MiRNA Alterations Elicit Pathways Involved in Memory Decline and Synaptic Function in the Hippocampus of Aged Tg4-42 Mice

The transcriptome of non-coding RNA (ncRNA) species is increasingly focussed in Alzheimer's disease (AD) research. NcRNAs comprise, among others, transfer RNAs, long non-coding RNAs and microRNAs (miRNAs), each with their own specific biological function. We used smallRNASeq to assess miRNA expression in the hippocampus of young and aged Tg4-42 mice, a model system for sporadic AD, as well as age-matched wildtype controls. Tg4-42 mice express N-truncated Aß4-42, develop age-related neuron loss, loss in neurogenesis and behavioral deficits. Our results do not only confirm known miRNA-AD associations in Tg4-42 mice, but more importantly pinpoint 22 additional miRNAs associated to the disease. Twenty-five miRNAs were differentially expressed in both aged Tg4-42 and aged wildtype mice while eight miRNAs were differentially expressed only in aged wildtype mice, and 33 only in aged Tg4-42 mice. No significant alteration in the miRNome was detected in young mice, which indicates that the changes observed in aged mice are down-stream effects of Aß-induced pathology in the Tg4-42 mouse model for AD. Targets of those miRNAs were predicted using miRWalk. For miRNAs that were differentially expressed only in the Tg4-42 model, 128 targets could be identified, whereas 18 genes were targeted by miRNAs only differentially expressed in wildtype mice and 85 genes were targeted by miRNAs differentially expressed in both mouse models. Genes targeted by differentially expressed miRNAs in the Tg4-42 model were enriched for negative regulation of long-term synaptic potentiation, learning or memory, regulation of trans-synaptic signaling and modulation of chemical synaptic transmission obtained. This untargeted miRNA sequencing approach supports previous reports on the Tg4-42 mice as a valuable model for AD. Furthermore, it revealed novel miRNAs putatively involved in AD, which will be further investigated as biomarkers or even therapeutic targets.