MicroRNAs (miRNAs) are small non-coding, single-stranded RNAs (ssRNAs) that are abundantly expressed in the brain. Their expression pattern is characteristically altered in central nervous system (CNS) disorders including neurodegenerative diseases. Evidence is accumulating that miRNAs mediate functions beyond their established gene regulatory function, as they circulate in blood and cerebrospinal fluid, and are transferred from cell to cell. In line with this, we recently identified miRNAs that are differentially released from injured neurons and act as signaling molecules for Toll-like receptors (TLRs) in microglia, thereby regulating the inflammatory response in the CNS. Our data indicate that distinct miRNAs directly bind to TLRs located in microglial endosomes. Based on these findings we will set out to decipher in detail the cellular and molecular mechanisms of microglial activation and neurodegeneration triggered by miRNAs. The ability of miRNAs acting as signaling molecules to regulate diverse microglial functions in a sequencespecific fashion will be assessed. As part of this, sequence and structural aspects of the interaction between select miRNAs and TLRs will be determined. Further, we will investigate the hypothesis that miRNAs released from microglia affect neighboring microglia and neurons in a paracrine fashion. Using co-culture systems and an Alzheimer’s disease mouse model, we will explore whether miRNAs acting as signaling molecules modulate neurodegenerative processes dependent on their sequence. Finally, the potential of distinct miRNAs to serve as biomarkers for neurodegenerative diseases will be evaluated.