Abstract: Cognitive impairment is a complex neurodegenerative disorder, and increased homocysteine levels are recognized as a major risk factor for this condition. Epigenetic modifications, particularly histone acetylation, have been implicated in the progression of cognitive impairment; however, the mechanisms underlying hyperhomocysteinemia-induced cognitive impairment remain unclear. In this study, we developed an hyperhomocysteinemia-induced cognitive impairment model by feeding mice a high-methionine diet and conducted behavioral and molecular analyses to elucidate the mechanisms involved in cognitive impairment. Behavioral experiments revealed significant cognitive deficits and neuroinflammation accompanied by a marked decrease in histone H3 lysine 27 acetylation in the hippocampus and cortex. Furthermore, metabolomic profiling and chromatin immunoprecipitation sequencing demonstrated substantial shifts in the levels of homocysteine metabolites and identified histone H3 lysine 27 acetylation-targeted genes involved in synaptic long-term potentiation, including Gria1, Gria3, Grin2a, Grin2b, Slc1a1, Slc24a2, Ptk2b, and Src. RNA sequencing  confirmed that hyperhomocysteinemia induced neurodegeneration. In vitro experiments confirmed that decreased histone H3 lysine 27 acetylation downregulates the expression of these target genes in homocysteine-treated HT-22 cells, thereby impairing synaptic plasticity. Collectively, these findings suggest that aberrant expression of long-term potentiation-related genes regulated by histone H3 lysine 27 acetylation is a key driver of hyperhomocysteinemia-induced cognitive impairment. Targeting histone H3 lysine 27 acetylation-mediated epigenetic dysregulation may be a promising therapeutic strategy, offering potential avenues for intervention in individuals with cognitive impairment and neurodegenerative disorders.

Key words: cognitive impairment, high-methionine diets, histone H3 lysine 27 acetylation, homocysteine, nerve regeneration, synaptic long-term potentiation