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

Project description

Extracellular vesicles in Alzheimer’s disease: pathogenesis or neuroprotection?

Most cells secrete extracellular vesicles (EVs) that contain various biomolecules including RNA and proteins. Emerging evidence indicates that EVs may have a dual role in Alzheimer’s disease (AD) contributing to both disease pathogenesis through spreading of protein aggregates and neuroprotection. The EU-funded EXOSOMES_AD project will characterise the composition of EVs from AD patients and identify protein and gene candidates related to neuroprotection. Insight into the mechanisms of neuroprotection in AD may lead to novel interventions that can delay or even prevent disease onset. Given that AD is the most prevalent age-related neurodegenerative condition, such a prospect will improve the quality of life of millions of people worldwide.

Objective

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.

Coordinator

UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF
Net EU contribution
€ 244 209,60
Address
Martinistrasse 52
20251 Hamburg
Germany

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Region
Hamburg Hamburg Hamburg
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 244 209,60