Treating microRNA dysregulation in AD mice models: A systematic review

Background Efficient treatments for Alzheimer’s disease are still not available. As miRNAs are becoming therapeutic targets, a critical review of the evidence in AD mice models is required. Method This is an ongoing review, following the recommendations of PRISMA guidelines. The search was conducted in in MEDLINE, Scopus and ProQuest. Only peer reviewed interventional studies of in vivo AD mice models are eligible. Information about model, intervention, targeting miR and efficacy measures is being extracted. Result From the 5239 retrieved studies, 10 have been completely reviewed. The most common targeting miRNA is miR‐146a, followed by miR‐124, miR‐30b and miR‐138. Cognitive impairment was rescued by intracerebral injections of miR‐146a antagomir (Islam et al., 2021; G. Wang et al., 2016), inhalation of a chemically modified 146a mimic (Mai et al., 2019), by environmental enrichment (Nakano, Kubota, Hashizume, et al., 2020) and by the intracerebral injection of bone‐marrow derived mesenchymal cells (Nakano, Kubota, Kobayashi, et al., 2020). Molecular mechanisms involved are decrease in neuroinflammation and tau phosphorylation and an increase in the synaptic density. Antagomirs of miR‐124 in the Tg2576 and P301S models, improve memory deficits, while improving synaptic density and function and decreasing tau‐phosphorylation and aggregation, respectively (Hafez et al., 2021; X. Wang et al., 2018). However, mice injected with oA42i, reported a downregulation of miR‐124 and intervention with 3,4‐dihydroxyphenylethanol produced a behavioral improvement as well (ArunSundar, Shanmugarajan, & Ravichandiran, 2018). miR‐138 and miR‐30b antagomirs decreased memory deficits by means of synaptic morphology and function improvement in the 5XFAD and APPswe/PSEN1dE mice (Lu, Tan, & Wang, 2019; Song, Hu, Zhang, Teng, & Chen, 2019). Nevertheless, the longest incubation time was 1 month and in any of the studies the intervention was repeated. No side effects were reported. Conclusion Several interventions targeting miRNAs are emerging and although positive effects are seen in the short run, longer observation times are needed. The molecular mechanisms under the effect of miRNAs are complex, as shown by the beneficial effects of both agonists and antagonists of miRNA‐146a. More studies are needed to elucidate the main mechanisms and the most adequate therapeutic approach.