Abstract:
One of the major challenges in cancer and Alzheimer’s disease (AD) is identification of early, non-invasive biomarkers and elucidation of their functions. Circulating microRNAs (miRNAs) have been extensively studied as potential biomarkers for cancer and AD. Their profiles have been analyzed in AD blood, cerebrospinal fluid (CSF) and brain tissue. However, due to the high variability between the reported data, stemming from the lack of methodological standardization and the heterogeneity of AD, the most promising miRNA biomarker candidates have not been selected. Our review of recent decade literature shows that out of 137 miRNAs found to be altered in AD blood, 36 have been replicated in at least one independent study, and out of 166 miRNAs reported as differential in AD CSF, 13 have been repeatedly found. Only 3 miRNAs have been consistently reported as altered in three analyzed specimens: blood, CSF and the brain (hsa-miR-146a, hsa-miR-125b, hsa-miR-135a). Nonetheless, all 36 repeatedly differential miRNAs in AD blood are promising as components of the AD diagnostic panel. In addition, the analysis revealed that the miRNAs dysregulated in AD overlap highly with miRNAs implicated in cancer. However, the directions of the miRNA changes are usually opposite in cancer and AD, indicative of an epigenetic trade-off between the two diseases. Using bioinformatic tools (TargetScan, MirTarBbase and KEGG) we identified putative mRNA targets of the selected differential miRNAs in AD blood, including proteins involved in amyloidogenic proteolysis as well as in cancerogenesis. We confirmed (luciferase assay, quantitative RT-PCR and immunoblotting) that hsa-miR-200a-3p, one of the mostly upregulated miRNAs in AD blood, regulates BACE1 mRNA and protein, and also significantly affects proliferation. These data indicate that such miRNA panel may report multiple pathways contributing to AD as well as cancer pathology and therefore they can be used for the design of personalized therapies.
