Silencing the ACAT1 gene in human SH-SY5Y neuroblastoma cells inhibits the expression of cyclo-oxygenase 2 (COX2) and reduces β-amyloid-induced toxicity due to activation of protein kinase C (PKC) and ERK

Ying Chen, Lu Zhu, Lei Ji, Ying Yang, Lu Lu, Xiaodong Wang, Guomin Zhou

Research output: Contribution to journalArticle

Abstract

Background: Acyl-coenzymeA: cholesterol acyltransferase (ACAT) 1, a key enzyme converting excess free cholesterol to cholesterol esters, has been demonstrated to be associated with the pathogenesis of Alzheimer disease (AD). However, the mechanism underlying the protective role of ACAT1 blockage in AD progression remains elusive. Material/Methods: Human neuroblastoma SH-SY5Y cells were treated for 24 h with increasing concentrations of aggregated Aβ 25–35 (5, 15, 25, and 45 μmol) with or without the ACAT1 siRNA pretreatment. Cell viability analysis was measured by CCK-8 assay. The genome-wide correlation between ACAT1 and all other probe sets was measured by the Pearson correlation coefficient (r). Western blotting was used to detect the ACAT1 protein expression in the hippocampus of APP/PSN transgenic AD mice. The mRNA level for each target was analyzed by qPCR. Western blotting was used to detect the ACAT1, cyclo-oxygenase-2 (Cox2), Calcium voltage-gated channel subunits (CACNAs), and ERK/PKC proteins in SH-SY5Y cells with or without the ACAT1 siRNA pretreatment in the presence of Aβ 25–35 . Results: The expression of ACAT1 was significantly increased in the hippocampus of APP/PSN mice, and also showed an increasing trend when SH-SY5Y cells were exposed to Aβ 25–35 . Silencing ACAT1 significantly attenuated Aβ-induced cytotoxicity and cell apoptosis in SH-SY5Y cells. The genome-wide correlation analysis showed that Ptgs2 had the most significant correlation with Acat1 in the hippocampus of BXD RI mice. We further determined the regulatory effect of ACAT1 on COX2 expression by silencing or over-expressing ACAT1 in SH-SY5Y cells and found that silencing ACAT1 played a protective role in AD progression by regulating CACNAs and PKC/ERK signaling cascades. Conclusions: Silencing ACAT1 attenuates Aβ 25–35 -induced cytotoxicity and cell apoptosis in SH-SY5Y cells, which may due to the synergistic effect of ACAT1 and COX2 through PKC/ERK pathways.

Original languageEnglish (US)
Pages (from-to)9007-9018
Number of pages12
JournalMedical Science Monitor
Volume24
DOIs
StatePublished - Dec 12 2018

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Gene Silencing
Prostaglandin-Endoperoxide Synthases
Neuroblastoma
Amyloid
Protein Kinase C
Alzheimer Disease
Hippocampus
Small Interfering RNA
Disease Progression
Western Blotting
Genome
Sterol O-Acyltransferase
Apoptosis
Sincalide
MAP Kinase Signaling System
Cholesterol Esters
Cell Survival
Proteins
Cholesterol
Calcium

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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Silencing the ACAT1 gene in human SH-SY5Y neuroblastoma cells inhibits the expression of cyclo-oxygenase 2 (COX2) and reduces β-amyloid-induced toxicity due to activation of protein kinase C (PKC) and ERK. / Chen, Ying; Zhu, Lu; Ji, Lei; Yang, Ying; Lu, Lu; Wang, Xiaodong; Zhou, Guomin.

In: Medical Science Monitor, Vol. 24, 12.12.2018, p. 9007-9018.

Research output: Contribution to journalArticle

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abstract = "Background: Acyl-coenzymeA: cholesterol acyltransferase (ACAT) 1, a key enzyme converting excess free cholesterol to cholesterol esters, has been demonstrated to be associated with the pathogenesis of Alzheimer disease (AD). However, the mechanism underlying the protective role of ACAT1 blockage in AD progression remains elusive. Material/Methods: Human neuroblastoma SH-SY5Y cells were treated for 24 h with increasing concentrations of aggregated Aβ 25–35 (5, 15, 25, and 45 μmol) with or without the ACAT1 siRNA pretreatment. Cell viability analysis was measured by CCK-8 assay. The genome-wide correlation between ACAT1 and all other probe sets was measured by the Pearson correlation coefficient (r). Western blotting was used to detect the ACAT1 protein expression in the hippocampus of APP/PSN transgenic AD mice. The mRNA level for each target was analyzed by qPCR. Western blotting was used to detect the ACAT1, cyclo-oxygenase-2 (Cox2), Calcium voltage-gated channel subunits (CACNAs), and ERK/PKC proteins in SH-SY5Y cells with or without the ACAT1 siRNA pretreatment in the presence of Aβ 25–35 . Results: The expression of ACAT1 was significantly increased in the hippocampus of APP/PSN mice, and also showed an increasing trend when SH-SY5Y cells were exposed to Aβ 25–35 . Silencing ACAT1 significantly attenuated Aβ-induced cytotoxicity and cell apoptosis in SH-SY5Y cells. The genome-wide correlation analysis showed that Ptgs2 had the most significant correlation with Acat1 in the hippocampus of BXD RI mice. We further determined the regulatory effect of ACAT1 on COX2 expression by silencing or over-expressing ACAT1 in SH-SY5Y cells and found that silencing ACAT1 played a protective role in AD progression by regulating CACNAs and PKC/ERK signaling cascades. Conclusions: Silencing ACAT1 attenuates Aβ 25–35 -induced cytotoxicity and cell apoptosis in SH-SY5Y cells, which may due to the synergistic effect of ACAT1 and COX2 through PKC/ERK pathways.",
author = "Ying Chen and Lu Zhu and Lei Ji and Ying Yang and Lu Lu and Xiaodong Wang and Guomin Zhou",
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T1 - Silencing the ACAT1 gene in human SH-SY5Y neuroblastoma cells inhibits the expression of cyclo-oxygenase 2 (COX2) and reduces β-amyloid-induced toxicity due to activation of protein kinase C (PKC) and ERK

AU - Chen, Ying

AU - Zhu, Lu

AU - Ji, Lei

AU - Yang, Ying

AU - Lu, Lu

AU - Wang, Xiaodong

AU - Zhou, Guomin

PY - 2018/12/12

Y1 - 2018/12/12

N2 - Background: Acyl-coenzymeA: cholesterol acyltransferase (ACAT) 1, a key enzyme converting excess free cholesterol to cholesterol esters, has been demonstrated to be associated with the pathogenesis of Alzheimer disease (AD). However, the mechanism underlying the protective role of ACAT1 blockage in AD progression remains elusive. Material/Methods: Human neuroblastoma SH-SY5Y cells were treated for 24 h with increasing concentrations of aggregated Aβ 25–35 (5, 15, 25, and 45 μmol) with or without the ACAT1 siRNA pretreatment. Cell viability analysis was measured by CCK-8 assay. The genome-wide correlation between ACAT1 and all other probe sets was measured by the Pearson correlation coefficient (r). Western blotting was used to detect the ACAT1 protein expression in the hippocampus of APP/PSN transgenic AD mice. The mRNA level for each target was analyzed by qPCR. Western blotting was used to detect the ACAT1, cyclo-oxygenase-2 (Cox2), Calcium voltage-gated channel subunits (CACNAs), and ERK/PKC proteins in SH-SY5Y cells with or without the ACAT1 siRNA pretreatment in the presence of Aβ 25–35 . Results: The expression of ACAT1 was significantly increased in the hippocampus of APP/PSN mice, and also showed an increasing trend when SH-SY5Y cells were exposed to Aβ 25–35 . Silencing ACAT1 significantly attenuated Aβ-induced cytotoxicity and cell apoptosis in SH-SY5Y cells. The genome-wide correlation analysis showed that Ptgs2 had the most significant correlation with Acat1 in the hippocampus of BXD RI mice. We further determined the regulatory effect of ACAT1 on COX2 expression by silencing or over-expressing ACAT1 in SH-SY5Y cells and found that silencing ACAT1 played a protective role in AD progression by regulating CACNAs and PKC/ERK signaling cascades. Conclusions: Silencing ACAT1 attenuates Aβ 25–35 -induced cytotoxicity and cell apoptosis in SH-SY5Y cells, which may due to the synergistic effect of ACAT1 and COX2 through PKC/ERK pathways.

AB - Background: Acyl-coenzymeA: cholesterol acyltransferase (ACAT) 1, a key enzyme converting excess free cholesterol to cholesterol esters, has been demonstrated to be associated with the pathogenesis of Alzheimer disease (AD). However, the mechanism underlying the protective role of ACAT1 blockage in AD progression remains elusive. Material/Methods: Human neuroblastoma SH-SY5Y cells were treated for 24 h with increasing concentrations of aggregated Aβ 25–35 (5, 15, 25, and 45 μmol) with or without the ACAT1 siRNA pretreatment. Cell viability analysis was measured by CCK-8 assay. The genome-wide correlation between ACAT1 and all other probe sets was measured by the Pearson correlation coefficient (r). Western blotting was used to detect the ACAT1 protein expression in the hippocampus of APP/PSN transgenic AD mice. The mRNA level for each target was analyzed by qPCR. Western blotting was used to detect the ACAT1, cyclo-oxygenase-2 (Cox2), Calcium voltage-gated channel subunits (CACNAs), and ERK/PKC proteins in SH-SY5Y cells with or without the ACAT1 siRNA pretreatment in the presence of Aβ 25–35 . Results: The expression of ACAT1 was significantly increased in the hippocampus of APP/PSN mice, and also showed an increasing trend when SH-SY5Y cells were exposed to Aβ 25–35 . Silencing ACAT1 significantly attenuated Aβ-induced cytotoxicity and cell apoptosis in SH-SY5Y cells. The genome-wide correlation analysis showed that Ptgs2 had the most significant correlation with Acat1 in the hippocampus of BXD RI mice. We further determined the regulatory effect of ACAT1 on COX2 expression by silencing or over-expressing ACAT1 in SH-SY5Y cells and found that silencing ACAT1 played a protective role in AD progression by regulating CACNAs and PKC/ERK signaling cascades. Conclusions: Silencing ACAT1 attenuates Aβ 25–35 -induced cytotoxicity and cell apoptosis in SH-SY5Y cells, which may due to the synergistic effect of ACAT1 and COX2 through PKC/ERK pathways.

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