MicroRNA-153-3p targets repressor element 1-silencing transcription factor (REST) and neuronal differentiation: Implications for Alzheimer's disease.

INTRODUCTION: Small non-coding microRNAs (miRNAs) play essential roles in Alzheimer's disease (AD) pathogenesis. Repressor element 1-silencing transcription factor (REST) is involved in AD, though its regulation remains unclear. METHODS: We performed real-time quantitative polymerase chain reaction (qPCR) in autopsied brain tissues to determine miR-153-3p and AD associations. A reporter-based assay measured the activity of REST mRNA 3'-untranslated region (3'-UTR). Induced pluripotent stem cells (iPSC)-derived neurons and human cell lines were applied to determine miR-153-3p regulation of endogenous proteins. RESULTS: Elevation of miR-153-3p is associated with a reduced probability of AD, while elevated REST is associated with a greater probability of AD. The 3'-UTR functional assay pinpointed the miR-153-3p binding sites. miR-153-3p treatment reduced REST, amyloid precursor protein (APP), and α-synuclein (SNCA) 3'-UTR activities and protein levels. miR-153-3p treatment altered REST and neuronal differentiation in iPSC-derived neuronal stem cells. RNA-sequencing and proteomics revealed miR-153-3p-associated networks. DISCUSSION: miR-153-3p reduces REST, APP, and SNCA expression, pointing toward its therapeutic and biomarker potential in neurodegenerative diseases. HIGHLIGHTS: With the increased emphasis on comorbidities of Alzheimer's disease (AD) and other neurodegenerative diseases, we identified that miR-153-3p, as a master regulator, reduced a group of neurodegeneration related proteins: REST, amyloid precursor protein (APP) and α-synuclein (SNCA) levels. The elevation of miR-153-3p levels is associated with reduced probability of AD in posterior cingulate cortex (PCC), while REST, by contrast, is associated with a greater probability of AD. miR-153-3p treatment alters REST protein levels and neuronal differentiation in induced pluripotent stem cells (iPSC) derived neuronal cells. RNA sequencing proteomics and interactome analysis revealed the role of miR-153-3p in axonal guidance.