Abstract
Alzheimer's disease (AD) affects more than 55 million people worldwide, yet current theories cannot fully explain its aetiology. Accordingly, gene expression profiling has been used to provide a holistic view of the biology underpinning AD. Focusing primarily on protein-coding genes, such approaches have highlighted a critical involvement of microglia-related inflammatory processes. Simultaneous investigation of transcriptional regulators and noncoding RNA (ncRNA) can offer further insight into AD biology and inform the development of disease-modifying therapies. We previously described a method for whole transcriptome sampling to simultaneously investigate protein-coding genes and ncRNA. Here, we use this technique to explore transcriptional changes in a murine model of AD (15-month-old APP/PS1 mice). We confirmed the extensive involvement of microglia-associated genes and gene networks, consistent with literature. We also report a wealth of differentially-expressed non-coding RNA - including microRNA, long non-coding RNA, small nuclear and small nucleolar RNA, and pseudogenes - many of which have been overlooked previously. Transcription factor analysis determined that six transcription factors likely regulate gene expression changes in this model (Irf8, Junb, c-Fos, Lmo2, Runx1, and Nfe2l2). We then utilised validated miRNA-target interactions, finding 60 interactions between 15 miRNA and 42 mRNA (messenger RNA) with largely consistent directionality. Furthermore, we found that eight transcription factors (Clock, Lmo2, Runx1, Nfe2l2, Egr2, c-Fos, Junb, and Nr4a1) are likely responsible for the regulation of miRNA expression. Taken together, these data indicate a complex interplay of coding and non-coding RNA, driven by a small number of specific transcription factors, contributing to transcriptional changes in 15-month-old APP/PS1 mice.