Evidence for a neuroprotective microRNA pathway in amnestic mild cognitive impairment

MicroRNAs (miRNAs) that regulate mRNA stability have been linked to amyloid production, tau phosphorylation, and inflammation in Alzheimer's disease (AD). However, whether cerebral miRNA networks are dysregulated during the earliest stages of AD remains underexplored. We performed miRNA expression analysis using frontal cortex tissue harvested from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI, a putative prodromal AD stage), or mild AD. Analysis revealed that the miRNA clusters miR-212/132 and miR-23a/23b were down-regulated in the frontal cortex of aMCI subjects. Both miR-212/132 and miR23a/b are predicted to destabilize the message for sirtuin 1 (sirt1); hence, down-regulation of either miR-212/132 or miR-23a/b in frontal cortex should promote sirt1 mRNA expression in this region. qPCR studies revealed that frontal cortex levels of sirt1 were increased in aMCI. Given the ability of frontal cortex to respond to the onset of dementia by neuronal reorganization, these data suggest that miRNA-mediated up-regulation of the sirt1 pathway represents a compensatory response to the onset of the disease. By contrast, qPCR analysis of inferior temporal cortex, an area affected early in the progression of AD, showed no changes in miR-212/132, miR-23a/b, or sirt1 transcripts in the same aMCI subjects. In vitro mechanistic studies showed that coordinated down-regulation of miR-212 and miR-23a increased sirt1 protein expression and provided neuroprotection from β-amyloid toxicity in human neuronal cells. Taken together, these data suggest a novel miRNA-mediated neuroprotective pathway activated during the progression of AD that may be amenable to therapeutic manipulation.