H3K18 lactylation of senescent microglia potentiates brain aging and Alzheimer & apos;s disease through the NF?B signaling pathway

Cellular senescence serves as a fundamental and underlying activity that drives the aging process, and it is intricately associated with numerous age-related diseases, including Alzheimer's disease (AD), a neurodegenerative aging-related disorder characterized by progressive cognitive impairment. Although increasing evidence suggests that senescent microglia play a role in the pathogenesis of AD, their exact role remains unclear. In this study, we quantified the levels of lactic acid in senescent microglia, and hippocampus tissues of naturally aged mice and AD mice models (FAD(4T) and APP/PS1). We found lactic acid levels were significantly elevated in these cells and tissues compared to their corresponding counterparts, which increased the level of pan histone lysine lactylation (Kla). We aslo identified all histone Kla sites in senescent microglia, and found that both the H3K18 lactylation (H3K18la) and Pan-Kla were significantly up-regulated in senescent microglia and hippocampus tissues of naturally aged mice and AD modeling mice. We demonstrated that enhanced H3K18la directly stimulates the NF?B signaling pathway by increasing binding to the promoter of Rela (p65) and NF?B1(p50), thereby upregulating senescence-associated secretory phenotype (SASP) components IL-6 and IL-8. Our study provides novel insights into the physiological func-tion of Kla and the epigenetic regulatory mechanism that regulates brain aging and AD. Specifically, we have identi-fied the H3K18la/NF?B axis as a critical player in this process by modulating IL-6 and IL-8. Targeting this axis may be a potential therapeutic strategy for delaying aging and AD by blunting SASP.

Automated summary

Cellular senescence is a fundamental activity driving the aging process and is closely associated with age-related diseases, including Alzheimer's disease (AD). In this study, the elevated levels of lactic acid in senescent microglia and hippocampus tissues of naturally aged mice and AD mice models were quantified. The study also identified the role of H3K18la/NF?B axis in modulating the production of IL-6 and IL-8, which are components of the senescence-associated secretory phenotype (SASP).