KAT7/HMGN1 signaling epigenetically induces tyrosine phosphorylation-regulated kinase 1A expression to ameliorate insulin resistance in Alzheimer’s disease

IF 3.9 4区医学 Q1 PSYCHIATRY

World Journal of Psychiatry Pub Date : 2024-03-19 DOI:10.5498/wjp.v14.i3.445

Qun-Shan Lu, Lin Ma, Wenjing Jiang, Xing-Bang Wang, Mei Lu

{"title":"KAT7/HMGN1 signaling epigenetically induces tyrosine phosphorylation-regulated kinase 1A expression to ameliorate insulin resistance in Alzheimer’s disease","authors":"Qun-Shan Lu, Lin Ma, Wenjing Jiang, Xing-Bang Wang, Mei Lu","doi":"10.5498/wjp.v14.i3.445","DOIUrl":null,"url":null,"abstract":"BACKGROUND\n Epidemiological studies have revealed a correlation between Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2D). Insulin resistance in the brain is a common feature in patients with T2D and AD. KAT7 is a histone acetyltransferase that participates in the modulation of various genes.\n AIM\n To determine the effects of KAT7 on insulin patients with AD.\n METHODS\n APPswe/PS1-dE9 double-transgenic and db/db mice were used to mimic AD and diabetes, respectively. An in vitro model of AD was established by Aβ stimulation. Insulin resistance was induced by chronic stimulation with high insulin levels. The expression of microtubule-associated protein 2 (MAP2) was assessed using immunofluorescence. The protein levels of MAP2, Aβ, dual-specificity tyrosine phosphorylation-regulated kinase-1A (DYRK1A), IRS-1, p-AKT, total AKT, p-GSK3β, total GSK3β, DYRK1A, and KAT7 were measured via western blotting. Accumulation of reactive oxygen species (ROS), malondialdehyde (MDA), and SOD activity was measured to determine cellular oxidative stress. Flow cytometry and CCK-8 assay were performed to evaluate neuronal cell death and proliferation, respectively. Relative RNA levels of KAT7 and DYRK1A were examined using quantitative PCR. A chromatin immunoprecipitation assay was conducted to detect H3K14ac in DYRK1A.\n RESULTS\n KAT7 expression was suppressed in the AD mice. Overexpression of KAT7 decreased Aβ accumulation and MAP2 expression in AD brains. KAT7 overexpression decreased ROS and MDA levels, elevated SOD activity in brain tissues and neurons, and simultaneously suppressed neuronal apoptosis. KAT7 upregulated levels of p-AKT and p-GSK3β to alleviate insulin resistance, along with elevated expression of DYRK1A. KAT7 depletion suppressed DYRK1A expression and impaired H3K14ac of DYRK1A. HMGN1 overexpression recovered DYRK1A levels and reversed insulin resistance caused by KAT7 depletion.\n CONCLUSION\n We determined that KAT7 overexpression recovered insulin sensitivity in AD by recruiting HMGN1 to enhance DYRK1A acetylation. Our findings suggest that KAT7 is a novel and promising therapeutic target for the resistance in AD.","PeriodicalId":23896,"journal":{"name":"World Journal of Psychiatry","volume":null,"pages":null},"PeriodicalIF":3.9000,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"World Journal of Psychiatry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.5498/wjp.v14.i3.445","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PSYCHIATRY","Score":null,"Total":0}

引用次数: 0

Abstract

BACKGROUND Epidemiological studies have revealed a correlation between Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2D). Insulin resistance in the brain is a common feature in patients with T2D and AD. KAT7 is a histone acetyltransferase that participates in the modulation of various genes. AIM To determine the effects of KAT7 on insulin patients with AD. METHODS APPswe/PS1-dE9 double-transgenic and db/db mice were used to mimic AD and diabetes, respectively. An in vitro model of AD was established by Aβ stimulation. Insulin resistance was induced by chronic stimulation with high insulin levels. The expression of microtubule-associated protein 2 (MAP2) was assessed using immunofluorescence. The protein levels of MAP2, Aβ, dual-specificity tyrosine phosphorylation-regulated kinase-1A (DYRK1A), IRS-1, p-AKT, total AKT, p-GSK3β, total GSK3β, DYRK1A, and KAT7 were measured via western blotting. Accumulation of reactive oxygen species (ROS), malondialdehyde (MDA), and SOD activity was measured to determine cellular oxidative stress. Flow cytometry and CCK-8 assay were performed to evaluate neuronal cell death and proliferation, respectively. Relative RNA levels of KAT7 and DYRK1A were examined using quantitative PCR. A chromatin immunoprecipitation assay was conducted to detect H3K14ac in DYRK1A. RESULTS KAT7 expression was suppressed in the AD mice. Overexpression of KAT7 decreased Aβ accumulation and MAP2 expression in AD brains. KAT7 overexpression decreased ROS and MDA levels, elevated SOD activity in brain tissues and neurons, and simultaneously suppressed neuronal apoptosis. KAT7 upregulated levels of p-AKT and p-GSK3β to alleviate insulin resistance, along with elevated expression of DYRK1A. KAT7 depletion suppressed DYRK1A expression and impaired H3K14ac of DYRK1A. HMGN1 overexpression recovered DYRK1A levels and reversed insulin resistance caused by KAT7 depletion. CONCLUSION We determined that KAT7 overexpression recovered insulin sensitivity in AD by recruiting HMGN1 to enhance DYRK1A acetylation. Our findings suggest that KAT7 is a novel and promising therapeutic target for the resistance in AD.

查看原文本刊更多论文

KAT7/HMGN1 信号通过表观遗传诱导酪氨酸磷酸化调控激酶 1A 的表达来改善阿尔茨海默病的胰岛素抵抗

背景流行病学研究表明，阿尔茨海默病（AD）与 2 型糖尿病（T2D）之间存在相关性。大脑中的胰岛素抵抗是 T2D 和 AD 患者的共同特征。KAT7 是一种组蛋白乙酰转移酶，参与多种基因的调控。目的确定 KAT7 对 AD 患者胰岛素的影响。方法使用 APPswe/PS1-dE9 双转基因小鼠和 db/db 小鼠分别模拟 AD 和糖尿病。通过 Aβ 刺激建立了 AD 体外模型。高胰岛素水平的慢性刺激诱导了胰岛素抵抗。免疫荧光法评估了微管相关蛋白2（MAP2）的表达。通过 Western 印迹检测了 MAP2、Aβ、双特异性酪氨酸磷酸化调节激酶-1A（DYRK1A）、IRS-1、p-AKT、总 AKT、p-GSK3β、总 GSK3β、DYRK1A 和 KAT7 的蛋白水平。活性氧（ROS）、丙二醛（MDA）和 SOD 活性的测定可确定细胞氧化应激。流式细胞术和 CCK-8 检测分别用于评估神经细胞的死亡和增殖。利用定量 PCR 检测了 KAT7 和 DYRK1A 的相对 RNA 水平。染色质免疫沉淀试验检测了 DYRK1A 中的 H3K14ac。结果 KAT7在AD小鼠中的表达受到抑制。KAT7的过表达减少了AD大脑中Aβ的积累和MAP2的表达。KAT7 的过表达降低了 ROS 和 MDA 水平，提高了脑组织和神经元中 SOD 的活性，同时抑制了神经元的凋亡。KAT7能上调p-AKT和p-GSK3β的水平，从而缓解胰岛素抵抗，同时还能提高DYRK1A的表达。消耗 KAT7 可抑制 DYRK1A 的表达，并损害 DYRK1A 的 H3K14ac。HMGN1 的过表达恢复了 DYRK1A 的水平，并逆转了 KAT7 缺失引起的胰岛素抵抗。结论我们通过招募 HMGN1 增强 DYRK1A 乙酰化，确定 KAT7 过表达可恢复 AD 的胰岛素敏感性。我们的研究结果表明，KAT7是治疗AD患者胰岛素抵抗的一个新颖而有前景的靶点。

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

World Journal of Psychiatry PSYCHIATRY-

自引率

6.50%

发文量

110

期刊介绍： The World Journal of Psychiatry (WJP) is a high-quality, peer reviewed, open-access journal. The primary task of WJP is to rapidly publish high-quality original articles, reviews, editorials, and case reports in the field of psychiatry. In order to promote productive academic communication, the peer review process for the WJP is transparent; to this end, all published manuscripts are accompanied by the anonymized reviewers’ comments as well as the authors’ responses. The primary aims of the WJP are to improve diagnostic, therapeutic and preventive modalities and the skills of clinicians and to guide clinical practice in psychiatry.