EMIRAD
'Exosomes are small vesicles which mediate cell-cell communication by transporting across the extracellular environment specific “packages” of RNA and proteins. Importantly, exosomes carry translation initiation factors (TIFs) and miRNAs, a class of short non-coding RNAs with regulatory activity on the expression of the transcriptome of a cell. In the brain, exosome-delivered miRNAs and proteins are thought to be involved in the coordinated modulation of gene expression required for the long-term modulation of synaptic connections in a neuronal circuit. A deregulation of this exosome-mediated mechanism would then result in the synaptic dysfunction and loss of connectivity typical of Alzheimer’s disease (AD). Indeed, aggregates of amyloid-β (Aβ) and of microtubule associated protein Tau disrupt synaptic activity in the brain of AD patients and lead to neurodegeneration by yet unknown mechanisms; moreover, the presence of Aβ and Tau deposits spreads along interconnected brain regions and correlates with disease progression. Using in vitro rodent primary neuron cultures as a model, we propose to characterize the cellular functions of exosome-delivered miRNAs and TIFs, to investigate the impact of Aβ and Tau aggregates on the exosome-mediated communication between neurons and to elucidate the role of exosomes in the spreading of intracellular Aβ and Tau aggregates between neurons. The relevance of a deregulation of exosomes in AD will also be studied in exosomes isolated from the cerebrospinal fluid of AD patients. The identification of AD-specific alterations in exosomes derived from AD patients compared to those isolated from elderly controls will highlight excellent AD biomarker candidates. Moreover, elucidation of the molecular mechanisms mediated by exosomes that are altered by AD-relevant protein aggregates will offer the possibility to identify novel therapeutical targets to treat this disease.'
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