With the aging of the world's population, the threat of age-related cognitive impairment is increasing. It is of great significance to study the mechanism of age-related cognitive impairment and find effective strategies to rescue it. Our previous studies have demonstrated that S-nitrosoglutathione reductase(GSNOR) was significantly increased in the hippocampus of aging mice and neuronal-specific GSNOR transgenic mice showed cognitive impairment in behavior tests. However, the mechanisms underlying this process remain unclear. Here, we found that CREB signaling was significantly decreased by GSNOR in cultured mice hippocampus neurons and GSNOR transgenic mice. Up regulation of the CREB signaling pathway by nobiletin rescued the cognitive impairment in GSNOR transgenic mice in Y-maze test. Nobiletin also showed protective effects on memory impairment in aging mice model. These results provide a new mechanism for the cognitive impairment in GSNOR transgenic mice and provide a new potential strategy to improve the cognitive function by nobiletin. GSNOR transgenic mice may be used as a screen model as age-related cognitive impairment.