OR(c) was increased to 4.5 (95% C.I. 1.4-15) for BCHE-K and 2.7 (95% C.I. 1.0-7.2) for BCHE-1914G carriers. The BCHE-K association with AD became even stronger in carriers of at least one APOE epsilon4 allele. Only three out of 19 controls compared with 39/81 AD cases carried BCHE-K in addition to APOE epsilon4, giving an odds ratio of confirmed AD of 5.0 (95% C.I. 1.3-19) for BCHE-K carriers within APOE epsilon4 carriers. Five out of 19 controls and 52/81 AD cases carried BCHE-1914G, giving the same odds ratio of confirmed AD of 5.0 (95% C.I. 1.6-16) for BCHE-1914G carriers within APOE epsilon4 carriers. In addition, our results suggest strong linkage disequilibrium between BCHE-K and BCHE-1914G but no major association of the sole BCHE-1914G chromosome with AD. We conclude that BCHE through its K-variant, rather than a nearby marker, is a susceptibility factor for AD and enhances the AD risk defined by APOE epsilon4 alone in an age-dependent manner.

Aged↗
PubMed1999

Cholinergic systems and long-term potentiation in memory-impaired apolipoprotein E-deficient mice.

Impairments in cholinergic neurotransmitter systems of the basal forebrain are a hallmark of Alzheimer's disease pathophysiology. The presence of the epsilon4 allele of apolipoprotein E was recently implicated as a major risk factor in both familial and sporadic Alzheimer's disease. The present study examined the integrity of cholinergic and non-cholinergic systems in apolipoprotein E-deficient, memory-impaired mice. Choline acetyltransferase activity, hippocampal acetylcholine release, nicotinic and muscarinic (M1 and M2) receptor binding sites and acetylcholinesterase cell or terminal density showed no signs of alteration in either three-month or 9.5-month-old apolipoprotein E-deficient mice compared to controls. In contrast, long-term potentiation was found to be markedly reduced in these mice, but increases in the strength of stimulation induced the same level of long-term potentiation as that observed in controls. These alterations did not appear to be the consequence of modifications in the binding properties of glutamatergic receptors (N-methyl-D-aspartate and [RS]-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid) but from defective regulation of the (RS)-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid receptor by phospholipase A2 activity. These results support the notion that apolipoprotein E plays a fundamental role in neuronal plasticity, which could in turn affect cognitive performance through imbalances in extra- and intracellular lipid homeostasis.

Acetylcholine↗