Molecular mechanisms involved in neuronal apoptosis induced by soluble oligomers of β-amyloid peptide: identification and functional validation of cellular targets.
Identifieur interne : 000201 ( Hal/Checkpoint ); précédent : 000200; suivant : 000202Molecular mechanisms involved in neuronal apoptosis induced by soluble oligomers of β-amyloid peptide: identification and functional validation of cellular targets.
Auteurs : Ihsen Youssef [France]Source :
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Abstract
Aging of population is correlated to the increase of neurodegenerative disease, more particularly Alzheimer disease. Defining early diagnostic markers and new therapeutic strategies are highly relevant. Among the molecular pathways which are currently developed, N-terminal-truncated forms of amyloid-ß (Aß) peptide have been recently suggested to play a pivotal role in the disease. Among them, Aß3(pE) 42 peptide is the dominant Aß species in amyloid plaques. We first investigated the effects of soluble oligomeric Aß3(pE) 42 after intracerebroventricular injection on mice learning capacities and the molecular mechanisms of in vitro neurotoxicity. Mice injected with soluble Aß3(pE) 42 displayed impaired spatial working memory and delayed memory acquisition. These cognitive alterations were associated with free radical overproduction in hippocampus and olfactory bulbs. In vitro, Aß3(pE) 42 oligomers induced a redox-sensitive neuronal apoptosis involving caspase activation and an arachidonic acid-dependent pathway. The second goal of this work was to investigate the protective effects of the apoptosis rescue endogenous peptide humanin (HN) and its S14G mutant (HNG). In vitro, we measured their inhibitory effect on neuronal death and apoptotic events resulting from soluble Ab oligomer treatment. What's of particular interest is the in vivo restoration of soluble Aß3(pE) 42 oligomer-induced mnesic impairment. Thus, HN peptides might serve as new drug candidates for treatment or prevention of early cellular damages linked to soluble Aß oligomers.
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transduction du signal</term><term>apoptose</term><term>apprentissage</term><term>comportement</term><term>humanine</term><term>maladie d'Alzheimer</term><term>mémoire</term><term>neurodégénérescence</term><term>neurotoxicité</term><term>oligomères solubles</term><term>peptide β-amyloïde</term><term>stratégies
thérapeutique</term><term>stratégies
thérapeutique.</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Aging of population is correlated to the increase of neurodegenerative disease, more particularly Alzheimer disease. Defining early diagnostic markers and new therapeutic strategies are highly relevant. Among the molecular pathways which are currently developed, N-terminal-truncated forms of amyloid-ß (Aß) peptide have been recently suggested to play a pivotal role in the disease. Among them, Aß3(pE) 42 peptide is the dominant Aß species in amyloid plaques. We first investigated the effects of soluble oligomeric Aß3(pE) 42 after intracerebroventricular injection on mice learning capacities and the molecular mechanisms of in vitro neurotoxicity. Mice injected with soluble Aß3(pE) 42 displayed impaired spatial working memory and delayed memory acquisition. These cognitive alterations were associated with free radical overproduction in hippocampus and olfactory bulbs. In vitro, Aß3(pE) 42 oligomers induced a redox-sensitive neuronal apoptosis involving caspase activation and an arachidonic acid-dependent pathway. The second goal of this work was to investigate the protective effects of the apoptosis rescue endogenous peptide humanin (HN) and its S14G mutant (HNG). In vitro, we measured their inhibitory effect on neuronal death and apoptotic events resulting from soluble Ab oligomer treatment. What's of particular interest is the in vivo restoration of soluble Aß3(pE) 42 oligomer-induced mnesic impairment. Thus, HN peptides might serve as new drug candidates for treatment or prevention of early cellular damages linked to soluble Aß oligomers.</div></front></TEI><hal api="V3"> <titleStmt> <title xml:lang="en">Molecular mechanisms involved in neuronal apoptosis induced by soluble oligomers of β-amyloid peptide: identification and functional validation of cellular targets.</title> <title xml:lang="fr">Etude des mécanismes moléculaires impliqués dans la mort neuronale induite par le peptide bêta amyloïde soluble : Recherche et validation fonctionnelle de cibles cellulaires.</title> <author role="aut"> <persName> <forename type="first">Ihsen</forename> <surname>Youssef</surname> </persName> <email type="md5">4d5c466933de51198aaac4142964bf74</email> <email type="domain">uhp-nancy.fr</email> <idno type="halauthorid">295643</idno> <affiliation ref="#struct-161001"></affiliation> </author> <editor role="depositor"> <persName> <forename>Ihsen</forename> <surname>Youssef</surname> </persName> <email type="md5">1e73b45fa1f1beebb8749685ee7ff6a9</email> <email type="domain">yahoo.fr</email> </editor> </titleStmt> <editionStmt> <edition n="v1" type="current"> <date type="whenSubmitted">2008-03-13 18:23:26</date> <date type="whenModified">2017-03-15 12:12:19</date> <date type="whenReleased">2008-03-13 20:21:51</date> <date type="whenProduced">2006-10-31</date> <date type="whenEndEmbargoed">2008-03-13</date> <ref type="file" target="https://tel.archives-ouvertes.fr/tel-00264025/document"> <date notBefore="2008-03-13"></date> </ref> <ref type="file" n="1" target="https://tel.archives-ouvertes.fr/tel-00264025/file/These_version_finale.pdf"> <date notBefore="2008-03-13"></date> </ref> </edition> <respStmt> <resp>contributor</resp> <name key="126646"> <persName> <forename>Ihsen</forename> <surname>Youssef</surname> </persName> <email type="md5">1e73b45fa1f1beebb8749685ee7ff6a9</email> <email type="domain">yahoo.fr</email> </name> </respStmt> </editionStmt> <publicationStmt> <distributor>CCSD</distributor> <idno type="halId">tel-00264025</idno> <idno type="halUri">https://tel.archives-ouvertes.fr/tel-00264025</idno> <idno type="halBibtex">youssef:tel-00264025</idno> <idno type="halRefHtml">Neurosciences [q-bio.NC]. Institut National Polytechnique de Lorraine - INPL, 2006. Français</idno> <idno type="halRef">Neurosciences [q-bio.NC]. Institut National Polytechnique de Lorraine - INPL, 2006. Français</idno> </publicationStmt> <seriesStmt> <idno type="stamp" n="INPL">Institut National Polytechnique de Lorraine</idno> <idno type="stamp" n="UNIV-LORRAINE">Université de Lorraine</idno> </seriesStmt> <notesStmt> <note type="commentary">2006</note> </notesStmt> <sourceDesc> <biblStruct> <analytic> <title xml:lang="en">Molecular mechanisms involved in neuronal apoptosis induced by soluble oligomers of β-amyloid peptide: identification and functional validation of cellular targets.</title> <title xml:lang="fr">Etude des mécanismes moléculaires impliqués dans la mort neuronale induite par le peptide bêta amyloïde soluble : Recherche et validation fonctionnelle de cibles cellulaires.</title> <author role="aut"> <persName> <forename type="first">Ihsen</forename> <surname>Youssef</surname> </persName> <email type="md5">4d5c466933de51198aaac4142964bf74</email> <email type="domain">uhp-nancy.fr</email> <idno type="halauthorid">295643</idno> <affiliation ref="#struct-161001"></affiliation> </author> </analytic> <monogr> <imprint> <date type="dateDefended">2006-10-31</date> </imprint> <authority type="institution">Institut National Polytechnique de Lorraine - INPL</authority> <authority type="school">Sciences et Ingénierie des Ressources, Procédés, Produits, Environnement</authority> <authority type="supervisor">PILLOT Thierry(Thierry.Pillot@mtm.nancy.inserm.fr)</authority> <authority type="jury">Pr. François Laurent (président)</authority> <authority type="jury">Dr Bernadette Allinquant, DR2 Inserm (rapporteur)</authority> <authority type="jury">Dr. Jean-Paul Fuchs, CR1 CNRS (rapporteur)</authority> <authority type="jury">Dr. Brigitte Leininger-Muller, MCU</authority> <authority type="jury">Dr. Thierry Pillot, DR2 Inserm</authority> </monogr> <ref type="seeAlso">http://www.rp2e.inpl-nancy.fr/</ref> </biblStruct> </sourceDesc> <profileDesc> <langUsage> <language ident="fr">French</language> </langUsage> <textClass> <keywords scheme="author"> <term xml:lang="en">Molecular mechanisms involved in neuronal apoptosis induced by soluble oligomers of β-amyloid
peptide: identification and functional validation of cellular targets.</term> <term xml:lang="fr">stratégies
thérapeutique</term> <term xml:lang="fr">maladie d'Alzheimer</term> <term xml:lang="fr">peptide β-amyloïde</term> <term xml:lang="fr">oligomères solubles</term> <term xml:lang="fr">neurodégénérescence</term> <term xml:lang="fr">apoptose</term> <term xml:lang="fr">
transduction du signal</term> <term xml:lang="fr">neurotoxicité</term> <term xml:lang="fr">comportement</term> <term xml:lang="fr">mémoire</term> <term xml:lang="fr">apprentissage</term> <term xml:lang="fr">humanine</term> <term xml:lang="fr">stratégies
thérapeutique.</term> </keywords> <classCode scheme="halDomain" n="sdv.neu">Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]</classCode> <classCode scheme="halTypology" n="THESE">Theses</classCode> </textClass> <abstract xml:lang="en">Aging of population is correlated to the increase of neurodegenerative disease, more particularly Alzheimer disease. Defining early diagnostic markers and new therapeutic strategies are highly relevant. Among the molecular pathways which are currently developed, N-terminal-truncated forms of amyloid-ß (Aß) peptide have been recently suggested to play a pivotal role in the disease. Among them, Aß3(pE) 42 peptide is the dominant Aß species in amyloid plaques. We first investigated the effects of soluble oligomeric Aß3(pE) 42 after intracerebroventricular injection on mice learning capacities and the molecular mechanisms of in vitro neurotoxicity. Mice injected with soluble Aß3(pE) 42 displayed impaired spatial working memory and delayed memory acquisition. These cognitive alterations were associated with free radical overproduction in hippocampus and olfactory bulbs. In vitro, Aß3(pE) 42 oligomers induced a redox-sensitive neuronal apoptosis involving caspase activation and an arachidonic acid-dependent pathway. The second goal of this work was to investigate the protective effects of the apoptosis rescue endogenous peptide humanin (HN) and its S14G mutant (HNG). In vitro, we measured their inhibitory effect on neuronal death and apoptotic events resulting from soluble Ab oligomer treatment. What's of particular interest is the in vivo restoration of soluble Aß3(pE) 42 oligomer-induced mnesic impairment. Thus, HN peptides might serve as new drug candidates for treatment or prevention of early cellular damages linked to soluble Aß oligomers.</abstract> <abstract xml:lang="fr">Le vieillissement des populations est corrélé à l'augmentation des pathologies neurodégénératives liées à l'âge, plus particulièrement la maladie d'Alzheimer. La recherche de marqueurs précoces de la maladie ainsi que l'élaboration de nouvelles stratégies thérapeutiques constituent un enjeu de taille. Parmi les mécanismes moléculaires de la formation des plaques amyloïdes actuellement explorés, les formes oligomériques tronquées de peptide amyloïde (Aß), notamment le peptide Aß3(pE) 42 retrouvé à des stades précoces de la maladie, joueraient un rôle déterminant. Ces travaux de thèse ont permis de montrer, dans un premier temps, que l'injection intracérébrale de ce peptide chez la souris entraîne des altérations de la mémoire de travail et des capacités d'apprentissage, associées à une accumulation d'espèces réactives dérivées de l'oxygène dans des régions cérébrales spécifiques (hippocampe et bulbes olfactifs) de ces animaux. Des essais menés in vitro sur des cultures primaires de neurones de souris montrent leur implication dans les voies apoptotiques impliquant l'activation des caspases et la cascade métabolique de l'acide arachidonique. La seconde étape de ces travaux a constitué en l'étude des effets protecteurs d'un peptide antiapoptotique d'origine endogène, l'humanine (HN) et son variant S14G (HNG). In vitro, un effet protecteur de ces peptides a été mesuré après traitement de neurones en culture par le peptide Aß3(pE) 42. Les résultats les plus marquants résident dans les observations faites in vivo : en effet, ces peptides inhibent l'effet délétère de l'injection intracérébroventriculaire du peptide Aß3(pE) 42, en restaurant les performances mnésiques des animaux dans les tests comportementaux. A la lumière de ces résultats, les peptides HN pourraient constituer de nouveaux outils thérapeutiques dans le traitement ou la prévention des dommages cellulaires précoces liés à la présence des oligomères solubles du peptide Aß.</abstract> </profileDesc> </hal></record>Pour manipuler ce document sous Unix (Dilib)
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