GSK126 mitigates oxidative stress in Alzheimer disease models via an enhancer of Zeste homolog 2-H3 lysine 27 trimethylation-superoxide dismutase 1 axis.

Abstract

Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss and with limited effective therapies. Oxidative stress, driven by disrupted redox balance and excessive reactive oxygen species (ROS), is believed to be a key pathogenic driver. This study aimed to explore the role and mechanism of the selective enhancer of Zeste homolog 2 (EZH2) methyltransferase inhibitor GSK126 in alleviating AD-related OS in AD models. Using Aβ1-42-induced AD model rats, we conducted Morris water maze tests, histologic and immunohistochemical staining, CCK-8/Annexin V-PI assays, Western blot, quantitative Reverse Transcription PCR (qRT-PCR), and Chromatin Immunoprecipitation quantitative Real-Time PCR (ChIP-qPCR). GSK126 shortened escape latency, reduced hippocampal pathology/apoptosis, upregulated Superoxide dismutase 1 (SOD1), and lowered ROS/malondialdehyde/protein carbonyls, thereby increasing antioxidant capacity in the AD model rats. In okadaic acid-treated SH-SY5Y cells, GSK126 enhanced viability, reduced apoptosis by downregulating Bax/c-Cas3 and upregulating Bcl-2 and upregulated SOD1 by inhibiting EZH2-mediated H3 lysine 27 trimethylation (H3K27me3) enrichment at the SOD1 promoter. SOD1 overexpression antagonized EZH2-induced damage. These results suggest that GSK126 could alleviate AD-related pathologic alterations in these models via the EZH2-H3K27me3-SOD1 axis, thereby suggesting a potential therapeutic target for AD.