Chronic stress disturbed the metabolism of homocysteine in mouse hippocampus and prefrontal cortex.

Stress is an independent risk factor for cognitive impairment, with elevated plasma homocysteine (HCY) levels playing a crucial role in stress-induced cognitive decline. While the rise in plasma HCY levels is linked to abnormal peripheral catabolism, the impact of stress on HCY catabolism in the brain remains unclear. This study investigated the effect of stress on HCY metabolism in the brain by analyzing HCY and its metabolic enzymes in the hippocampus and prefrontal cortex. The results showed a significant decrease in enzymes MS (methionine-synthase), CBS (cystathionineβ-synthase), and CSE (cystathionine γ-lyase) in these brain regions of mice subjected to 3 weeks of restraint stress, leading to HCY accumulation. Additionally, the enzyme MTHFR (methylenetetrahydrofolate reductase) remained unchanged. Immunofluorescence double-labeling revealed the downregulation of HCY metabolic enzymes in neurons of stressed mice. The transcription factor KLF4 (Kruppel-likefactor4), known for its inhibitory role, increased after stress or glucocorticoid treatment and suppressed the expression of MS, CBS, and CSE, contributing to elevated HCY levels in the brain. These findings offer new insights into the impairment of HCY catabolism in the stressed brain, suggesting that the downregulation of HCY metabolic enzymes may underlie HCY accumulation and exacerbate stress-induced cognitive dysfunction.