Anti-inflammatory Activity of a Polypeptide Fraction From Achyranthes bidentate in Amyloid β Oligomers Induced Model of Alzheimer's Disease.

Xiangyu Ge,Yicong Chen,Fei Ding,Yitong Wang,Qiong Cheng,Shu Yu,Xuemin Cao

doi:10.3389/fphar.2021.716177

Abstract

Neuroinflammation plays a crucial role in neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), and anti-inflammation has been considered as a potential therapeutic strategy. Achyranthes bidentate polypeptide fraction k (ABPPk) was shown to protect neurons from death and suppress microglia and astrocyte activation in PD model mice. However, how ABPPk regulates neuroinflammation to exert a neuroprotective role remains unclear. Toxic Aβ oligomers (AβOs) can trigger inflammatory response and play an important role in the pathogenesis of AD. In the present study, for the first time, we investigated the effects and underlying mechanisms of ABPPk on neuroinflammation in AβOs-induced models of AD. In vitro, ABPPk pretreatment dose-dependently inhibited AβOs-induced pro-inflammatory cytokines mRNA levels in BV2 and primary microglia. ABPPk pretreatment also reduced the neurotoxicity of BV2 microglia-conditioned media on primary hippocampal neurons. Furthermore, ABPPk down-regulated the AβOs-induced phosphorylation of IκBα and NF-κB p65 as well as the expression of NLRP3 in BV2 microglia. In vivo, ABPPk pre-administration significantly improved locomotor activity, alleviated memory deficits, and rescued neuronal degeneration and loss in the hippocampus of AβOs-injected mice. ABPPk inhibited the activation of microglia in hippocampal CA3 region and suppressed the activation of NF-κB as well as the expression of NLRP3, cleaved caspase-1, and ASC in the brain after AβOs injection. ABPPk hindered the release of pro-inflammatory cytokines and promoted the release of anti-inflammatory cytokines in the brain. Notably, the polarization experiment on BV2 microglia demonstrated that ABPPk inhibited M1-phenotype polarization and promoted M2-phenotype polarization by activating the LPS- or AβOs-impaired autophagy in microglia. Taken together, our observations indicate that ABPPk can restore the autophagy of microglia damaged by AβOs, thereby promoting M2-phenotype polarization and inhibiting M1-phenotype polarization, thus playing a role in regulating neuroinflammation and alleviating neurotoxicity.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs), and neuroinflammation (Probst et al, 1991; Webers et al, 2020)
Our observations indicate that A. bidentate polypeptide fraction k (ABPPk) can restore the autophagy of microglia damaged by Aβ oligomers (AβOs), thereby promoting M2-phenotype polarization and inhibiting M1-phenotype
The results showed that 10 μg/ml ABPPk significantly increased the mRNA levels of Arg1 and CD206 in AβOs-stimulated BV2 microglia, but this promotion could be abolished by pretreatment with 3-MA (Figure 10I), suggesting that ABPPk may promote M2-type polarization of microglia by promoting or maintaining autophagy

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs), and neuroinflammation (Probst et al, 1991; Webers et al, 2020). As a hallmark of neuroinflammation, microglia activation has received increasing attention in the pathogenesis of AD. Excessive production and deposition of Aβ has been considered as the principal inducer of microglia activation and neuroinflammation in the AD brain (Selkoe, 2001). Compelling evidence has indicated the dual roles of microglia in the pathogenesis of AD. Microglia can play a beneficial role in the pathogenesis of AD by producing anti-inflammatory mediators and clearing amyloid plaque (Lyman et al, 2014; Morales et al, 2014). On the other hand, activated microglia and released inflammatory mediators can enhance Aβ deposition and aggravate neuroinflammation, induce the formation of a vicious cycle, and eventually lead to irreversible loss of neurons (Cai et al, 2014)

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