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The role of extracellular vesicles in Alzheimer’s Disease: towards obtaining mechanistic insights to intrinsic protection mechanisms

Description du projet

Des vésicules extracellulaires dans la maladie d’Alzheimer: pathogenèse ou neuroprotection?

La plupart des cellules sécrètent des vésicules extracellulaires (VE) qui contiennent différentes biomolécules, dont de l’ARN et des protéines. De nouvelles données indiquent que les VE pourraient avoir un rôle double dans la maladie d’Alzheimer (MA) en contribuant à la pathogenèse de la maladie via la propagation des agrégats de protéines et à la neuroprotection. Le projet EXOSOMES_AD, financé par l’UE, caractérisera la composition des VE chez des patients atteints de MA et identifiera les protéines et les gènes candidats liés à la neuroprotection. Des informations sur les mécanismes de neuroprotection dans la MA pourraient mener à de nouvelles interventions susceptibles de retarder voire de prévenir l’apparition de la maladie. Étant donné que la MA est la maladie neurodégénerative liée à l’âge la plus répandue, une telle perspective améliorera la qualité de vie de millions de personnes dans le monde.

Objectif

Alzheimer’s disease (AD) is the leading cause of dementia worldwide (>30 million people). The cause of the disease is not known, and there is no causal treatment. Extracellular vesicles (EVs), including exosomes and microvesicles, are structures released by most if not all cells. EVs carry competent signalling proteins, lipids and nucleic acids, participating in cell-to-cell communication. Recently, EVs emerged as relevant actors in neurodegenerative diseases, especially in AD, and they were described as biomarkers in patient’s fluids. Interestingly, they seem to have a dual role in AD: spreading of pathological aggregates, and neuroprotection against the progression of the pathology. In this project, I will describe in detail the EVs biology in AD elucidating how they act neuroprotective. I will characterise the composition, source and uptake mechanisms of EVs throughout AD progression. I will extract EVs from brains of AD patients (sporadic and familial) and age/sex-matched controls in two stages of the disease. RNA and protein profile will be characterised by novel RNA sequencing and mass spectrometry technics. From these omics analysis, protein and gene candidates related to the EVs functions in AD will emerge. Moreover, to investigate putative mechanisms of neuroprotection in AD, I will treat neural cultures from hiPSCs with AD-derived EVs and stress them with AD-like inputs. The effects of these treatments will be assessed by advanced analysis (i.e. Ca2+ imaging, and mitochondrial trafficking analysis). The endocytic pathways and surface proteins involved in EVs’ uptake will also be evaluated. Finally, AD-iPSC cultures will be used to functionally modify the targets obtained from the omics analysis to foster their neuroprotective role in AD.
My project will generate mechanistic insight in EVs’ neuroprotection in AD by combing the deep phenotyping of patient-derived EVs with hypothesis-driven experiments in hiPSC to open the door to new EV-based AD treatment.

Champ scientifique

CORDIS classe les projets avec EuroSciVoc, une taxonomie multilingue des domaines scientifiques, grâce à un processus semi-automatique basé sur des techniques TLN.

Coordinateur

UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF
Contribution nette de l'UE
€ 244 209,60
Adresse
Martinistrasse 52
20251 Hamburg
Allemagne

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Région
Hamburg Hamburg Hamburg
Type d’activité
Higher or Secondary Education Establishments
Liens
Coût total
€ 244 209,60