Systematic evaluation of the therapeutic potential of microRNA-132 in Alzheimer's disease.

Abstract

microRNA profiles in the brain of Alzheimer's disease (AD) patients are altered with disease progression, suggesting that microRNAs may contribute to AD pathology. Of particular interest is microRNA-132 (miR-132), which is consistently and robustly downregulated in AD patient brain and has been shown to be involved in pivotal processes in the central nervous system that are also affected in AD, such as amyloid plaque deposition, TAU phosphorylation, inflammation, synaptic plasticity and memory formation. Restoring miR-132 levels could therefore be a potential strategy to combat or modulate AD pathology at the molecular and functional level. In order to fully assess the therapeutic potential of this microRNA, the miR-132-regulated targets and underlying pathways that play a role in disease progression need to be systematically characterized. Taken the cellular complexity of brain tissue and its impact on AD pathology, single-cell genome-wide approaches are required to dissect the cell-specific regulatory repertoire of miR-132. Intracerebroventricular infusions of miR-132 synthetic mimics or antisense oligonucleotides were employed in order to elevate or knock down miR-132 levels in the mouse brain. Hippocampal tissue was subsequently processed and subjected to complementary unbiased proteomics analysis (MaxLFQ) and single-cell RNA sequencing (10X Genomics) to identify miR-132 targets. Following differential expression, pathway enrichment approaches and integrative analysis of the resulting datasets, previously validated and new potential miR-132 targets were identified and are currently further validated. Overall, our data suggest that miR-132 may be a potent regulator of previously reported and novel molecular pathways with multilayered implications in AD pathology.