Activation of innate immunity by host-derived factors may exacerbate central nervous system (CNS) damage, but the identity of such factors and the cellular mechanisms involved remain elusive. MicroRNAs (miRNAs) are small non-coding RNAs abundantly expressed in the brain that exhibit gene regulatory functions. The expression pattern of miRNAs is characteristically altered in CNS diseases including neurodegenerative disorders. There is increasing evidence that miRNAs mediate functions beyond gene regulation, since they circulate in blood and cerebrospinal fluid and are transferred from cell to cell. Based on our recent findings, we hypothesize that extracellularly delivered miRNAs bind to innate immune receptors such as Toll-like receptors (TLRs), thereby activating microglia and macrophages. In this context, we propose a novel mechanism of action for miRNAs as signaling molecules in neurodegenerative diseases. The project’s aim is to identify miRNAs as ligands of TLRs expressed in the brain’s immune cells and to determine their function in CNS inflammation and neurodegenerative processes. Identification of such miRNAs and their role in immune activation of the CNS may open the way to the development of new diagnostic and therapeutic strategies for CNS diseases.