Basic Study
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World J Psychiatry. Mar 19, 2024; 14(3): 445-455
Published online Mar 19, 2024. doi: 10.5498/wjp.v14.i3.445
KAT7/HMGN1 signaling epigenetically induces tyrosine phosphorylation-regulated kinase 1A expression to ameliorate insulin resistance in Alzheimer’s disease
Qun-Shan Lu, Lin Ma, Wen-Jing Jiang, Xing-Bang Wang, Mei Lu
Qun-Shan Lu, Lin Ma, Wen-Jing Jiang, Xing-Bang Wang, Mei Lu, Department of Geriatric Medicine, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
Lin Ma, Wen-Jing Jiang, Xing-Bang Wang, Mei Lu, Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
Author contributions: Lu QS and Lu M designed the study; Lu QS, Ma L, Jiang WJ, and Wang XB performed the experiments; Lu QS and Lu M wrote the manuscript.
Supported by Natural Science Foundation of Shandong Province, No. ZR2020MH147; and National Natural Science Foundation of China, No. 82002343.
Institutional review board statement: All experiments were performed under the authorization and guidelines of Ethics Committee of Qilu Hospital of Shandong University, No. KYLL-2020 (KS)-102.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Shandong University, No. MDL2021-08-17-02.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: Further information and requests for resources and reagents should be directed to and will be fulfilled by the corresponding author at lumei@qiluhospital.com.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Mei Lu, MD, Professor, Department of Geriatric Medicine, Qilu Hospital of Shandong University, No. 107 Wenhua Xilu, Jinan 250012, Shandong Province, China. lumei@qiluhospital.com
Received: November 30, 2023
Peer-review started: November 30, 2023
First decision: December 18, 2023
Revised: December 31, 2023
Accepted: February 1, 2024
Article in press: February 1, 2024
Published online: March 19, 2024
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.

Keywords: Alzheimer's disease, Diabetes, Insulin resistance, KAT7, Dual-specificity tyrosine phosphorylation-regulated kinase-1A, HMGN1

Core Tip: Type 2 diabetes mellitus (T2D) is closely associated with neurodegenerative diseases, such as Alzheimer’s disease (AD), in which insulin resistance dysfunction plays a critical role. However, the pathological mechanisms underlying diabetes mellitus-related atopic dermatitis remain unclear. Our study demonstrated that the histone acetyltransferase KAT7 ameliorated neuronal death and oxidative stress in AD and restored insulin sensitivity in insulin-resistant neurons by recruiting HMGN1 to enhance the acetylation of the dual-specificity tyrosine phosphorylation-regulated kinase-1A gene, suggesting the promising therapeutic potential of KAT7 in diabetes mellitus-associated AD.