Expression of Tirna and Trf in APP/PS1 Transgenic Mice and the Change of Related Proteins Expression.

Background: Transcriptomics, such as that of non-coding RNA (ncRNA), which include microRNA (miRNA), circular RNA, and the transfer RNA (tRNA)-derived fragments (tiRNA and tRF) in Alzheimer's disease (AD) have attracted much attention recently. The tiRNA and tRFs are produced when the tRNA splits at specific sites. The expression change and related function of tiRNA and tRFs in AD has not been fully investigated. Methods: In our study, APP/PS1 transgenic mice (AD mice model) and healthy control mice were used to discover the differentially expressed tiRNA and tRFs with high-throughput sequencing. Among the differentially expressed tiRNA and tRFs, we chose two tRFs (tRF-Thr-CGT-003 and tRF-Leu-CAA-004) and predicted the target messenger RNAs (mRNAs) with miRanda and Target Scan. The target mRNAs of tRF-related function and pathways were analyzed, then we performed quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blot to validate the related target mRNAs and pathways. Results: A total of 27 significantly different tiRNA and tRFs were detected between wild type (WT) and APP/PS1 groups, including 14 up-regulated and 13 down-regulated. Through analyzing the target mRNAs of all differentially expressed tiRNA and tRFs with GO enrichment, we found the target mRNAs could take part in the learning and memory biological process, synapse organization, cognition biological process, synaptic transmission, amyloid-beta (A beta) metabolic process, and so on. We then chose three differentially expressed tRFs for further qPCR validation and passed two tRFs: tRF-Thr-CGT-003 and tRF-Leu-CAA-004, that were found to regulate the calcium regulation-related proteins (the voltage-gated calcium channel gamma 2 subunit and the RYR1 endoplasmic reticulum calcium released protein) and the retinol metabolism-related proteins (retinoic acid metabolic enzymes CYP2S1, CYP2C68, CYP2S1). Conclusions: The APP expression and presenilin mutation in APP/PS1 mice could cause tiRNA and tRFs expression change. Among the differentially expressed tiRNA and tRFs, we found some tRFs took part in the voltage-gated calcium channel gamma 2 subunit expression and regulation, influencing the neuron calcium homeostasis. Moreover, we also found the tRFs may participate in the regulation of retinol metabolism. Our findings suggest that the dysregulated tiRNA and tRFs may be beneficially exploited as potential diagnostic biomarkers and/or therapeutic targets of AD.