Oxidative stress (OS) is one of the major pathomechanisms of
Alzheimer's disease (AD), which is closely associated with other key events in neurodegeneration such as
mitochondrial dysfunction,
inflammation,
metal dysregulation, and
protein misfolding. Oxidized RNAs are identified in brains of AD patients at the
prodromal stage. Indeed, oxidized
mRNA, rRNA, and
tRNA lead to retarded or aberrant
protein synthesis. OS interferes with not only these translational machineries but also regulatory mechanisms of noncoding RNAs, especially
microRNAs (
miRNAs).
MiRNAs can be oxidized, which causes misrecognizing target mRNAs. Moreover, OS affects the expression of multiple
miRNAs, and conversely,
miRNAs regulate many genes involved in the OS response. Intriguingly, several
miRNAs embedded in upstream regulators or downstream targets of OS are involved also in neurodegenerative pathways in AD. Specifically, seven upregulated
miRNAs (miR-125b, miR-146a, miR-200c, miR-26b, miR-30e, miR-34a, miR-34c) and three downregulated
miRNAs (miR-107, miR-210, miR-485), all of which are associated with OS, are found in vulnerable brain regions of AD at the
prodromal stage. Growing evidence suggests that altered
miRNAs may serve as targets for developing diagnostic or therapeutic tools for early-stage AD. Focusing on a neuroprotective transcriptional repressor, REST, and the concept of hormesis that are relevant to the OS response may provide clues to help us understand the role of the
miRNA system in cellular and organismal adaptive mechanisms to OS.