THE ROLE OF MIR-15/107 FAMILY IN p35/CDK5 REGULATION IN ALZHEIMER'S DISEASE

Alzheimer’s disease (AD) is characterized by the presence of β-amyloid plaques and neurofibrillary tangles of hyperphosphorylated Tau. CDK5 kinase has a key role in abnormal phosphorylation of Tau and β-Amyloid Precursor Protein (APP). CDK5 is activated by p35, encoded by CDK5R1, whose 3’-UTR remarkable size and conservation are strongly indicative of an important function in post-transcriptional regulation. Two miRNAs, miR-103 and miR-107, were recently found to regulate CDK5R1 expression and affect the levels of p35. Since miR-103 and miR-107 belong to the same family of miRNAs, miR-15/107, we hypothesized that other representative members of the family were involved in the regulation of CDK5R1 expression. In this study, we demonstrated that several members of miR-15/107 family regulate p35 levels. We also observed that miR-15/107 miRNAs modulate the expression of BACE1, another key protein involved in AD. Furthermore, we showed that miR-15/107 miRNAs can influence CDK5 activity on APP. qRT-PCR analysis on post-mortem brain tissue samples revealed a significant reduction of miR-15/107 expression in temporal cortex and hippocampus, but not in cerebellum, of AD patients. Also, an increase of CDK5R1 mRNA levels was evidenced in AD hippocampus AD samples. These data suggest that increased levels of CDK5R1/p35 and consequent enhanced CDK5 activity caused by downregulation of the miR-15/107 family might have a role in AD pathogenesis CDK5R1 3’-UTR was also reported to bind nELAV and hnRNPA2/B1 RNA-binding proteins (RBPs). In order to asses whether nELAVs and hnRNPA2/B1 binding to CDK5R1 3’-UTR can influence CDK5R1 transcript stability, we performed mRNA degradation kinetics assays. These experiments showed that the two RBPs oppositely control CDK5R1 mRNA stability: nELAVs display a stabilizing effect while hnRNPA2/B1 shows a negative action. Altogether, these data highlight the complexity of CDK5R1 post-transcriptional regulation and its possible involvement in AD pathogenesis.