OBJECTIVE: Research has shown that hydrogen sulfide (H2S) plays a protective role in many diseases of the nervous system. The aim of this study is to investigate the effect of hypoxia on endogenous H2S concentration in the cerebral cortex of Alzheimer's disease (AD) transgenic mice and its mechanism. METHODS: AD transgenic mice were raised in closed boxes and pure nitrogen was introduced to reduce the oxygen concentration to 8%-10%, establishing an animal model of hypoxia. Oxygen partial pressure was measured with an oxygen meter. The expression of cystathionine-β-synthase (CBS) in cerebral cortex tissue was determined by Western blot, and H2S concentration was measured by a modified methylene blue method. RESULTS: (1) Hypoxia down-regulated CBS expression in cerebral cortex tissue of AD transgenic mice (p < 0.05). (2) The concentration of H2S in the cerebral cortex tissue of the hypoxic transgenic group was significantly lower than that of the Control group (p < 0.01). (3) Overexpression of CBS reversed the hypoxia-induced decrease of H2S concentration in the cerebral cortex tissue of AD transgenic mice (p < 0.01). CONCLUSIONS: Hypoxia decreased the concentration of endogenous H2S in the cerebral cortex tissue of AD transgenic mice by down-regulating the expression of CBS.