MFG-E8 Selectively Inhibited A β-Induced Microglial M1 Polarization via NF-κB and PI3K-Akt Pathways

AbstractActivated microglia are classified into two specific states: classically activated (M1) and alternatively activated (M2) subtypes. It is believed that the polarization of M1/M2 phenotype plays an important role in Alzheimer ’s disease (AD). However, the mechanisms regulating this process remain unclear. Thus, we addressed this question focusing on milk fat globule epidermal growth factor 8 (MFG-E8). MFG-E8 is a unique protein which can bind to microglia and regulate its inflammatory responses. It is speculated that i t might play a role in the balance of microglial polarization. In the current study, we used fibril Aβ42 in vitro to stimulate mouse primary microglial cultures and found subsequent M1 marker expression, along with retained M2 marker production. Then, we discovered that MFG-E8 pretreatment reversed the increased trend of M1 markers and the decreased expression of M2 markers, which were induced by Aβ42. Moreover, MFG-E8 effects could be effectively blocked by an MFG-E8 antibody. Further analysis on the signaling pathways showed that NF-κB upregulation and Akt downregulation in microglial cul tures were observed after Aβ42 incubation. And the alteration of these pathways could also be reversed by MFG-E8. We then assessed the effects of NF-κB and PI3K-Akt on M1/M2 alteration using their specific inhibitors. Pyrrolidine dithiocarbamate, a NF-κB inhibitor, inhibited M1 marker expression; moreover, LY294002, an Akt inhibitor, enhanced M1 marker expressi...

Source: Molecular Neurobiology - November 14, 2017 Category: Neurology Source Type: research