About 70% of the human genome is transcribed into non-coding RNAs (ncRNAs) that play essential roles in regulating gene expression. These ncRNAs constitute a large yet underexplored pool of therapeutic targets for various diseases. We focus on miR-132, a key microRNA (miRNA) downregulated in Alzheimer’s disease (AD), whose replacement may provide a new therapeutic strategy for AD and other tauopathies. However, current strategies to upregulate miRNAs through miRNA mimics or gene delivery are limited by poor distribution and high immunogenicity, therefore necessitating further innovation. Small molecule compounds likely offer better pharmacodynamics, pharmacokinetics, and safety profile. Consequently, we developed a high-throughput screen of small molecule compounds that modulated miRNAs, including miR-132. From screening 2000 compounds in human-induced neurons, several top hits that upregulated miR-132 were identified and validated, including digoxin – which is in clinical use for heart failure. We are testing whether these compounds are neuroprotective in cellular and animal models of neurodegeneration. In the long run, we aim to establish a pipeline for identifying ncRNA-modulating compounds to treat various diseases.