Description du projet
Interactions cellulaires et moléculaires dans la maladie d’Alzheimer
La maladie d’Alzheimer (MA) est une forme fréquente de démence associée à une neuroinflammation et à une perte de synapses neuronales. Pour fonctionner correctement, les neurones ont besoin de microtubules, un réseau de structures à base de protéines qui facilitent le mouvement des substances et des organites. Une protéine appelée tau, qui se replie mal dans la maladie d’Alzheimer et entraîne la perte des synapses, joue un rôle central dans la formation des microtubules. Financé par le programme Actions Marie Skłodowska-Curie, le projet SynapTau vise à lever le voile sur le rôle joué par la microglie, à savoir les cellules immunitaires innées du système nerveux central, dans la perte synaptique médiée par tau. Dans un milieu expérimental, les chercheurs étudieront le rôle protecteur de molécules spécifiques contre les dommages synaptiques, ouvrant ainsi la voie à l’identification de cibles thérapeutiques pour la MA.
Objectif
The overall aim of SynapTau is to evaluate the contribution of microglia on tau-mediated synaptic loss in Alzheimer’s disease (AD), based on synaptosomal changes, which may help to develop therapeutic strategies against AD. Determining the impact of tau accumulation on synaptic loss is critical since it correlates with cognitive decline in AD. Beyond tau and amyloid-β pathologies, gliosis is also an AD hallmark and is thought to play a pivotal role on synaptic loss. Despite the link between tau, synapses and inflammation in AD, we do not yet understand the specific interactions between synaptic proteins, glia and pathological tau that lead to synaptic loss. My objective is to provide a better understanding of the role of microglia in tau-mediated synaptic loss based on recent observations I made. I recently explored synaptosomes containing glial processes near synapses from microglia depleted P301S mice, a mouse model of tauopathy, to identify changes resulting from microglia depletion that account for synaptic protection against tau pathology. I reported an upregulation of UCH-L1, an enzyme required for normal synaptic function. Moreover, most of the upregulated proteins in the synaptosomes of microglia depleted-P301S mice are expressed by astrocytes. I propose to study potential protective mechanisms against tau-mediated synaptotoxicity set in motion by microglial depletion that target neurons and neuron/astrocyte interactions. In objective 1, I hypothesize that enhancing UCH-L1 expression in neurons will protect against tau-mediated synaptic damages. In objective 2, I hypothesize that neuron-glia interactions are modified after microglia depletion, with changes in the formation and function of perisynaptic astrocytic processes that may support beneficial pathological outcomes. SynapTau is a highly significant project as it aims to discover new therapeutic targets to maintain synaptic integrity and function to slow down AD neurodegeneration and cognitive decline.
Champ scientifique
Mots‑clés
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régime de financement
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinateur
13284 Marseille
France