MiR-191-5p alleviates microglial cell injury by targeting Map3k12 (mitogen-activated protein kinase kinase kinase 12) to inhibit the MAPK (mitogen-activated protein kinase) signaling pathway in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease. Multiple reports have elucidated that microRNAs are promising biomarkers for AD diagnosis and treatment. Herein, the effect of miR-191-5p on microglial cell injury and the underlying mechanism were explored. APP/PS1 transgenic mice were utilized to establish mouse model of AD. Amyloid-β protein 1–42 (Aβ1-42)-treated microglia were applied to establish in vitro cell model of AD. MiR-191-5p expression in hippocampus and microglia was measured by reverse transcription quantitative polymerase chain reaction. The viability and apoptosis of microglia were evaluated by Cell Counting Kit-8 assays and flow cytometry analyses, respectively. The binding relationship between miR-191-5p and its downstream target mitogen-activated protein kinase kinase kinase 12 (Map3k12) was determined by luciferase reporter assays. Pathological degeneration of hippocampus was tested using hematoxylin-eosin staining and Nissl staining. Aβ expression in hippocampus was examined via immunohistochemistry. In this study, miR-191-5p was downregulated in Aβ1-42-stimulated microglia and hippocampal tissues of APP/PS1 mice. MiR-191-5p overexpression facilitated cell viability and inhibited apoptosis rate of Aβ1-42-treated microglia. Mechanically, miR-191-5p targeted Map3k12 3ʹ-untranslated region to downregulate Map3k12 expression. MiR-191-5p inhibited Aβ1-42-induced microglial cell injury and inactivated the MAPK signaling by downregulating Map3k12. Overall, miR-191-5p alleviated Aβ1-42-induced microglia cell injury by targeting Map3k12 to inhibit the MAPK signaling pathway in microglia.

Therapeutic Potential of Exosomes Derived from Adipose Tissue-Sourced Mesenchymal Stem Cells in the Treatment of Neural and Retinal Diseases

“…Results obtained in animal studies showed that AT-MSC-Exos prevented apoptotic cell death and attenuated ongoing inflammation in neural and retinal tissues (Table 2) [20][21][22][23][24][25][26][27]38,42,53,57,58]. AT-MSC-Exos play a crucially important role in the regulation of intercellular communication of injured parenchymal cells, immune cells, and ECs in the inflamed neural, corneal and retinal tissues [19].…”

“…As determined by transcriptome and multi-omics sequencing technologies, AT-MSC-Exos are enriched with bioactive molecules (microRNAs (miRNAs), enzymes, cytokines, chemokines, immunoregulatory, trophic, and growth factors), that are responsible for AT-MSC-Exo-dependent beneficial effects in inflamed and injured neural and retinal tissues (Table 1) [20][21][22][23][24][25][26][27].…”

“…Among more than 170 different miRNAs, which are found in exosomes from different stem cell sources [21], miR-486-5p, miR-10a-5p, miR-10b-5p, miR-191-5p, miR-222-3p, and miR146a were the most frequent miRNAs in AT-MSC-Exos. AT-MSC-Exo-sourced miR-486-5p regulate neurogenesis and brain development [22], miR-10a-5p and miR-10b-5p prevent apoptosis of injured neurons [23], miR-191-5p facilitates cell viability and inhibited apoptosis of microglial cells [24], miR222-3p regulates angiogenesis [25] and miR146a down-regulates the expression of IFN-γ in Th1 lymphocytes [26].…”

MiR-191-5p Attenuates Tau Phosphorylation, Aβ Generation, and Neuronal Cell Death by Regulating Death-Associated Protein Kinase 1

“…2 Pairing to the seed region is important for functional binding specificity, and miR-191-5p recognizes canonical target sites by base-pairing in the 3′UTR of human DAPK1. In addition to DAPK1, miR-191-5p has been found to target oxidative stress responsive 1 (OXSR1), 57 special AT-rich binding protein 1 (SATB1), 58 CCAAT-box/enhancer binding protein β (C/EBPβ), 59 mitogen-activated protein kinase kinase kinase 12 (Map3k12), 60 and tripartite motif-containing 14 (TRIM14). 61 These targets have similar sequences that bind to the short seed sequences at the 5′ ends (nucleotides 2−8) of miR-191-5p.…”

Mechanism of Zhinao Capsule in Treating Alzheimer’s Disease Based on Network Pharmacology Analysis and Molecular Docking Validation

“…MAPKs are serine-threonine kinases in eukaryotes that mediate a wide variety of intracellular processes, including cell proliferation, differentiation, survival, death, and transformation [ 49 ]. Furthermore, the MAPK pathway is involved in the pathogenesis of AD through multiple downstream signaling pathways, including the induction of neuronal apoptosis [ 50 ]. The above findings indicate that ZNC may ameliorate AD by regulating TCR, TNF, and the MAPK signaling pathway.…”