Analysis of miRNA expression in Alzheimer's disease : potential use as early biomarkers

    Student thesis: Doctoral thesis


    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by early loss of synapses followed by progressive neurodegeneration and memory deficits, eventually leading to dementia. To date, AD can only be clinically diagnosed in its later stages, when neurodegeneration has already spread to several brain areas, making it difficult for potential therapies to prevent its progression. Recent evidence has shown that levels of specific microRNAs (miRNAs) are altered during AD pathology, suggesting that some of these small non coding RNAs could be involved in the development of the disease. However, at the beginning of this doctoral project, the role of miRNAs during AD pathology was largely unexplored. Interestingly, several miRNAs have been detected in dendrites, where they regulate expression of synaptic proteins, suggesting that miRNAs can play a role during AD-associated synaptic dysfunction. On the other hand, miRNAs can be detected in circulating biological fluids, raising the possibility of using them as biomarkers for diagnosis of incipient AD. Therefore, since it is believed that alterations in synaptic function are related to mild cognitive impairment (MCI), it is feasible to assume that plasma levels of specific plasticity-related microRNAs could predict AD progression. Thus, the hypothesis of this doctoral thesis is that alterations of synaptic plasticity-related miRNAs are associated to AD pathology, and their detection in circulating fluids could represent a promising strategy for early diagnosis of AD. To test this hypothesis I evaluated the levels of candidate miRNAs related to synaptic proteins in human brain at different stages of AD pathology, and in experimental models including a transgenic mice model and an in vitro approach. Furthermore, I examined the levels of specific miRNAs related to synaptic proteins in plasma samples obtained from controls, MCI and AD patients. An upregulation of miR-92a-3p, miR-181c-5p and miR-210-5p was observed in hippocampal neurons after exposure to oAβ, consistent with an increase in human brain in different brain areas during AD development. Although no changes were observed in the experimental animal model, the three miRNAs were upregulated in plasma samples from MCI and AD subjects. Importantly, the receiver operating characteristic curve analysis indicates that when the three miRNAs are combined, the diagnostic accuracy for MCI and AD improves compared to each miRNA alone. Considering the urgent need of finding reliable biomarkers that could detect AD at early (preclinical) stages, we suggest the potential use of this molecular signature for early diagnosis of AD.
    Date of Award16 Nov 2018
    Original languageEnglish
    SupervisorJose Rodriguez Alvarez (Director) & Alfredo Jesús Miñano Molina (Director)

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