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Biomedical subjects

J Poirier

Publications and source records attributed to J Poirier.

At least 73 records · Page 4Linked to original sources
PubMed1999

Oxidative damage and protection by antioxidants in the frontal cortex of Alzheimer's disease is related to the apolipoprotein E genotype.

A great number of epidemiological studies have demonstrated that the frequency of the epsilon4 allele of the apolipoprotein E gene (APOE) is markedly higher in sporadic and in familial late onset Alzheimer disease (AD). In the frontal cortex of AD patients, oxidative damage is elevated. We address the hypothesis that the APOE genotype and reactive oxygen-mediated damage are linked in the frontal cortex of AD patients. We have related the APOE genotype to the levels of lipid oxidation (LPO) and to the antioxidant status, in frontal cortex tissues from age-matched control and AD cases with different APOE genotypes. LPO levels were significantly elevated in tissues from Alzheimer's cases which are homozygous for the epsilon4 allele of APOE, compared to AD epsilon3/epsilon3 cases and controls. Activities of enzymatic antioxidants, such as catalase and glutathione peroxidase (GSH-PX), were also higher in AD cases with at least one epsilon4 allele of APOE, while superoxide dismutase (SOD) activity was unchanged. In the frontal cortex, the concentration of apoE protein was not different between controls and AD cases, and was genotype independent. The Ginkgo biloba extract (EGb 761), the neurosteroid dehydroepiandrosterone (DHEA) and human recombinant apoE3 (hapoE3rec) were able to protect control, AD epsilon3/epsilon3 and epsilon3/epsilon4 cases against hydrogen peroxide/iron-induced LPO, while hapoE4rec was completely ineffective. Moreover, EGb 761 and DHEA had no effect in homozygous epsilon4 cases. These results demonstrate that oxidative stress-induced injury and protection by antioxidants in the frontal cortex of AD cases are related to the APOE genotype.

Aged↗
PubMed1999

Apolipoprotein E: a pharmacogenetic target for the treatment of Alzheimer's disease.

BACKGROUND: The discovery that the apolipoprotein E4 (apoE4) allele is strongly linked to both sporadic and familial late-onset Alzheimer's disease (AD) raises the possibility that a dysfunction of the lipid transport system could seriously affect lipid homeostasis in the brain. We recently proposed that the abnormally low concentrations of apoE observed in the brains of apoE4 AD subjects could compromise cholesterol, fatty acid, and phospholipid transport in the central nervous system. This, in turn, would indirectly impair the cholinergic system, which, in contrast to other neurotransmitters in the central nervous system, relies heavily on lipids to synthesize acetylcholine. Several independent investigators have now confirmed the original observation of an inverse relationship between apoE4 allele copy number and residual brain choline acetyltransferase activity and nicotinic-receptor binding sites in the brains of subjects with AD. More importantly, it has been shown that the presence of the apoE4 allele differentially affects the quality and size of drug responsiveness in subjects with AD treated with cholinomimetic and noncholinomimetic agents. We also examine the role of apoE as a potent therapeutic target for AD.

Alzheimer Disease↗
PubMed1999

Location score and haplotype analyses of the locus for autosomal recessive spastic ataxia of Charlevoix-Saguenay, in chromosome region 13q11.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a clinically homogeneous form of early-onset familial spastic ataxia with prominent myelinated retinal nerve fibers. More than 300 patients have been identified, and most of their families originated in the Charlevoix-Saguenay region of northeastern Quebec, where the carrier prevalence has been estimated to be 1/22. Consistent with the hypothesis of a founder effect, we observed excess shared homozygosity at 13q11, among patients in a genomewide scan of 12 families. Analysis of 19 pedigrees demonstrated very tight linkage between the ARSACS locus and an intragenic polymorphism of the gamma-sarcoglycan (SGCG) gene, but genomic DNA sequence analysis of all eight exons of SGCG revealed no disease-causing mutation. On the basis of haplotypes composed of seven marker loci that spanned 11.1 cM, the most likely position of the ARSACS locus was 0.42 cM distal to the SGCG polymorphism. Two groups of ARSACS-associated haplotypes were identified: a large group that carries a common SGCG allele and a small group that carries a rare SGCG allele. The haplotype groups do not appear to be closely related. Therefore, although chromosomes within each haplotype group may harbor a single ARSACS mutation identical by descent, the two mutations could have independent origins.

Alleles↗
PubMed1999

Brain lipoprotein metabolism and its relation to neurodegenerative disease.

Lipoproteins are macromolecular complexes composed of lipids and proteins. The role of these complexes is to provide cells of the organism with lipids to be used as a source of energy, building blocks for biomembrane synthesis, and lipophilic molecules (e.g., steroid hormones and vitamin E) for other physiological purposes, such as cell signaling and antioxidative mechanisms. Lipoproteins also promote the cellular efflux of cholesterol for its disposal into bile. Thus, lipoproteins play an important role in the maintenance of lipid homeostasis throughout the organism. Accordingly, lipoprotein particles have been found circulating in blood, lymph, and interstitial fluid. Despite the existence of the blood-brain barrier, lipoprotein particles have been shown to be also present in the cerebrospinal fluid (CSF). Although a portion of their protein components may filter through the barrier from the vascular compartment, experimental evidence indicates that these particles originate from the nervous tissue. The other protein components include apolipoproteins E, J, and D, and these have been shown to be synthesized by cells within the central nervous system (CNS). Furthermore, it was shown that lipoprotein particles can be isolated from the conditioned medium of astrocytic cultures. The differences in size, structure, and composition of in vitro assembled particles compared with those isolated from the CSF suggest that the particles are modified following their secretion in vivo. This is supported by observations that lipoprotein-modifying enzymes and transfer proteins are also present within CNS tissue and CSF. The fate of CSF lipoproteins is unclear but is probably related to the turnover and clearance of lipids from the CNS or, alternatively, the particles may be recaptured and recycled back into the CNS tissue. The presence of several cell surface receptors for apoE-containing lipoproteins on ependymal cells, as well as on neurons and glial cells, supports this notion and suggests that the isolated brain possesses its own system to maintain local lipid homeostasis. This is further exemplified by the salvage and recycling of lipids shown to occur following a lesion in order to allow surviving neurons to sprout and reestablish lost synapses. Not much is currently known about lipoprotein metabolism in neurodegenerative diseases, but lipid alterations have been repeatedly reported in Alzheimer brains in which neuronal loss and deafferentation are major features. Although the mechanism underlying the link between the epsilon4 allele of the apolipoprotein E gene and Alzheimer's disease is presently unclear, it may well be postulated that it is related to disturbances in brain lipoprotein metabolism.

Animals↗
PubMed1999

Bone giant cell tumour in neuropathological practice. A fifty year overview.

We report a case of a 29-year-old female patient who suffered from visual disturbance, resulting from a lesion in the sphenoid bone which, histologically, proved to be a giant cell tumour. Reviewing our laboratory practice over a 50 year period, only 7 cases of true giant cell tumour were found and they were in two major locations, i.e. the skull and vertebrae. These few cases led us to focus on the problem raised by the lack of histological patterns of malignancy. In agreement with Mazabraud's theory, it seems that a vertebral location is associated with a good prognosis and that gene mapping of chromosome 17 in relation to p53 mutations could be a valuable tool in the diagnosis of potential malignant behaviour.

Adult↗
PubMed1999

Apolipoprotein E4, cholinergic integrity and the pharmacogenetics of Alzheimer's disease.

Recent evidence indicates that apolipoprotein E (apoE) plays a central role in the brain's response to injury. The coordinated expression of apoE and its receptors (the so-called LDL [low density lipoprotein] receptor family) appears to regulate the transport and internalization of cholesterol and phospholipids during the early phase of the re-innervation process in the adult brain. During dendritic remodelling and synaptogenesis, neurons progressively repress the synthesis of cholesterol in favour of cholesterol internalization through the apoE/LDL receptor pathway. The discovery a few years ago, that the apolipoprotein epsilon 4 allele found in 15% of the normal population is strongly linked to both sporadic and familial late-onset Alzheimer's disease (AD), raises the possibility that a dysfunction of the lipid transport system associated with compensatory sprouting and synaptic remodelling could be central to the AD process. The role of apoE in the central nervous system is particularly important in relation to the cholinergic system, which relies to a certain extent on the integrity of phospholipid homeostasis in neurons. Recent evidence obtained by 4 independent research teams indicates that apo epsilon 4 allele directly affects cholinergic activity in the brain of AD subjects. It was also shown to modulate the drug efficacy profile of several cholinomimetic and noncholinomimetic drugs used for the treatment of AD patients.

Adult↗
PubMed1999

[Cerebral lacunae: still under debate].

During the last fifteen years, a new interest has been shown in cerebral lacunes due to the development of brain imagery using Magnetic Resonance Imaging (MRI). The concept of lacunar infarction as defined par Fisher (lacunar hypothesis) can no longer be accepted. Clinical data showed that the so-called lacunar clinical syndromes were far from being specific and could be observed in corticosubcortical infarcts. Epidemiological data pointed out that hypertensive disease was not found in many cases of lacunar infarction. Pathological studies suggest that there are two types of lacunar infarction. Lacunar infarcts resulting in clinical stroke syndromes (type 1 a lacunae) seem to be mainly due to obstruction of the trunk of a perforating artery by atherosclerosis. Silent lacunar infarcts (type 1 b lacunae) result from obstruction of small ramifications of the perforating arteries by a non specific microangiopathy related to age, atherosclerosis, cardiovascular disease as well as to hypertensive disease. Silent lacunar infarcts and dilatation of perivascular spaces (type 3 lacunae) are associated with the white matter hyperintensities shown by MRI in elderly subjects. Lacunar infarcts and diffuse white matter hyperintensities are related to small vessel changes and ischaemic damages resulting from (a) arteriolar occlusion and or (b) loss of autoregulation associated with variations in systemic blood pressure. Both lesions constitute a high risk to develop Vascular Cognitive Impairment (Hachinski) and are frequently associated with Alzheimer's disease. Cases of giant or expanding type 3 lacunae have been reported in the last ten years but the physiopathology of such lacunes and their relationship with clinical symptoms remain a puzzle.

Aged↗
PubMed1999

[Intracranial cholesterol granulomas. Report of 2 cases].

Two cases of cholesterolic granuloma, one intraorbital and the other of the petrous apex, are reported. The xanthogranulomatous and/or cystic process localized in the intracranial cavities or in the brain parenchyma are discussed. A simple topographical and histological classification is attempted in answer to a rather ambiguous terminology.

Adult↗
PubMed1998

ApoE associated with lipid has a reduced capacity to inhibit beta-amyloid fibril formation.

Apolipoprotein E (apoE) and the beta-amyloid peptide are both found in the senile plaques associated with Alzheimer's disease. Several studies have recently determined that apoE can prevent beta-amyloid fibril (Abetaf) formation in vitro. In vivo, apoE is normally associated with a lipid source. We show that both recombinant and purified plasma apoE inhibit Abetaf formation in a dose-dependent manner. The three major apoE isoforms were equipotent at inhibiting Abetaf formation. ApoE associated with either cholesterol-containing liposomes or very low density lipoproteins displayed less potent inhibition of Abetaf formation than their unlipidated counterparts. These results indicate that the presence of associated lipids reduce the ability of apoE to inhibit the formation of Abetaf in vitro.

Aging↗
PubMed1998

Effect of the MAO-B inhibitor, MDL72974, on superoxide dismutase activity and lipid peroxidation levels in the mouse brain.

MDL72974 is a member of a series of MAO-B inhibitors to be used as potential therapeutic agents in the treatment of Parkinson's and Alzheimer's diseases. However, we have recently observed a reduction in the density of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra of mice treated with MDL72974. As oxidative stress is known to play a significant role in the nigrostriatal pathway, analysis of the relationship between TH+ cell losses induced by MDL72974 and by free radical production was investigated in the present study. Results demonstrate a significant increase in superoxide dismutase (SOD) activity, a key antioxidant, in the striatum and cerebellum of MDL72974-treated mice, presumably in response to free radical production. An increase in lipid peroxidation levels was also observed in the striatum of these animals in a manner which is consistent with oxidative stress-inducing agents. We therefore suggest that MDL72974 may be detrimental to dopaminergic neurons of the nigrostriatal pathway via free radical-mediated reactions.

Allyl Compounds↗
PubMed1998

Apolipoprotein E4, cholinergic integrity and the pharmacogenetics of Alzheimer's disease.

Recent evidence indicates that apolipoprotein E (apoE) plays a central role in the brain's response to injury. The coordinated expression of apoE and its receptors (the so-called LDL receptor family) appears to regulate the transport and internalization of cholesterol and phospholipids during the early phase of the reinnervation process in the adult brain. During dendritic remodelling and synaptogenesis, neurons progressively repress the synthesis of cholesterol in favor of cholesterol internalization through the apoE/LDL receptor pathway. The discovery a few years ago that the apolipoprotein E4 allele found normal in 15% of the normal population is strongly linked to both sporadic and familial late onset Alzheimer's disease (AD) raises the possibility that a dysfunction of the lipid transport system associated with compensatory sprouting and synaptic remodelling could be central to the AD process. The role of apoE in the CNS is particularly important in relation to cholinergic system which relies to a certain extent on the integrity of phospholipid homeostasis in neurons. Recent evidence obtained in our laboratory indicates that apo epsilon 4 allele has a direct impact on cholinergic system activity in the brain as well as on drug efficacy profile in AD subjects treated with cholinomimetic agents.

Aged↗
PubMed1998

The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease.

The importance of apolipoproteins in the central nervous system became increasingly clear with the association in 1993 of the epsilon4 allele of apolipoprotein E with familial and sporadic late-onset Alzheimer's disease. Apolipoprotein E is a ligand for several receptors, most of which are found to some extent in the brain. This review summarizes the various apolipoproteins and lipoprotein receptors found in the brain. A growing body of evidence now implicates irregular lipoprotein metabolism in several neurodegenerative disorders. We then focus on research linking apolipoprotein E and Alzheimer's disease, from clinical studies to biochemical models, which may explain some of the complex neurobiology of this disorder.

Alzheimer Disease↗
PubMed1998

Beta-amyloid peptides increase the binding and internalization of apolipoprotein E to hippocampal neurons.

The frequency of the epsilon4 allele of apolipoprotein E (apoE) is increased in late-onset and sporadic forms of Alzheimer's disease (AD). ApoE also binds to beta-amyloid (A beta) and both proteins are found in AD plaques. To further investigate the potential interaction of apoE and A beta in the pathogenesis of AD, we have determined the binding, internalization, and degradation of human apoE isoforms in the presence and absence of A beta peptides to rat primary hippocampal neurons. We demonstrate that the lipophilic A beta peptides, in particular A beta(1-42), A beta(1-40), and A beta(25-35), increase significantly apoE-liposome binding to hippocampal neurons. For each A beta peptide, the increase was significantly greater for the apoE4 isoform than for the apoE3 isoform. The most effective of the A beta peptides to increase apoE binding, A beta(25-35), was further shown to increase significantly the internalization of both apoE3- and apoE4-liposomes, without affecting apoE degradation. Conversely, A beta(1-40) uptake by hippocampal neurons was shown to be increased in the presence of apoE-liposomes, more so in the presence of the apoE4 than the apoE3 isoform. These results provide evidence that A beta peptides interact directly with apoE lipoproteins, which may then be transported together into neuronal cells through apoE receptors.

Amyloid beta-Peptides↗