EMIRAD

Impact of neuronal exosomes-delivered microRNA and proteins on the pathogenesis of Alzheimer's disease

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

Alzheimer's disease (AD) is a leading cause of dementia. While early-onset AD is caused by genetic mutations, the causes of sporadic late-onset AD are still unknown.

Descrizione progetto (Article)

AD is a neurodegenerative disorder, characterised by synapse loss, extracellular amyloid plaque composed of amyloid-? peptide (A?) and intracellular aggregates of hyper-phosphorylated Tau protein. Understanding the molecular mechanisms leading to AD will offer the possibility to identify novel therapeutic targets for its treatment.

Increasing evidence points at the importance of expression deregulation of microRNAs (miRNAs) in the development of neurodegenerative diseases. The EU-funded project EMIRAD was dedicated to examining the role of miRNAs in AD.

Scientists investigated whether deregulation of miRNAs expression can be used to diagnose AD. They profiled miRNAs isolated from samples of cerebrospinal fluid (CSF) of AD patients and age-matched healthy control subjects. They found that the levels of one of the miRNAs (miR-27a-3p) were significantly reduced in the CSF of AD patients. Researchers also confirmed that mRNAs encoding for AD-relevant proteins are indeed targets of this miRNA. Interestingly, the expression levels of miRNA in CSF drawn before and after death were not correlated. That means that CSF from living patients should be studied for biomarker discovery.

Next, the team addressed deregulation of miRNAs in the AD brain. Nanostring molecular counting, deep-sequencing and quantitative PCR allowed profiling of miRNAs in the prefrontal cortex and hippocampus of AD patients and healthy control subjects. A different miRNA (miR-132-3p) was consistently down-regulated in the AD brain. In situ hybridisation and immunostaining methods showed that neurons with lower expression of miR-132-3p also had higher levels of phosphorylated Tau, an AD-relevant protein.

EMIRAD increased understanding of the roles of miRNAs in AD pathology. Measuring the expression levels of miR-27a-3p in CSF can be helpful for AD diagnosis and monitoring. Down regulation of miR-132-3p in AD contributes to AD pathology. The results are described in two peer-reviewed scientific publications, Neurology and EMBO Molecular Medicine.