THE ROLE OF MICRORNAS (MIRNAs) IN THE REGULATION OF TAU PATHOLOGY

Abstract

Tauopathies are a class of sporadic neurodegenerative disorders including Alzheimer’s disease (AD), Pick’s disease, Corticobasal degeneration and Progressive supranuclear palsy, characterized by hyperphosphorylation and aggregation of the microtubule-associated protein tau in the brain parenchyma. Currently, there are no effective therapies for the treatment of tauopathies and the understanding of its pathogenesis is still incomplete. Despite in recent years, miRNAs dysregulation has been constantly reported in Alzheimer’s disease (AD) and related tauopathies, the fundamental challenge of the current research is to understand whether these miRNA changes contribute to the onset and progression of these disorders or instead occur as a secondary event to tau pathology. Due to the ability of miRNAs to modulate disease-related gene networks, we hypothesized that dysregulation of these small molecules promotes abnormal tau phosphorylation and aggregation and that the restoration of their normal level of expression represents a valuable therapeutic approach for the treatment of these disorders. To test our hypothesis, we investigated the temporal and regional specific miRNAs expression profile and its association with the onset and/or progression of tau pathology in the mouse model that currently, best recapitulates the human condition. In addition, we explored the pathophysiological mechanisms regulated by the screened miRNAs in vitro and the feasibility of using miRNAs as therapeutic targets for the treatment of tauopathies. Compared with age-matched control, we found three specific miRNAs (miR-132-3p, miIR-146a-5p, miR-22-3p) significantly upregulated already in the pre-symptomatic stage in the hTau mice, and the investigation of their predicted targets highlighted pathways relevant to neuronal survival and synaptic function. In vitro mechanistic studies demonstrated that, miR-22-3p promotes increased levels of total soluble, MC1-conformational change and insoluble tau via dysregulation of the cell cycle and inhibition of the autophagy pathway. Moreover, for the first time we report miR-22-3p upregulation also in the cortex of Pick’s patients. Finally, we demonstrated that downregulation of endogenous miR-22-3p rescued tau phosphorylation and conformational change in the hTau mouse model of tauopathy. In conclusion, this study provides new clues ino the relationship between miRNAs dysregulation and tau protein and highlights the potentially beneficial effect of targeting miRNA molecules for the treatment of tauopathies.