Upregulates CDC42 Expression and Promotes Hippocampal Neuron Dendritic Spine Formation by Competing with miR-330-5p.

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease. Recent studies employing microRNA-seq and genome-wide sequencing have identified some non-coding RNAs that are influentially involved in AD pathogenesis. Non-coding RNAs can compete with other endogenous RNAs by microRNA response elements (MREs) and manipulate biological processes, such as tumorigenesis. However, only a few non-coding RNAs have been reported in the pathogenesis of AD. In this study, we constructed the first competing endogenous RNA (ceRNA) network leveraging whole transcriptome sequencing and a previously studied microRNA-seq of APPswe/PS1ΔE9 transgenic mice. The underlying mechanisms for the involvement of ceRNA in AD were validated using the Dual Luciferase Reporter Assay, detection of transcription levels by quantitative RT-PCR and translation levels by Western blotting, and morphological examination in primary cultured neurons. In the ceRNA network, four lncRNAs (C030034L19Rik, , A830012C17Rik, and Gm15477) and five miRNAs (miR-182-5p, miR-330-5p, miR-326-3p, miR-132-3p, and miR-484) are enriched in nine pathways and an AD-related gene pool. Among them, Ribonuclease P RNA component H1 () is upregulated in the cortex of APPswe/PS1ΔE9 mice compared to wild type controls. binds to miR326-3p/miR-330-5p and causes the release of their downstream target , which leads to CDC42 upregulation. This effect was disrupted upon mutation of the MRE on . Moreover, overexpression of increased dendritic spine density in primary cultured hippocampal pyramidal neurons, whereas knocking down of had the reverse effect. In conclusion, modulates CDC42 expression level in a ceRNA-dependent manner, which may represent a compensatory mechanism in the early stage of the AD pathogenesis.