The main purpose of this research was to explore the molecular mechanisms of Jumonji Domain-Containing Protein 3 (JMJD3) in Alzheimer's disease (AD) and to analyze its role in the anti-AD mechanism of curcumin (CUR). In the in vitro study of AD, JMJD3 overexpression promoted the trimethylation of histone H3 lysine 27 (H3K27me3), downregulated brain-derived neurotrophic factor (BDNF ), improved the abnormality of mitochondrial stress response (MSR) markers, Aβ accumulation, increased cell proliferation and inhibited apoptosis. Upregulating BDNF also achieved above similar results. Knockout of JMJD3 could downregulate BDNF, upregulate the level of H3K27me3 methylation and inhibit MSR markers, while transfection of JMJD3 RNAi could counteract the upregulated effect of BDNF. Then, MSR activator could also improve AD. In addition, JMJD3 in AD in vitro models was obviously upregulated under CUR stimulation, and it triggered a series of reactions as mentioned above. In the in vivo study, the levels of JMJD3, the mRNA and protein levels of BDNF in the right brain tissues of AD mice were downregulated, the methylation of H3K27me3 increased, and the MSR markers (ClpP, HSP6, HSP-60, ATFS-1, etc.) were downregulated; the above indexes were improved in varying degrees with the intervention of CUR. Thus, we conclude that CUR can induce the upregulation of JMJD3 and improve BDNF expression by promoting the demethylation of H3K27me3, thereby maintaining the balance of MSR and thus, preventing AD development.
Keywords: Alzheimer’s disease; BDNF; H3K27me3; JMJD3; curcumin.
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