Mechanism of Alzheimer type II astrocyte development in hepatic encephalopathy

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international Pub Date : 2024-10-05 DOI:10.1016/j.neuint.2024.105866

Xiao Y. Tong , Michael D. Norenberg , Michael J. Paidas , Nagarajarao Shamaladevi , Luis Salgueiro , Miklos Jaszberenyi , Binu John , Hussain Hussain , Omar El hiba , El got Abdeljalil , El-Mansoury Bilal , Sampath Natarajan , Rita Romaguera , Stanislav Papayan , Arianna K. Carden , Rajalakshmi Ramamoorthy , Nila Elumalai , Andrew V. Schally , Jayakumar Nithura , Rebecca Patrizio , Arumugam R. Jayakumar

{"title":"Mechanism of Alzheimer type II astrocyte development in hepatic encephalopathy","authors":"Xiao Y. Tong , Michael D. Norenberg , Michael J. Paidas , Nagarajarao Shamaladevi , Luis Salgueiro , Miklos Jaszberenyi , Binu John , Hussain Hussain , Omar El hiba , El got Abdeljalil , El-Mansoury Bilal , Sampath Natarajan , Rita Romaguera , Stanislav Papayan , Arianna K. Carden , Rajalakshmi Ramamoorthy , Nila Elumalai , Andrew V. Schally , Jayakumar Nithura , Rebecca Patrizio , Arumugam R. Jayakumar","doi":"10.1016/j.neuint.2024.105866","DOIUrl":null,"url":null,"abstract":"<div><div>Type C hepatic encephalopathy (Type C HE) is a major and complex neurological condition that occurs following chronic liver failure. The molecular basis of Type C HE remains elusive. Type C HE is characterized by mental confusion, cognitive and motor disturbances. The presence of Alzheimer type II astrocytes (AT2A) is the key histopathological finding observed in Type C HE. However, nothing is currently known regarding AT2A development and its involvement in cognitive, and motor deficits in Type C HE. We, therefore, examined in rats the mechanisms by which liver failure contributes to the progression of AT2A, and its role in the development of cognitive and motor deficits in thioacetamide (TAA) model of Type C HE. We and others earlier reported increased oxidative/nitrosative stress (ONS), JNK1/2, and cMyc activation in ammonia-treated astrocyte cultures, as well as in brains from chronic liver failure. We now found increased levels of astrocytic glia maturation factor (GMF, a factor strongly implicated in neuroinflammation), as well as various inflammatory factors (IL-1β, TNF-α, IL-6, MMP-3, COX2, CXCL1, and PGE2), and reduced levels of GFAP and increased levels of aggregated nuclear protein Lamin A/C in rat brain cortex post-chronic liver failure. We also found increased levels of GMF and inflammatory factors (MMP-3, COX2, CXCL1, and PGE2) in astrocytes post-ammonia treatment <em>in vitro</em>. Additionally, pharmacological inhibition of upstream signaling of GMF (ONS, JNK1/2, and cMyc) or GMF inhibitors W-7 and trifluoperazine significantly reduced the levels of inflammatory factors, the number of AT2A cells, as well as the cognitive and motor deficits in TAA-treated rats. Increased levels of GMF were also identified in human post-mortem brain sections. These findings strongly suggest that increased levels of astrocytic GMF due to elevated levels of ONS, JNK1/2, and cMyc and the subsequent inflammation contribute to the development of AT2A and the consequent cognitive, and motor deficits in chronic liver failure.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"180 ","pages":"Article 105866"},"PeriodicalIF":4.4000,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurochemistry international","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0197018624001931","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Type C hepatic encephalopathy (Type C HE) is a major and complex neurological condition that occurs following chronic liver failure. The molecular basis of Type C HE remains elusive. Type C HE is characterized by mental confusion, cognitive and motor disturbances. The presence of Alzheimer type II astrocytes (AT2A) is the key histopathological finding observed in Type C HE. However, nothing is currently known regarding AT2A development and its involvement in cognitive, and motor deficits in Type C HE. We, therefore, examined in rats the mechanisms by which liver failure contributes to the progression of AT2A, and its role in the development of cognitive and motor deficits in thioacetamide (TAA) model of Type C HE. We and others earlier reported increased oxidative/nitrosative stress (ONS), JNK1/2, and cMyc activation in ammonia-treated astrocyte cultures, as well as in brains from chronic liver failure. We now found increased levels of astrocytic glia maturation factor (GMF, a factor strongly implicated in neuroinflammation), as well as various inflammatory factors (IL-1β, TNF-α, IL-6, MMP-3, COX2, CXCL1, and PGE2), and reduced levels of GFAP and increased levels of aggregated nuclear protein Lamin A/C in rat brain cortex post-chronic liver failure. We also found increased levels of GMF and inflammatory factors (MMP-3, COX2, CXCL1, and PGE2) in astrocytes post-ammonia treatment in vitro. Additionally, pharmacological inhibition of upstream signaling of GMF (ONS, JNK1/2, and cMyc) or GMF inhibitors W-7 and trifluoperazine significantly reduced the levels of inflammatory factors, the number of AT2A cells, as well as the cognitive and motor deficits in TAA-treated rats. Increased levels of GMF were also identified in human post-mortem brain sections. These findings strongly suggest that increased levels of astrocytic GMF due to elevated levels of ONS, JNK1/2, and cMyc and the subsequent inflammation contribute to the development of AT2A and the consequent cognitive, and motor deficits in chronic liver failure.

查看原文本刊更多论文

肝性脑病中阿尔茨海默 II 型星形胶质细胞的发育机制

C 型肝性脑病（C 型 HE）是慢性肝功能衰竭后出现的一种严重而复杂的神经系统疾病。C 型肝性脑病的分子基础至今仍不清楚。C 型肝性脑病的特点是精神错乱、认知和运动障碍。阿尔茨海默II型星形胶质细胞（AT2A）的存在是C型肝癌的主要组织病理学发现。然而，目前人们对 AT2A 的发展及其与 C 型高血压患者认知和运动障碍的关系还一无所知。因此，我们研究了肝衰竭导致 AT2A 进展的机制，以及 AT2A 在硫代乙酰胺（TAA）C 型 HE 模型中认知和运动障碍发展中的作用。我们和其他研究人员早先报告了氨处理星形胶质细胞培养物以及慢性肝衰竭患者大脑中氧化/亚硝基应激（ONS）、JNK1/2和cMyc活化的增加。我们现在发现，在慢性肝衰竭后的大鼠大脑皮层中，星形胶质细胞成熟因子（GMF，一种与神经炎症密切相关的因子）以及各种炎症因子（IL-1β、TNF-α、IL-6、MMP-3、COX2、CXCL1 和 PGE2）水平升高，GFAP 水平降低，聚集核蛋白 Lamin A/C 水平升高。我们还发现氨治疗后体外星形胶质细胞中 GMF 和炎症因子（MMP-3、COX2、CXCL1 和 PGE2）水平升高。此外，药理学抑制 GMF 上游信号传导（ONS、JNK1/2 和 cMyc）或 GMF 抑制剂 W-7 和三氟拉嗪可显著降低炎症因子水平、AT2A 细胞数量以及 TAA 处理大鼠的认知和运动障碍。在人类死后大脑切片中也发现了 GMF 水平的升高。这些研究结果有力地表明，由于 ONS、JNK1/2 和 cMyc 水平升高，星形胶质细胞 GMF 水平升高，以及随后的炎症，导致了 AT2A 的发展，进而造成慢性肝衰竭患者的认知和运动障碍。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Neurochemistry international 医学-神经科学

CiteScore

8.40

自引率

2.40%

发文量

128

审稿时长

37 days

期刊介绍： Neurochemistry International is devoted to the rapid publication of outstanding original articles and timely reviews in neurochemistry. Manuscripts on a broad range of topics will be considered, including molecular and cellular neurochemistry, neuropharmacology and genetic aspects of CNS function, neuroimmunology, metabolism as well as the neurochemistry of neurological and psychiatric disorders of the CNS.