Early miR-155 upregulation contributes to neuroinflammation in Alzheimer's disease triple transgenic mouse model

Abstract

MicroRNAs (miRNAs) have emerged as a class of small, endogenous, regulatory RNAs that exhibit the ability to epigenetically modulate the translation of mRNAs into proteins. This feature enables them to control cell phenotypes and, consequently, modify cell function in a disease context. The role of inflammatory miRNAs in Alzheimer's disease (AD) and their ability to modulate glia responses are now beginning to be explored. In this study, we propose to disclose the functional role of miR-155, one of the most well studied immune-related miRNAs in AD-associated neuroinflammatory events, employing the 3xTg AD animal model. A strong upregulation of miR-155 levels was observed in the brain of 12-month-old 3xTg AD animals. This event occurred simultaneously with an increase of microglia and astrocyte activation, and before the appearance of extracellular Aβ aggregates, suggesting that less complex Aβ species, such as Aβ oligomers may contribute to early neuroinflammation. In addition, we investigated the contribution of miR-155 and the c-Jun transcription factor to the molecular mechanisms that underlie Aβ-mediated activation of glial cells. Our results suggest early miR-155 and c-Jun upregulation in the 3xTg AD mice, as well as in Aβ-activated microglia and astrocytes, thus contributing to the production of inflammatory mediators such as IL-6 and IFN-β. This effect is associated with a miR-155-dependent decrease of suppressor of cytokine signaling 1. Furthermore, since c-Jun silencing decreases the levels of miR-155 in Aβ-activated microglia and astrocytes, we propose that miR-155 targeting can constitute an interesting and promising approach to control neuroinflammation in AD.

Retinal and Circulating miRNAs in Age-Related Macular Degeneration: An In vivo Animal and Human Study

“…We found down-regulation of miR-155 in serum of AMD patients and Aβ injected rats; whereas we found up-regulation of miR-155 in the retina of Aβ injected rats, along with miR-27a and miR-146a. Our results are in accordance to the report by Guedes et al (2014), showing the up-regulation of miR-155 in hippocampal and cortical brain regions of 3-Tg AD animals as well as in cultured microglia and astrocytes treated with Aβ oligomers. Because miR-155 is associated to blood brain barrier dysfunction (Lopez-Ramirez et al, 2014), the up-regulation of miR-155 in retina of rats injected with Aβ oligomers might also influence the integrity of blood retinal barrier (BRB).…”

In vivo inhibition of miR-155 significantly alters post-stroke inflammatory response

“…miR-155 has been implicated in regulating various physiological and pathological processes including immunity and inflammation [13, 14]. Recent investigations identified miR-155 as a potent regulator of the neuroinflammatory response in Japanese encephalitis and Alzheimer’s disease [15, 16]. Microglia-mediated immune response associated with several pathological states is regulated by miR-155 [17–19].…”

Inflammation-induced miRNA-155 inhibits self-renewal of neural stem cells via suppression of CCAAT/enhancer binding protein β (C/EBPβ) expression

“…Guedes et al ., observed upregulation of miR-155 in a transgenic Alzheimer model mice, as well as in Aβ-activated microglia and astrocytes73. Increased production of inflammatory mediators73 and activation of T-cell immune functions have been suggested as possible mechanisms74. Although direct evidence linking miR-155 upregulation and stem cell dysfunction have not been observed previously, production of pro-inflammatory cytokines and overexpression of the markers for early neurons such as TUC-4 and DCX have been observed in AD patients75.…”

“…Indeed, increased differentiation of NSCs were observed in some studies using EAE7172. Guedes et al ., observed upregulation of miR-155 in a transgenic Alzheimer model mice, as well as in Aβ-activated microglia and astrocytes73. Increased production of inflammatory mediators73 and activation of T-cell immune functions have been suggested as possible mechanisms74.…”