Abstract
The present study aimed to explore the role and possible underlying mechanisms of histone lactylation (Kla) modifications in diabetes-associated cognitive impairment (DACD). In this study, behavioral tests, H&E staining, and immunohistochemistry were used to evaluate cognitive function and the extent of cerebral tissue injury. We quantified the levels of lactic acid and pan-lysine Kla (Pan-Kla) in the brains of type 2 diabetes mellitus (T2DM) mice and in high glucose–treated microglia. We also identified all Kla sites in isolated microglia. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were subsequently conducted to identify the functions and pathways that were enriched at the differentially expressed modification sites. Cleavage under targets and tagmentation (CUT&Tag) technology was used to identify candidate genes that are regulated by histone H3 lactylated at Lys-18 (H3K18la). siRNA and H3K18R mutant sequences were used to knock down crucial components in key signaling pathways to assess the effects of histone Kla on microglial polarization. We found that lactic acid levels were significantly greater in the brains of T2DM mice and high glucose–treated microglia than in those of their corresponding controls, which increased the level of Pan-Kla. We discovered that lactate can directly stimulate an increase in H3K18la. The global landscape of the lactylome reveals information about modification sites, indicating a correlation between the upregulation of H3K18la and protein Kla and Toll-like receptor (TLR) signaling. CUT&Tag demonstrated that enhanced H3K18la directly stimulates the NF-κB signaling pathway by increasing binding to the promoter of TLR4, thereby promoting M1 microglial polarization. The present study demonstrated that enhanced H3K18la directly stimulates TLR4 signaling to promote M1 microglial polarization, thereby facilitating DACD phenotypes. Targeting such loop may be a potential therapeutic approach for the treatment of DACD.
Authors
Ying Yang, Fei Chen, Lulu Song, Liping Yu, Jinping Zhang, Bo Zhang
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
Having trouble reading a PDF?
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Having trouble saving a PDF?
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.
Having trouble printing a PDF?
- Try printing one page at a time or to a newer printer.
- Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
- Make sure you are using the latest version of Adobe's Acrobat Reader.
