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Synaptotoxicity in Alzheimer's Disease

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Synaptotoxicity in Alzheimer's Disease Synaptotoxicity in Alzheimer’s disease : Influence of APP processing on excitatory synapses Rebecca Powell To cite this version: Rebecca Powell. Synaptotoxicity in Alzheimer’s disease : Influence of APP processing on excitatory synapses. Neurons and Cognition [q-bio.NC]. Université Grenoble Alpes, 2019. English. NNT : 2019GREAV051. tel-02953383 HAL Id: tel-02953383 https://tel.archives-ouvertes.fr/tel-02953383 Submitted on 30 Sep 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE Pour obtenir le grade de DOCTEUR DE LA COMMUNAUTE UNIVERSITE GRENOBLE ALPES Spécialité : Neurosciences - Neurobiologie Arrêté ministériel : 25 mai 2016 Présentée par Rebecca POWELL Thèse dirigée par Alain BUISSON, Professeur, UGA Préparée au sein du l’institut des Neurosciences de Grenoble INSERM U1216 – Equipe Neuropathologies et Dysfonctions Synaptiques Dans l'École Doctorale de Chimie et Sciences du vivant Synaptotoxicité dans la maladie d’Alzheimer : Influence du processing de l’APP sur les synapses excitatrices Thèse soutenue publiquement le 6 décembre 2019, devant le jury composé de : Pr Rémy SADOUL Professeur - Université Grenoble Alpes - Président du jury Dr Claire MEISSIREL Chargée de recherche - Université Claude Bernard Lyon 1 - Rapporteur Dr Marc DHENAIN Directeur de recherche - CNRS, Université Paris -Sud - Rapporteur Dr Montserrat SOLER-LOPEZ Laboratory Scientist and Manager - ESRF, Grenoble - Examinateur Dr Harold MacGillavry Assistant Professor - Universiteit Utrect, Netherlands - Examinateur Pr Alain BUISSON Professeur - Université Grenoble Alpes - Directeur de thèse Synaptotoxicity in Alzheimer’s disease: Influence of APP processing on excitatory synapses Acknowledgments First and foremost, I would like to kindly thank the members of the jury: Claire Meissirel, Montse Soler- Lopez, Marc Dhenain, Harold Mac Gillavry and Rémy Sadoul for accepting to be part of my thesis jury and making time for evaluating my work. En particulier j’aimerais remercier Claire Meissirel et Marc Dhenain d’avoir accepté d’être rapporteur de ma thèse et d’avoir pris le temps d’analyser mon manuscrit. A special thanks to Montse, for following the evolution of my thesis project and, now, for being member of my thesis jury. Also, I would like to warmly thank Harold Mac Gillavry for travelling all the way from Utrecht to assess my work. Je tiens à remercier tout particulièrement Rémy Sadoul pour avoir accepté d’être examinateur dans ce jury de thèse, mais surtout pour m’avoir fait découvrir les neurosciences en L3. C’est en grande partie grâce à toi que j’en suis là où en j’en suis aujourd’hui! A very special thank you my PhD director, Alain Buisson. Thank you for believing in me and giving me the opportunity to carry out my thesis in your team. During these four years you’ve taught me a lot professionally, scientifically and even on a personal level. By trusting me I’ve learned to trust myself. Thank you for mentoring, advice and inspiration, I couldn’t have asked for a better boss! Un grand merci à toute mon équipe avec qui nous avons toujours partagé de bons moments, eu de bonnes conversations et de bonnes rigolades! C’était un plaisir de me lever le matin sachant que j’allais à ma « deuxième maison » où il y faisait bon vivre grâce à vous! Merci à Muriel, Mireille et Fabien, mes profs de fac (que je redoutais) qui sont devenus mes collègues de travail (que j’apprécie énormément, les profs sont des humains vraiment gentils en fait!). Merci de m’avoir appris les sciences, en cours et aussi pendant ma thèse! Mais surtout merci pour vos conseils, votre soutien, votre ouverture d’esprit, votre gentillesse et votre bonne humeur! Merci à mes voisines de bureau, Sylvie et Eve (mes deuxièmes mamans), pour m’avoir soutenue dans les bons et les moins bons moments, d’avoir toujours veillées sur moi et pour toutes les barres de rires qu’on s’est payées! Votre bonne humeur (et bon humour) est sans faille et je vous en remercie sincèrement! Et puis, merci au « petit frère » PhD, Adrien, pour tous les moments que nous avons partagé au labo, les discussions de tout et n’importe quoi et les fous rires en tout genre (et surtout pour nos comparaisons de performances sportives qui ne servaient à rien puisque j’étais la plus nulle à chaque fois haha!). I would like to thank the rest of the members of the 2nd floor of the institute, as well as all the members of the rest of the GIN, for taking part in making these four years absolutely unforgettable! Un merci tout spécial aux amis. Tout d’abord les amies « labos » Marta, Elé et Perrine! Merci les filles d’avoir été là à mes débuts comme stagiaires M2! Merci à toi Perrine d’avoir été ma camarade de galère pendant le stage M2 et un infini merci pour m’avoir fait comprendre les stats en un temps éclair haha! Merci à vous Elé et Marta, sans vous je crois que je n’en serais pas là aujourd’hui. Je ne vous remercierais jamais assez pour votre bonne humeur, votre gentillesse, votre amitié. Je n’aurais jamais imaginé rencontrer des filles aussi géniales que vous! Don’t change a thing ;) Un grand merci aussi aux amis « pas labos », Kelly, Tony, Laura, Tam, Pex, Tazo, Tris (et encore d’autres que je ne peux citer par soucis de place)! Merci d’avoir été là, et juste merci d’être vous! Don’t change a thing either ;) Diolch yn fawr Mammy, Daddy! Thank you for always believing in me, for your continuous support through thick and thin, for your patience especially in the last few months (I know I’ve been a real pain in the back side!) and for everything that you do (I could make a list of things to thank you for as long as this thesis) you’re the best! And mustn’t forget the bros! Alex, Liam and Jonathan! What a great gang! U ma homies, u da best! Mes derniers remerciements vont à toi Pup. Toi qui es à mes côtés depuis le tout début. On en aura fait du chemin! On a grandi ensemble et je te remercie du fond du cœur pour tout ce que tu es, tout ce que tu m’as apporté et tout ce que tu as dû endurer! Si j’en suis là aujourd’hui, autant sur le plan professionnel que personnel, c’est grâce à toi! Love you long time <3 To my mams, Résumé La maladie d’Alzheimer (MA) est définie comme une maladie neurodégénérative où des altérations synaptiques mènent à la perte neuronale parallèlement à des défauts de mémoire et d’apprentissage. Il est établi que les dysfonctions synaptiques observées dans la MA sont initiées par les formes oligomériques du peptide β-amyloïde (Aβ), un dérivé protéolytique de l’Amyloïd Precursor Protein (APP). Cependant, le chemin qu’empreinte Aβ, selon son origine intra- ou extracellulaire, afin d’induire ces effets délétères et la façon dont ses effets sont maintenus et se propagent dans le cerveau restent encore à définir. Dans cette étude, nous avons utilisé plusieurs formes mutées de l’APP qui conduisent à des peptides Aβ avec des signatures moléculaires uniques, tel que : la mutation Swedish (K670M/N671L) (APPswe) qui augmentent la sécrétion (extracellulaire) d’Aβ; la mutation Osaka (E693Δ) (APPosa) qui cause une accumulation intraneuronale (intracellulaire) d’Aβ; ainsi que la mutation Icelandic (A673T) (APPice) qui a été établi comme diminuant la production d’Aβ et protégeant contre la MA. Ces formes mutées d’APP ont été surexprimées dans des cultures de neurones corticaux murins et on permit : i) d’étudier la morphologie et fonction des épines dendritiques, l’élément post-synaptique, par microscopie confocale; ii) de tenter de mieux comprendre comment la pathologie se développe et se propage dans le cerveau et iii) d’identifier un nouveau partenaire d’intéraction avec l’Aβ faisant la lumière sur un possible rôle physiologique de ce peptide dans les neurones. Nous montrons qu’une accumulation pathologique d’Aβ, due à la surexpression d’APPwt, APPswe et APPosa mais pas APPice, induit une diminution significative de la densité synaptique particulièrement celle des épines les plus fonctionnelles, dites « mushroom ». Ses épines mushroom restantes présentent également une augmentation significative de leur volume et il semblerait que l’Aβ intracellulaire soit suffisant pour induire ses effets. Ses épines mushroom élargies présentent également une plasticité structurale altérée puisqu’elles n’ont pas augmenté d’avantage de volume à la suite d’une activation synaptique. Il semblerait que ceci soit la résultante d’un défaut de la dynamique activité-dépendante du cytosquelette d’actine dans les épines. Ces altérations de la morphologie, structure et plasticité synaptique serait dû à une intéraction, nouvellement identifiée, de l’Aβ avec l’actine et pourrait faire lumière sur un possible rôle physiologique de l’Aβ dans la plasticité synaptique activité-dépendante. De plus, nous montrons que le clivage amyloïde de l’APP est aussi activité-dépendant et que la séquence du peptide Aβ généré est aussi importante, dans l’induction de la synaptotoxicité, que sa concentration. En effet, car nous montrons que des concentrations pathologiques du peptide Aβice n’engendrent pas de perte ou de gonflement des épines mushroom. Enfin, nous mettons en lumière que l’Aβ sécrété dans le milieu extracellulaire affecte, non seulement le neurone sécrétant lui-même, mais aussi la densité synaptique des neurones sains avoisinant (qui ne surexpriment pas d’APP) d’une manière APP-dépendante, rappelant un mécanisme de propagation du type prion.
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