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Professeur(e) des Universités, Praticien(ne) hospitalier(ère)
Faculté des Sciences et Technologies - Nancy
Université de Lorraine
+33 (0)3 72 74 51 91 | Jean-Luc.Olivier@univ-lorraine.fr
Nutrients, 14 (24), pp. 5338.
Pinchaud, K., Hafeez, Z., Auger, S., Chatel, J.-M., Chadi, S., Langella, P., Paoli, J., Dary-Mourot, A., Maguin-Gaté, K., Olivier, J.-L.
Although arachidonic acid (ARA) is the precursor of the majority of eicosanoids, its influence as a food component on health is not well known. Therefore, we investigated its impact on the gut microbiota and gut–brain axis. Groups of male BALB/c mice were fed either a standard diet containing 5% lipids (Std-ARA) or 15%-lipid diets without ARA (HL-ARA) or with 1% ARA (HL + ARA) for 9 weeks. Fatty acid profiles of all three diets were the same. The HL-ARA diet favored the growth of Bifidobacterium pseudolongum contrary to the HL + ARA diet that favored the pro-inflammatory Escherichia–Shigella genus in fecal microbiota. Dietary ARA intake induced 4- and 15-fold colic overexpression of the pro-inflammatory markers IL-1β and CD40, respectively, without affecting those of TNFα and adiponectin. In the brain, dietary ARA intake led to moderate overexpression of GFAP in the hippocampus and cortex. Both the hyperlipidic diets reduced IL-6 and IL-12 in the brain. For the first time, it was shown that dietary ARA altered the gut microbiota, led to low-grade colic inflammation, and induced astrogliosis in the brain. Further work is necessary to determine the involved mechanisms.
International Journal of Genomics, doi.org/10.1155/2019/2085496
Grova, N., Schroeder, H., Olivier, J.-L., Tuner, J.D.
The incidence of neurodevelopmental and neurodegenerative diseases worldwide has dramatically increased over the last decades. Although the aetiology remains uncertain, evidence is now growing that exposure to persistent organic pollutants during sensitive neurodevelopmental periods such as early life may be a strong risk factor, predisposing the individual to disease development later in life. Epidemiological studies have associated environmentally persistent organic pollutant exposure to brain disorders including neuropathies, cognitive, motor, and sensory impairments; neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD); and neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). In many ways, this expands the classical “Developmental Origins of Health and Disease” paradigm to include exposure to pollutants. This model has been refined over the years to give the current “three-hit” model that considers the individual’s genetic factors as a first “hit.” It has an immediate interaction with the early-life exposome (including persistent organic pollutants) that can be considered to be a second “hit.” Together, these first two “hits” produce a quiescent or latent phenotype, most probably encoded in the epigenome, which has become susceptible to a third environmental “hit” in later life. It is only after the third “hit” that the increased risk of disease symptoms is crystallised. However, if the individual is exposed to a different environment in later life, they would be expected to remain healthy. In this review, we examine the effect of exposure to persistent organic pollutants and particulate matters in early life and the relationship to subsequent neurodevelopmental and neurodegenerative disorders. The roles of those environmental factors which may affect epigenetic DNA methylation and therefore influence normal neurodevelopment are then evaluated.
Journal of Nuclear Cardiology, https://doi.org/10.1007/s12350-018-1404-7
Clément, A., Boutley, H., Poussier, S., Pierson, J., Lhuillier, M., Kolodziej, A., Olivier, J.-L., Karcher, G., Marie, P.-Y., Maskali, F.
Oilseeds and fats, Crops and Lipids, 25 (4), pp. D406-D413.
Pinchaud, K., Maguin Gaté, K., Olivier, J.-L.
L’acide arachidonique alimentaire : un acteur à deux faces dans le cerveau et la maladie d’Alzheimer ? L’acide arachidonique est le second acide gras polyinsaturé cérébral et le premier de la série des ω-6. Les apports alimentaires d’acide arachidonique varient entre 50 et 300 mg/jour dans les régimes occidentaux mais pourraient être sous-estimés. Les triglycérides de la partie grasse des viandes fourniraient des quantités similaires aux phospholipides de la partie maigre. La maladie d’Alzheimer est une maladie neurodégénérative associée à l’âge et un problème de santé publique majeur dans le monde. Les oligomères de peptides β amyloïde en sont désormais reconnus comme l’agent principal, bien que la présence de la protéine tau est nécessaire à leur action. Avec d’autres auteurs, nous avons établi que la phospholipase A2 cytosolique, spécifique de l’acide arachidonique, assure les effets neurotoxiques des oligomères de peptide β amyloïde. Nous avons ensuite montré qu’un régime riche en acide arachidonique augmente la sensibilité des souris aux effets de ces oligomères, sans augmentation majeure de ses niveaux cérébraux. Ceci suggère que cet acide gras peut agir sur le cerveau par des effets périphériques comme une sub-inflammation dont le rôle dans la relation intestin-cerveau est discutée dans la littérature. Les apports alimentaires d’acide arachidonique devrait être intégrés dans la prévention de la maladie d’Alzheimer.
Arachidonic acid is the second polyunsaturated fatty acid in brain and the first one belonging to the ω-6 series. Dietary intakes of arachidonic are between 50 and 300 mg/day in western diets but they might be underestimated. Triglycerides from fat would provide similar amounts than phospholipids of lean meat. Alzheimer’s disease is an age-associated degenerative disease and a critical health concern worldwide. Amyloid-β peptide oligomers are presently recognized as the main and earliest agents of Alzheimer’s disease although their neurotoxicity requires the presence of tau protein. We and others established that the arachidonic-specific cytosolic phospholipase A2 is critical for the amyloid-β peptide oligomer neurotoxicity. Then, we showed that an arachidonic acid-rich diet increases the mouse sensitivity to the amyloid-β peptide oligomer deleterious effect without major increase of arachidonic acid levels in brain. This suggests that dietary arachidonic acid can exert its effects in brain through peripheral modifications. Involvement of systemic sub-inflammation and gut-brain communications are discussed based on the recent literature. The various data suggest that dietary arachidonic acid should be taken into account in the design of preventive strategies against Alzheimer’s disease.
Journal of Alzheimer's Disease, 57 (2), pp. 437-445.
Gervaise-Henry, C., Watfa, G., Albuisson, E., Kolodziej, A., Dousset, B., Olivier, J.-L., Rivasseau Jonveaux, T., Malaplate-Armand, C.
Alzheimer's Research & Therapy, 9 (1), p. 69 : doi: 10.1186/s13195-017-0295-1
Thomas, M.H., Paris, C., Magnien, M., Colin, J., Pelleïeux, S., Coste, F., Escanyé, M.-C., Pillot, T., Olivier, J.-L.
Polyunsaturated fatty acids play a crucial role in neuronal function, and the modification of these compounds in the brain could have an impact on neurodegenerative diseases such as Alzheimer's disease. Despite the fact that arachidonic acid is the second foremost polyunsaturated fatty acid besides docosahexaenoic acid, its role and the regulation of its transfer and mobilization in the brain are poorly known.
Two groups of 39 adult male BALB/c mice were fed with an arachidonic acid-enriched diet or an oleic acid-enriched diet, respectively, for 12 weeks. After 10 weeks on the diet, mice received intracerebroventricular injections of either NaCl solution or amyloid-β peptide (Aβ) oligomers. Y-maze and Morris water maze tests were used to evaluate short- and long-term memory. At 12 weeks on the diet, mice were killed, and blood, liver, and brain samples were collected for lipid and protein analyses.
We found that the administration of an arachidonic acid-enriched diet for 12 weeks induced short-term memory impairment and increased deleterious effects of Aβ oligomers on learning abilities. These cognitive alterations were associated with modifications of expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, postsynaptic density protein 95, and glial fibrillary acidic protein in mouse cortex or hippocampus by the arachidonic acid-enriched diet and Aβ oligomer administration. This diet also led to an imbalance between the main ω-6 fatty acids and the ω-3 fatty acids in favor of the first one in erythrocytes and the liver as well as in the hippocampal and cortical brain structures. In the cortex, the dietary arachidonic acid also induced an increase of arachidonic acid-containing phospholipid species in phosphatidylserine class, whereas intracerebroventricular injections modified several arachidonic acid- and docosahexaenoic acid-containing species in the four phospholipid classes. Finally, we observed that dietary arachidonic acid decreased the expression of the neuronal form of acyl-coenzyme A synthetase 4 in the hippocampus and increased the cytosolic phospholipase A2 activation level in the cortices of the mice.
Dietary arachidonic acid could amplify Aβ oligomer neurotoxicity. Its consumption could constitute a risk factor for Alzheimer's disease in humans and should be taken into account in future preventive strategies. Its deleterious effect on cognitive capacity could be linked to the balance between arachidonic acid-mobilizing enzymes.
Journal of Neurology & Neuromedicine, 1 (9), pp. 1-6.
Thomas, M., Pelleieux, S., Vitale, N., Olivier, J.-L.
Alzheimer’s disease is a very complex disease in which neuroinflammation and synaptic dysfunctions play a critical role in association with the two well-known molecular agents of the disease, the Aβ1-42 peptide oligomers and the hyperphosphorylated tau protein. Arachidonic acid, the main member of the ω-6 series, is quantitatively the second polyunsaturated fatty acid in brain and is mainly esterified in membrane phospholipids. It is specifically released by the cytosolic phospholipase A2 whose inhibition or gene suppression counteract the deleterious effects of Aβ1-42 peptide oligomers on cognitive abilities. Arachidonic acid can be reincorporated under the action of the acyl-CoA synthetase-4 and lysophospholipid acyltransferases which remain to be characterized. Free arachidonic acid can be involved in Alzheimer’s disease through several mechanisms. First it is converted by cyclooxygenases-1/2 and the specific prostaglandin synthases into PGE2 and PGD2 which contributes to the occurrence and progression of neuroinflammation. Neuroinflammation has positive as well as negative effects, by favoring Aβ1-42 peptide clearance on one hand and by increasing the production of neurotoxic compounds on the other hand. Second, free arachidonic acid is also involved in synaptic functions as a retrograde messenger and as a regulator of neuromediator exocytosis. Third, some studies indicated that free arachidonic acid and its derivatives activate kinases involved in tau hyperphosphorylation. In addition, the dietary intakes of arachidonic acid in western food increased in the last period. Taken together, these various reports support the hypothesis that arachidonic acid is interesting target in nutrition-based preventive strategies against this disease.
Biochimie, S0300-9084 (16) 30145-6
Thomas, M., Pelleieux, S., Vitale, N., Olivier, J.-L.
Alzheimer's disease and associated diseases constitute a major public health concern worldwide. Nutrition-based, preventive strategies could possibly be effective in delaying the occurrence of these diseases and lower their prevalence. Arachidonic acid is the second major polyunsaturated fatty acid (PUFA) and several studies support its involvement in Alzheimer's disease. The objective of this review is to examine how dietary arachidonic acid contributes to Alzheimer's disease mechanisms and therefore to its prevention. First, we explore the sources of neuronal arachidonic acid that could potentially originate from either the conversion of linoleic acid, or from dietary sources and transfer across the blood-brain-barrier. In a second part, a brief overview of the role of the two main agents of Alzheimer's disease, tau protein and Aβ peptide is given, followed by the examination of the relationship between arachidonic acid and the disease. Third, the putative mechanisms by which arachidonic acid could influence Alzheimer's disease occurrence and evolution are presented. The conclusion is devoted to what remains to be determined before integrating arachidonic acid in the design of preventive strategies against Alzheimer's disease and other neurodegenerative diseases.
Transl Psychiatry., 5, e595.
Corlier, F., Rivals, I., Lagarde, J., Hamelin, L., Corne, H., Dauphinot, L., Ando, K., Cossec, J.-C., Fontaine, G., Dorothée, G., Malaplate-Armand, C., Olivier, J.-L., Dubois, B., Bottlaender, M., Duyckaerts, C., Sarazin, M., Potier, M.-C., ImaBio3
Identification of blood-based biomarkers of Alzheimer's disease (AD) remains a challenge. Neuropathological studies have identified enlarged endosomes in post-mortem brains as the earliest cellular change associated to AD. Here the presence of enlarged endosomes was investigated in peripheral blood mononuclear cells from 48 biologically defined AD patients (25 with mild cognitive impairment and 23 with dementia (AD-D)), and 23 age-matched healthy controls using immunocytochemistry and confocal microscopy. The volume and number of endosomes were not significantly different between AD and controls. However, the percentage of cells containing enlarged endosomes was significantly higher in the AD-D group as compared with controls. Furthermore, endosomal volumes significantly correlated to [C(11)]PiB cortical index measured by positron emission tomography in the AD group, independently of the APOE genotype, but not to the levels of amyloid-beta, tau and phosphorylated tau measured in the cerebrospinal fluid. Importantly, we confirmed the presence of enlarged endosomes in fibroblasts from six unrelated AD-D patients as compared with five cognitively normal controls. This study is the first, to our knowledge, to report morphological alterations of the endosomal compartment in peripheral cells from AD patients correlated to amyloid load that will now be evaluated as a possible biomarker.
J Alzheimers Dis, 45 (1), pp. 195-204.
Pincon, A., Thomas, M., Huguet, M., Allouche, A., Colin, J., Georges, A., Derrien, A., Lanhers, M.-C., Malaplate-Armand, C., Oster, T., Corbier, C., Pillot, T., Olivier, J.-L., Yen, F.T.
Alzheimer’s disease (AD) is a neurodegenerative disease that has been linked to changes in cholesterol metabolism. Neuronal cholesterol content significantly influences the pro-apoptotic effect of amyloid-beta peptide42 (Abeta42), which plays a key role in AD development. We previously reported that aged mice with reduced expression of the lipolysis stimulated lipoprotein receptor (LSR+/−), demonstrate membrane cholesterol accumulation and decreased intracellular lipid droplets in several brain regions, suggesting a potential role of LSR in brain cholesterol distribution.We questioned if these changes rendered the LSR+/− mouse more susceptible to Abeta42-induced cognitive and biochemical changes. Results revealed that intracerebroventricular injection of oligomeric Abeta42 in male 15-month old LSR+/+ and LSR+/− mice led to impairment in learning and long-term
memory and decreased cortical cholesterol content of both groups; these effects were significantly amplified in the Abeta42- injected LSR+/− group. Total latency of the Morris test was significantly and negatively correlated with cortical cholesterol content of the LSR+/− mice, but not of controls. Significantly lower cortical PSD95 and SNAP−25 levels were detected in Abeta42-injected LSR+/− mice as compared to Abeta42-injected LSR+/+ mice. In addition, 24S-hydroxy cholesterol metabolite levels were significantly higher in the cortex of LSR+/− mice. Taken together, these results suggest that changes in cortex cholesterol regulation as a result of the LSR+/− genotype were linked to increased susceptibility to amyloid stress, and we would therefore propose the aged LSR+/− mouse as a new model for understanding the link between modified cholesterol regulation as risk
factor for AD.
J Alzheimers Dis, 41 (2), pp. 377-386.
Sauvée, M., DidierLaurent, G., Latarche, C., Escanyé, M.-C., Olivier, J.-L., Malaplate-Armand, C.
Cerebrospinal fluid (CSF) biomarkers have recently been included in the criteria for the diagnosis of Alzheimer's disease (AD). Since interpretation of CSF profile requires the combination of three parameters, biological data are not always conclusive and isolated elevation of phosphorylated tau (P-tau) or reduction of amyloid-β (Aβ)42 alone can be observed. In these cases, Aβ42/Aβ40 ratio could be more relevant than Aβ42 absolute values by considering inter-individual variations in the total amyloid load.
The objective of this study was to assess the use of Aβ42/Aβ40 ratio to improve the accuracy of biological conclusions in the diagnosis of patients with ambiguous CSF Aβ42 or tau results.
Among 386 lumbar punctures analyzed in the lab in 2 years, 122 showed ambiguous biological data that were completed by CSF Aβ40 quantification and Aβ42/Aβ40 ratio calculation. A biological conclusion was then made using 0.05 as the Aβ42/Aβ40 ratio cut-off.
Our results showed that one-third of the biological profiles of patients with atypical dementia were ambiguous. The addition of Aβ42/Aβ40 ratio increased the proportion of interpretable biological profiles from 69% to 87%, without changing the conclusion when usual biomarkers (Aβ42 and P-tau) were concordant.
Our results support the use of the Aβ42/Aβ40 ratio in addition to the usual CSF AD biomarkers for patients with ambiguous biological profiles. This method could be specifically directed to this population in order to improve the level of certainty for clinical routine practice.
Chem Biol Interact, 206 (2), pp. 356-363.
Fabian, J., Hanekamp, W., Thomas, M.H., Olivier, J.-L., Lehr, M.
Cytosolic phospholipase A2α (cPLA2α) plays a key role in the pathogenesis of many inflammatory diseases, such as rheumatoid arthritis, atopic dermatitis and Alzheimer's disease. Therefore, inhibition of this enzyme is assumed to provide a novel therapeutic option for the treatment of these maladies. In this study we investigated the metabolism of the potent cPLA2α inhibitors 1-[3-(4-phenoxyphenoxy)-2-oxopropyl]indole-5-carboxylic acid (1) and 3-isobutanoyl-1-[3-(4-phenoxyphenoxy)-2-oxopropyl]indole-5-carboxylic acid (2). Incubation of 1 with a mixture of human recombinant CYP1A2, 2C8, 2C9, 2C19, 2D6, 3A4 and NADPH-cytochrome P450 reductase enzymes led to reduction of its keto group and to hydroxylation at the terminal phenoxy residue. To identify the enzymes responsible for the observed reactions, experiments with isoform inhibitors were performed. In rat liver S9 fractions the only metabolite found was the alcohol 3 formed by the reduction of the keto group of 1. This reaction here was mainly catalyzed by cytosolic short-chain dehydrogenases/reductases (cSDR) as shown by inhibition experiments with different carbonyl reductase inhibitors. Furthermore, the metabolic stability of 2 in mouse brains was studied after intracerebroventricular application of this compound into the right brain hemispheres of mice. HPLC/MS analyses revealed that 2 is also readily reduced in the brain to an inactive alcohol metabolite most likely by carbonyl reductases.
Neurobiol Aging, 33 (6), pp. e17-e29.
Desbene, C., Malaplate-Armand, C., Youssef, I., Garcia, P., Stenger, C., Sauvée, M., Fischer, N., Rimet, D., Koziel, V., Escanyé, M.-C., Oster, T., Kriem, B., Yen, F.T., Pillot, T., Olivier, J.-L.
Soluble beta-amyloid (Aβ) oligomers are considered to putatively play a critical role in the early synapse loss and cognitive impairment observed in Alzheimer's disease. We previously demonstrated that Aβ oligomers activate cytosolic phospholipase A(2) (cPLA(2)), which specifically releases arachidonic acid from membrane phospholipids. We here observed that cPLA(2) gene inactivation prevented the alterations of cognitive abilities and the reduction of hippocampal synaptic markers levels noticed upon a single intracerebroventricular injection of Aβ oligomers in wild type mice. We further demonstrated that the Aβ oligomer-induced sphingomyelinase activation was suppressed and that phosphorylation of Akt/protein kinase B (PKB) was preserved in neuronal cells isolated from cPLA(2)(-/-) mice. Interestingly, expression of the Aβ precursor protein (APP) was reduced in hippocampus homogenates and neuronal cells from cPLA(2)(-/-) mice, but the relationship with the resistance of these mice to the Aβ oligomer toxicity requires further investigation. These results therefore show that cPLA(2) plays a key role in the Aβ oligomer-associated neurodegeneration, and as such represents a potential therapeutic target for the treatment of Alzheimer's disease.
J Neurochem, 123 (4), pp. 467-476.
Stenger, C., Pinçon, A., Hanse, M., Royer, L., Koziel, V., Comte, A., Olivier, J.-L., Pillot, T., Yen, F.T.
Brain lipid homeostasis is important for maintenance of brain cell function and synaptic communications, and is intimately linked to age-related cognitive decline. Because of the blood–brain barrier’s limiting nature, this tissue relies on a complex system for the synthesis and receptor-mediated uptake of lipids between the different networks of neurons and glial cells. Using immunofluorescence, we describe the region-specific expression of the lipolysis-stimulated lipoprotein receptor (LSR), in the mouse hippocampus, cerebellum Purkinje cells, the ependymal cell interface between brain parenchyma and cerebrospinal fluid, and the choroid plexus. Colocalization with cell-specific markers revealed that LSR was expressed in neurons, but not astrocytes. Latency in arms of the Y-maze exhibited by young heterozygote LSR+/ mice was significantly different as compared to control LSR+/+, and increased in older LSR+/ mice. Filipin and Nile red staining revealed membrane cholesterol content accumulation accompanied by significantly altered distribution of LSR in the membrane, and decreased intracellular lipid droplets in the cerebellum and hippocampus of old LSR+/ mice, as compared to control littermates as well as young LSR+/ animals. These data therefore suggest a potential role of LSR in brain cholesterol distribution, which is particularly important in preserving neuronal integrity and thereby cognitive functions during aging.
In "Arachidonic Acid: Sources, Biosynthesis and Health Effects", O'Keefe J.M., Ed., Nova Science Publishers, Hauppauge, NY, États-Unis
Thomas, M., Pelleieux, S., Allouche, A., Colin, J., Oster, T., Malaplate-Armand, C., Olivier, J.-L.
Colloque Annuel de la Société Cerveau et Maladies Cérébrovasculaires - Maturation et vieillissement du système cérébrovasculaire, 28-29 mars, Lille, France
Olivier, J.-L.
Nos travaux antérieurs ont montré qu’un régime riche en acide arachidonique augmente la sensibilité des souris à la neurotoxicité des oligomères de peptide Aβ, principaux agents de la maladie d’Alzheimer, en termes d’atteintes des capacités cognitives et d’expression de protéines impliqués dans la transmission synaptique. Dans ce travail, nous avons étudié l’action positive de souches de Streptococcus thermophilus dont certaines présentent des propriétés anti-inflammatoires, sur l’association négative régime alimentaire riche en acide arachidonique – neurotoxicité des oligomères de peptide Aβ. Nous avons cherché à déterminer les mécanismes sous-jacents, notamment le rôle de la barrière hémato-encéphalique dans la transmission du signal intestin - cerveau.
43ème Colloque de la Société de Neuroendocrinologie, 2-4 octobre, Tours, France
Pinchaud, K., Hafeez, Z., Chatel, J.-M., Chadi, S., Auger, S., Dary, A., Maguin Gaté, K., Olivier, J.-L.
L’acide arachidonique (ARA) est le second acide gras polyinsaturé dans le cerveau. L’apport d’ARA est associé à la consommation d’aliments d’origine animale qui semble sous-estimée dans les régimes occidentaux. Une précédente étude de notre laboratoire a montré qu’un régime enrichi en ARA à hauteur de 1% augmente la sensibilité des souris BalB/C males à la neurotoxicité des oligomères de peptides β-amyloïdes, considérés comme étant un des principaux acteurs de la maladie d’Alzheimer. L’objectif de cette étude est d’évaluer l’impact d’un régime enrichi en ARA sur les fonctions cérébrales au travers de modifications du microbiote intestinal et d’altération des communications intestin-cerveau. Pour cela, deux groupes de souris BalB/C ont été nourries avec un régime moyennement hyperlipidique HL-ARA (15% de lipides non enrichi en ARA) ou HL+ARA (15% de lipides et enrichi en ARA à hauteur de 1%) ou encore Std-ARA 5% de lipides non enrichi en ARA) durant 8 semaines complètes. Notre étude n’a montré aucune différence significative concernant le poids des animaux durant l’expérimentation dans chacun des groupes, excepté une augmentation du poids du tissu adipeux mésentérique pour le groupe HL-ARA. Une augmentation du groupe de Bifidobacteriaceae (anti-inflammatoires) dans le microbiote intestinal des souris nourries avec le régime HL-ARA a été mise en évidence comparé au groupe Std-ARA. Cette augmentation de Bifidobacteriaceae est corrélée avec une plus forte présence de lipides dans le régime mais cet effet est renversé par l’ajout d’ARA dans le régime. Aucune modification des marqueurs de l’inflammation n’a été détecté dans le plasma et les fèces de chacun des groupes de souris, mais une augmentation du marqueur des astrocytes GFAP a été observée dans l’hippocampe des souris nourries avec le régime HL+ARA. Il serait intéressant d’étudier les altérations de communication entre l’intestin et cerveau incluant les signaux neuroendocriniens afin de comprendre la cascade impliquée dans la modulation des fonctions cérébrales par l’intestin.
Arachidonic acid (ARA) is the second polyunsaturated fatty acid in the brain. ARA intake is associated with consumption of animal origin products and seems to be underestimated in western diet. A previous study in our laboratory showed that a diet containing 1% ARA increased the sensitivity of male Balb/C mice to the neurotoxicity of the amyloid-β peptide oligomers, considered as the main Alzheimer’s disease agents. The objective of this study was to evaluate the impact of dietary ARA intake on brain functions through gut microbiota modifications and alteration of gut-brain communications. For this, two groups of male BalB/C mice were orally fed with moderately high fat diet, i.e., HL-ARA (15% lipid without ARA) and HL+ARA (15% lipid with 1% ARA) and the third group was fed on standard diet (Std-ARA, 5% lipids without ARA) during 9 weeks. No significant difference was observed in weight gain among the 3 groups except an increase in mesenteric fat tissue in HL-ARA diet group. An increase in Bifidobacteriaceae group (potentially anti-inflammatory) in gut microbiota of HL-ARA diet group was noted compared to standard diet group. This increase in Bifidobacteriaceae was correlated to high lipid contents in diet but this effect was reversed in HL+ARA diet group. No modifications in inflammatory markers were highlighted in plasma and feces samples of the three groups. Contrariwise, higher expression levels of the Glial fibrillary acidic protein were observed in hippocampus of HL+ARA group. It could be interesting to further investigate alterations of the gut-brain communications including neuroendocrine signals.
Lipid and Brain IV dedicated to “Lipids in Alzheimer disease” Journées Chevreul, 8-11 octobre, Nancy, France
Thomas, M., Paris, C., Magnien, M., Colin, J., Pelleieux, S., Coste, F., Escanyé, M.-C., Pillot, T., Olivier, J.-L.
Polyunsaturated fatty acids play crucial role in neuronal functions and the modification of these compounds in brain could have an impact on neurodegenerative diseases such as Alzheimer’s disease. Despite the fact that arachidonic acid is the second foremost polyunsaturated fatty acid besides docosahexaenoic acid, its role and the regulation of its transfer and mobilization in brain are poorly known.
In this work, two groups of 39 adult male Balb/C mice were fed respectively with an arachidonic or an oleic acid-enriched diet for 12 weeks. After 10 weeks of diet, mice received intracerebroventricular injections of either NaCl solutions or Aβ oligomers. Y-maze and Morris water maze tests were used to evaluate short- and long-term memory. At 12 weeks of diet mice were sacrificed and blood, liver and brain samples were collected for lipid and protein analyses.
Administration of the arachidonic acid-enriched diet induced short-term memory impairment and increased deleterious effects of amyloid-β oligomers on learning abilities. These cognitive alterations were associated to modifications of expression of AMPA receptors, PSD95 and GFAP in mouse cortex or hippocampus by arachidonic acid-enriched diet and Aβ oligomer administration. This diet also led to an unbalance between the main ω?6 fatty acids and the ω-3 fatty acids in favor of the first one in erythrocytes and liver as well as in the brain structures hippocampus and cortex. In the cortex, the dietary arachidonic acid induced also an increase of arachidonic acid-containing phospholipid species in phosphatidylserine class while intracerebroventricular injections modified several arachidonic and docosahexaenoic acids-containing species in the 4 phospholipid classes. Finally, we observed that dietary arachidonic acid decreased the expression of the neuronal form of acyl-coA synthetase 4 in the hippocampus and increased the cytosolic phospholipase A2 activation level in the cortex of our mice.
We concluded that dietary arachidonic acid could amplify Aβ oligomers neurotoxicity. Its consumption could constitute a risk factor of Alzheimer’s disease in humans and should be taken into account in the future preventive strategies. Its deleterious effect on the cognitive capacities could be linked to the balance between the arachidonic acid-mobilizing enzymes.
Lipids in Agronomy, Health and Disease : Congrés GERLI, 25-28 octobre, Bischoffsheim, France
Thomas, M., Paric, C., Escanyé, M.-C., Heintz, D., Vitale, N., Olivier, J.-L.
Journées Chevreul 2015. Lipids & Brain 3 (FIAP Jean Monnet), 16-18 mars, Paris, France
Thomas, M., Paris, C., Yen F.T., Olivier, J.-L.
12th International Conference on Alzheimer's and Parkinson's Diseases (AD/PD), 18-22 mars, Nice, France
Thomas, M., Paris, C., Yen F.T., Olivier, J.-L.
Journées Thématiques de la Société des Neurosciences: Perturbations métaboliques dans les maladies neurologiques et mentales, 19-20 mai, Lille, France
Pinçon, A., Allouche, A., Derrien, A., Lanhers, M.-C., Thomas, M., Colin, J., Malaplate-Armand, C., Oster, T., Olivier, J.-L., Yen, F.T.
Alzheimer’s disease is a neurodegenerative disease with accumulation of β-amyloid peptide (Aβ) within the brain associated with cognitive impairment. Cholesterol is important for normal brain function including synaptic plasticity, learning and memory and in preserving neuronal integrity and thereby cognitive functions during aging. Although high risk of Alzheimer’s disease has been associated with modified lipid homeostasis, the molecular mechanisms underlying the correlation between altered cholesterol metabolism and the neurological deficits and cognitive impairments remain unclear due in part to lack of animal models. Recently, we described the expression of the lipolysis-stimulated lipoprotein receptor (LSR) in different regions of mouse brain including the hippocampus, cerebellum (Purkinje cells), the ependymal cell interface between brain parenchyma and cerebrospinal fluid, the choroid plexus and the cortex. Furthermore, we have shown altered cholesterol distribution in aged LSR heterozygous mice with membrane cholesterol content accumulation accompanied by decreased intracellular droplets in cerebellum and hippocampus (J. Neurochem, 2012). Here, we tested whether dyslipidemic LSR+/- mice were susceptible to amyloid stress. Male 15-month old LSR+/+ and LSR+/- mice were subjected to intracerebroventricular (i.c.v.) injection of soluble Aβ oligomers. Learning and memory were evaluated by Y-Maze and Morris Water-Maze tests, and synaptic alterations by immunoblots. Results revealed increased impairment in learning and long-term memory of Aβ–injected LSR+/- as compared to Aβ–injected LSR+/+ animals. Furthermore, these Aβ-induced behavioral alterations were associated with significantly lower PSD95 and SNAP-25 levels in the cortex of LSR+/- mice, as compared to LSR+/+ mice. In conclusion, reduced LSR expression in aged mice leads to cognitive deficits as well as synaptic alterations that are amplified when exposed to amyloid stress, which lead us to propose the dyslipidemic LSR+/- mouse as a new model for understanding the link between modified lipid homeostasis as risk factor for Alzheimer’s disease.
Groupe d'études et de recherche en lipidomique (GERLI) 2013, 10-14 Novembre, Saint-Jean-Cap-Ferrat), France.
Thomas, M., Pelleieux, S., Yen Potin, F., Olivier, J.-L.
11ème Réunion Francophone sur la Maladie d’Alzheimer et les Syndromes Apparentés, 22-24 Mai, Toulouse, France.
Malaplate-Armand, C., Desbene, C., Sauvée, M., Yen Potin, F., Oster, T., Pillot, T., Olivier, J.-L.
11ème Réunion Francophone sur la Maladie d’Alzheimer et les Syndromes Apparentés, 22-24 Mai, Toulouse, France.
Malaplate-Armand, C., Sauvée, M., Didierlaurent, G., Escanyé, M.-C., Olivier, J.-L.
Groupe d'études et de recherche en lipidomique (GERLI) 2012, 17-19 Octobre, Paris, France.
Allouche, A., Colin, J., Royer, L., Escanyé, M.-C., Olivier, J.-L., Yen Potin, F., Pillot, T., Dhaussy, A., Breton, S., Huertas, A., Malaplate-Armand, C., Oster, T.
Groupe d'études et de recherche en lipidomique (GERLI) 2012, 17-19 Octobre, Paris, France.
Pinçon, A., Stenger, C., Hanse, M., Comte, A., Pillot, T., Olivier, J.-L., Yen, F.T.
FEBS Congress, 25-30 Juin, Turin, Italie.
Hanse, M., Stenger, C., Akbar, S., Malaplate-Armand, C., Olivier, J.-L., Oster, T., Yen, F.T.
The 10th International Conference on Alzheimer’s and Parkinson’s diseases AD/PD 2011, 09-13 Mars, Barcelone, Espagne.
Allouche, A., Royer, L., Youssef, I., Escanyé, M.-C., Koziel, V., Malaplate-Armand, C., Olivier, J.-L., Yen, F.T., Pillot, T., Oster, T., Dhaussy, A., Breton, S., Huertas, A.
