A cell-type-resolved directory of human brain reveals microRNAs and tRNA fragments associated with aging and Alzheimer’s disease

Background MicroRNAs (miRs) play a role in the regulation of diverse brain processes ranging from neurogenesis to neurological disease. While miRs have been implicated in cell-type-specific regulation, most studies have been based on whole tissue bulk analysis, due to technical limitations of single-cell small RNA sequencing. Consequently, the cell-type specificity of brain miRs remains poorly characterized, limiting our ability to understand their roles. Results To generate a comprehensive, cell-type-resolved atlas of miRs in the human brain, we isolated neurons, astrocytes, microglia, and oligodendrocytes from fresh neurosurgery-derived brain samples and profiled their small RNA repertoires by RNA sequencing. The results reveal pronounced cell-type-specific differences in miR expression, identify novel cell-type-specific miR markers, and shed light on the contribution of genomic locus to cell-type specificity. We also characterized the cell-type-specific patterns of strand preference and isomiR processing. In addition, we explored cell-type-dependent profiles of another small non-coding RNA class, tRNA-derived fragments, identifying an enrichment of 5′-tRNA halves in neurons as compared to glia. Finally, the atlas resource enabled the identification of miR programs associated with brain aging, and the resolution of their cell-type origin. Conclusions We have shown that human brain miRs exhibit pronounced cell-type-specific differences in expression levels, accompanied by more modest differences in strand preference and isomiR abundance. In addition, our atlas, combined with its accompanying statistical tool, provide a publicly available resource for miR cell-type enrichment analysis and resolution of the cell-type origin of miRs in the human brain.