Serum amyloid A inhibits astrocyte migration via activating p38 MAPK

Aihua Lin,Ping Gong,Yang Yu,Haibo Zhang,Jin Liu,Yanqing Chen,Yan Zhang

doi:10.1186/s12974-020-01924-z

Abstract

BackgroundThe accumulation of astrocytes around senile plaques is one of the pathological characteristics in Alzheimer’s disease (AD). Serum amyloid A (SAA), known as a major acute-phase protein, colocalizes with senile plaques in AD patients. Here, we demonstrate the role of SAA in astrocyte migration.MethodsThe effects of SAA on astrocyte activation and accumulation around amyloid β (Aβ) deposits were detected in APP/PS1 transgenic mice mated with Saa3−/− mice. SAA expression, astrocyte activation, and colocalization with Aβ deposits were evaluated in mice using immunofluorescence staining and/or Western blotting. The migration of primary cultures of mouse astrocytes and human glioma U251 cells was examined using Boyden chamber assay and scratch-would assay. The actin and microtubule networks, protrusion formation, and Golgi apparatus location in astrocytes were determined using scratch-would assay and immunofluorescence staining.ResultsSaa3 expression was significantly induced in aged APP/PS1 transgenic mouse brain. Saa3 deficiency exacerbated astrocyte activation and increased the number of astrocytes around Aβ deposits in APP/PS1 mice. In vitro studies demonstrated that SAA inhibited the migration of primary cultures of astrocytes and U251 cells. Mechanistic studies showed that SAA inhibited astrocyte polarization and protrusion formation via disrupting actin and microtubule reorganization and Golgi reorientation. Inhibition of the p38 MAPK pathway abolished the suppression of SAA on astrocyte migration and polarization.ConclusionsThese results suggest that increased SAA in the brain of APP/PS1 mice inhibits the migration of astrocytes to amyloid plaques by activating the p38 MAPK pathway.

Highlights

The accumulation of astrocytes around senile plaques is one of the pathological characteristics in Alzheimer’s disease (AD)
Inhibition of the p38 Mitogen-activated protein kinase (MAPK) pathway abolished the suppression of Serum amyloid A (SAA) on astrocyte migration and polarization
Saa3 deficiency increases astrocyte activation and colocalization with amyloid β (Aβ) plaques in APP/PS1 mice Since SAA plays a role in inflammatory response by acting on glial cells [29] and its expression is significantly induced in AD mouse brain, we explored whether SAA is involved in astrocyte activation and migration toward Aβ deposits in AD mice

Summary

Introduction

The accumulation of astrocytes around senile plaques is one of the pathological characteristics in Alzheimer’s disease (AD). Serum amyloid A (SAA), known as a major acute-phase protein, colocalizes with senile plaques in AD patients. Serum amyloid A (SAA) is a major acute-phase protein that is released to blood circulation in the event of infection and injury [9]. The inducible SAA proteins are almost undetectable in normal brains, SAA has been found in the brain of AD patients and to colocalize with Aβ in senile (neuritic) plaques [27, 28]. SAA induces the production of inflammatory cytokines including IL-6, TNF-α, IL-12, IL23, and iNOS in primary cultures of mouse astrocytes. All these observations suggest that SAA may contribute to the progression of AD by acting on astrocytes

Methods

Results

Discussion

Conclusion