Serum amyloid A inhibits astrocyte migration via activating p38 MAPK

Abstract

Background: 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. Here, we demonstrate the role of SAA in astrocyte migration. Methods: The 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. Results: Saa3 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. Conclusions: These 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.

Green Tea Catechins Attenuate Human Primary Pterygium Cell Survival and Migration Via Modulation of ERK p42/p44 and p38 Pathways

“…41 Moreover, activation of the p38 pathway has been shown to inhibit mouse astrocyte and human glioma U251 cell migration upon serum amyloid A treatment. 49 Consistent with our result, EGCG could inhibit the growth and invasion of pancreatic cancer in xenografted mice by reducing ERK activity but enhancing p38 activity. 50 Therefore, our results could suggest that the attenuated survival and migration in primary pterygium cells after green tea extract and EGCG treatments could be associated with the reduction in ERK p42/p44 pathway and elevation in p38 pathway activation.…”

“…EGCG could also inhibit the viability and migration of human thyroid carcinoma cells through reduction of ERK1/2 phosphorylation . Moreover, activation of the p38 pathway has been shown to inhibit mouse astrocyte and human glioma U251 cell migration upon serum amyloid A treatment . Consistent with our result, EGCG could inhibit the growth and invasion of pancreatic cancer in xenografted mice by reducing ERK activity but enhancing p38 activity .…”

Amyloid Beta Pathology Exacerbates Weight Loss and Brain Cytokine Responses following Low-Dose Lipopolysaccharide in Aged Female Tg2576 Mice

“…It has been shown that SAA1 overexpression in APP transgenic mice promotes the accumulation of Aβ in the brain and increases gliosis [36]. Conversely, APP overexpression was also found to increase SAA1 and SAA3 deposition in the brain [36,37]. However, SAA3 was shown to inhibit astrogliosis in Aβ-overproducing APP/PS1 mice, indicating that the functions of SAA in the brain may differ by isoform and depend on the conditions of expression.…”

“…SAA is highly upregulated by the liver during an acute inflammatory insult, and the magnitude of increase indicates the severity of the systemic inflammatory response [34]. SAA can also cross the intact BBB, and it has been shown to contribute to plaque deposition and to regulate gliosis [35][36][37][38] and depressive-like behaviors [39]. Thus, we also evaluated concentrations of soluble and insoluble SAA in the brain.…”

Aggregation of Mouse Serum Amyloid A Protein Was Promoted by Amyloid-Enhancing Factors with the More Genetically Homologous Serum Amyloid A

“…2021, 22, x FOR PEER REVIEW 2 of 13 Serum amyloid A (SAA), an evolutionarily highly conserved acute phase protein in vertebrates and invertebrates, is predominantly secreted by hepatocytes in the liver and is also produced by a variety of cells and tissues [9][10][11]. In fields of regulating inflammation and immunity and lipid metabolism, SAA protein plays an important role that benefits the body [6,11,12]. SAA is an important amyloid precursor and plays a key role in AA amyloidosis which impacts ∼1% of patients with chronic inflammation [13,14].…”