MicroRNA-146a switches microglial phenotypes to resist the pathological processes and cognitive degradation of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and currently has no effective treatment. Mainstream research on the mechanisms and therapeutic targets of AD is focused on the two most important hallmarks, Aβ and Tau, but the results from clinical studies are not encouraging. Abnormal microglial polarization is a clear typical pathological feature in the progression of AD. Microglia can be neuroprotective by degrading and removing Aβ and Tau. However, under AD conditions, microglia transform into a pro-inflammatory phenotype that decreases the phagocytic activity of microglia, damages neurons and promotes the pathology of AD. We previously reported that a miR-146a polymorphism is associated with sporadic AD risk, and the nasal administration of miR-146a mimics reduced cognitive impairment and the main pathological features of AD. However, it is not clear by what mechanism miR-146a resists the pathological process of AD. In this study, we discovered that microglia-specific miR-146a overexpression reduced cognitive deficits in learning and memory, attenuated neuroinflammation, reduced Aβ levels, ameliorated plaque-associated neuritic pathology, and prevented neuronal loss in APP/PS1 transgenic mice. In addition, we found that miR-146a switched the microglial phenotype, reduced pro-inflammatory cytokines and enhanced phagocytic function to protect neurons in vitro and in vivo . Moreover, transcriptional analysis confirmed that miR-146a opposed the pathological process of AD mainly through neuroinflammation-related pathways. In summary, our results provide sufficient evidence for the mechanism by which miR-146a opposes AD and strengthen the conclusion that miR-146a is a promising target for AD and other microglia-related diseases.

Inflamma-MicroRNAs in Alzheimer’s Disease: From Disease Pathogenesis to Therapeutic Potentials

“…MiR-146a is widely involved in the regulation of immune cells and its expression is localized in astrocytes and microglia. This miRNA is also involved in microglial polarization and is significantly upregulated in inflammatory activated microglia (M1 type) (Rom et al, 2010;Cunha et al, 2016;Liang et al, 2021). Further, miR-146a is also upregulated in the temporal cortex of AD patients and is involved in the negative feedback regulation of NF-κB activation (Alexandrov et al, 2014).…”

Differences in Immune-Related Genes Underlie Temporal and Regional Pathological Progression in 3xTg-AD Mice

“…The upregulation of miR-124 in the cortex of 3xTg-AD at 3-month-old may justify the reduction we observed for its target C/EBP- α at this age. As for miR-146a, recently considered to oppose the pathological processes of AD [ 49 ], elevated expression was only found in the early 3 months stage in both the cortex and the hippocampus (~1.8- and 1.4-fold, respectively, p < 0.05, Figure 7 C), significantly decreasing thereafter (~35% and ~25% for cortex and hippocampus, respectively, p < 0.05, Figure 7 C), which may explain the increase of inflammatory molecules we noticed in 9-month-old 3xTg-AD animals. In summary, miR-155 can be sorted as an early and continuous biomarker involved in the emergence of AD pathological processes in both the cortex and the hippocampus to which the miR-146a switch from upregulated to downregulated expression levels may be accounted.…”

Potential prognostic value of circulating inflamma-miR-146a-5p and miR-125a-5p in relapsing-remitting multiple sclerosis

“…To this regard, miR-125a-5p was previously shown to reduce neuroinflammation by preserving the blood-brain barrier integrity and preventing the release of pro-inflammatory cytokines and chemokines by brain endothelial cells (Reijerkerk et al, 2013). Similarly, miR-146a-5p induces a switch of the microglial transcriptional landscape that results in reduced neuroinflammation and enhanced neuroprotection (Liang et al, 2021). Overall, the release of inflamma-miRs occurs to counteract inflammation and their circulating levels reflect the extent of systemic inflammation associated with many disorders.…”