Accumulating evidence has indicated that activation of microglia and neuroinflammation reaction play a prominent role in Alzheimer's disease (AD). Inhibition of toll-like receptor 4 (TLR4) has been shown to be associated with immune responses and brain damage, but its effects on AD remain unclear. This study mainly aimed to investigate the protective effect of TAK-242 (TLR4-specific inhibitor) on microglial polarization and neuroprotection in an AD mouse model and the underlying mechanisms. We found that APP/PS1 transgenic AD mice exhibited a dramatic increase in TLR4 levels concomitant with a significantly higher expression of inflammatory microglia compared to C57BL/6 wildtype mice. Furthermore, inhibition of TLR4 by TAK-242 administration significantly improved neurological function, decreased the level of Bax, and caused a significant reduction in the levels of M1-markers (iNOS and TNFα), while the expressions of M2-phenotype markers (Trem-2 and Arg-1) were increased both in vivo and in vitro. Furthermore, TAK-242 treatment enhanced BV2 microglial phagocytosis. Moreover, Aβ 25−35 caused the upregulation of inflammatory cytokine production, MyD88, NF-kappaB-p65, and NLRP3, which could be ameliorated by NLRP3-siRNA or TAK-242. These findings indicated that TLR4 inhibition provided neuroprotection and promoted a microglial switch from the inflammatory M1 phenotype to the protective M2 phenotype in AD. The mechanism involved may be related to modulation of the MyD88/NF-kappaB/NLRP3 signaling pathway.
BackgroundThe in ammatory response caused by microglia in the central nervous system plays an important role in Alzheimer's disease. Neuregulin-1 (NRG1) is a member of the neuregulin family and has been demonstrated to have anti-in ammatory properties. The relationship between NRG1, microglia phenotype and neuroin ammation remains unclear. Materials and MethodsBV2 cells were used to examine the mechanism of NRG1 in regulating microglia polarization. Neuronal apoptosis, in ammatory factors TNF-α and iNOS, microglia polarization, ErbB4 and NF-κB p65 expression were assessed. ResultsWe found that exogenous NRG1 treatment or overexpression improved microglial activity and reduced the secretion of the in ammatory factors TNF-α and iNOS in vitro. The expression of Bax in SH-SY5Y neuron cells incubated with medium collected from the NRG1 treatment group decreased. Additionally, our study showed that NRG1 treatment reduced the levels of the M1 microglia markers CD120 and iNOS and increased the levels of the M2 microglia markers CD206 and Arg-1. Furthermore, we observed that NRG1 treatment attenuated Aβ-induced NF-κB activation and promoted the expression of p-ErbB4 and that knockdown of ErbB4 abrogated the effects of NRG1 on NF-κB, Bax levels and M2 microglial polarization. ConclusionNRG1 inhibits the release of in ammatory factors in microglia and regulates the switching of the M1/M2 microglia phenotype, most likely via ErbB4-dependent inhibition of the NF-κB pathway.
cognitive impairment and neuro-inflammatory responses are the distinctive characteristics of alzheimer's disease (ad). Tormentic acid (Ta) is one of the major active components of Potentilla chinensis and has been demonstrated to have anti-inflammatory properties. However, the potential effects of Ta on neuro-inflammatory responses and memory impairment in AD remain unknown. The present study investigated the therapeutic effect of Ta on neuro-inflammation, as well as learning and memory impairment in ad mice. in addition, the effects of Ta treatment were also examined in a co-culture system of microglia and primary neurons. intraperitoneal administration of Ta attenuated memory deficits in amyloid β precursor protein/presenilin 1 transgenic mice, with a marked decrease in amyloid plaque deposition. Ta also reduced microglial activation and decreased the secretion of pro-inflammatory factors in AD mice. Furthermore, pre-treatment with TA suppressed the production of pro-inflammatory markers, as well as the nuclear translocation of nuclear factor-κB (nF-κB) p65 induced by aβ exposure in BV2 cells. TA also reduced inhibited neurotoxicity and improved neuron survival in a neuron-microglia co-culture system. Taken together, these findings suggested that Ta could attenuate neuro-inflammation and memory impairment, which may be closely associated with regulation of the nF-κB pathway.
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