Journal of Aging Science

Abstract

Target Genes of Circulating miR-34c as Plasma Protein Biomarkers of Alzheimer’s Disease and Mild Cognitive Impairment

Arin L Zirnheld, Erik L Regalado, Vikranth Shetty, Howard Chertkow, Hyman M Schipper and Eugenia Wang

MicroRNAs repress post-transcriptional expression of a variety of genes, several of which are involved in neurological development and Alzheimer’s disease (AD) pathology. In previous studies, we have shown that plasma miR-34c and miR-34a levels are increased in probable AD patients. In this study, we show that four key gene products silenced by these miRNAs, Onecut homoebox 2 (ONECUT2), B-cell lymphoma (BCL2), sirtuin 1 (SIRT1), and presenilin 1 (PSEN1), are all decreased in abundance in plasma specimens from mild cognitive impairment (MCI) and probable AD individuals. Additionally, there is a statistically significant inverse correlation between levels of miR-34c and expression of all four proteins, and between miR-34a and ONECUT2 expression. In particular, our results suggest that ONECUT2 plasma levels may act as a novel biomarker for early stages of cognitive decline. Additionally, we find statistically significant differences in expression levels of the other three targets, BCL2, SIRT1, and PSEN1, in circulating plasma, and levels of these proteins effectively distinguish among all three groups: normal elderly controls (NEC), MCI, and probable AD. Therefore, the inverse relationship between miR-34c and miR-34a and their targets may initially be detected by early decline in ONECUT2 expression, upon entry to the MCI stage, followed by decreased BCL2, SIRT1 and PSEN1 expression as patient’s transition to full-blown AD dementia.