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

Yvonne Bouter,Lars R Jensen,Thomas A Bayer,Tim Kacprowski,Andreas W Kuss,Fanny Rößler

doi:10.3389/fnins.2020.580524

Abstract

The transcriptome of non-coding RNA (ncRNA) species is increasingly focused in Alzheimer’s disease (AD) research. NcRNAs comprise, among others, transfer RNAs, long non-coding RNAs and microRNAs (miRs), each with their own specific biological function. We used smallRNASeq to assess miR expression in the hippocampus of young (3 month old) and aged (8 month old) Tg4-42 mice, a model system for sporadic AD, as well as age-matched wildtype controls. Tg4-42 mice express N-truncated Aβ4–42, develop age-related neuron loss, reduced neurogenesis and behavioral deficits. Our results do not only confirm known miR-AD associations in Tg4-42 mice, but more importantly pinpoint 22 additional miRs associated to the disease. Twenty-five miRs were differentially expressed in both aged Tg4-42 and aged wildtype mice while eight miRs 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 Aβ-induced pathology in the Tg4-42 mouse model for AD. Targets of those miRs were predicted using miRWalk. For miRs that were differentially expressed only in the Tg4-42 model, 128 targets could be identified, whereas 18 genes were targeted by miRs only differentially expressed in wildtype mice and 85 genes were targeted by miRs differentially expressed in both mouse models. Genes targeted by differentially expressed miRs 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 miR sequencing approach supports previous reports on the Tg4-42 mice as a valuable model for AD. Furthermore, it revealed miRs involved in AD, which can serve as biomarkers or therapeutic targets.

Highlights

MiRs are short non-coding RNAs that are heavily involved in post-transcriptional regulation of gene expression through targeting specific mRNAs (Bartel, 2004)
There was a significant change in expression of 58 miRs observed between young and aged Tg4-42, as well as between young and aged WT mice (Figure 1C)
Of 33 differentially expressed miRs exclusively found in aged Tg4-42 mice, some were reported to be association with Alzheimer’s disease (AD)

Summary

Introduction

MiRs are short non-coding RNAs that are heavily involved in post-transcriptional regulation of gene expression through targeting specific mRNAs (Bartel, 2004). The miR transcriptome (miRNome) includes all miR species and renders a profile of gene regulation at the studied time point and location. Altered miR expression profiles provide information about the miRs themselves, and about their target genes and, the regulated processes. As miRs have already been implicated in neurodevelopment and brain aging, as well as in synapse function and cognitive performance, in both, health and disease (Salta and De Strooper, 2012, 2017b), this information can pinpoint mechanisms involved in the molecular pathogenesis of Alzheimer’s disease (AD). MiRs can be targeted by artificial oligonucleotides to influence gene regulation for therapeutic processes (Roshan et al, 2009). MiRNome profiling promotes the search for new biomarkers and therapeutics

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