GSNOR Impaired Cognitive Function in Aging Through De-Nitrosation of CamKIIalpha

As a result of the acceleration of population aging, an increasing number of people suffer from age related cognitive impairment. However, the mechanisms that underlie this process are unclear. Here we found that S-nitrosoglutathione reductase (GSNOR), the key enzyme metabolizing the intracellular nitric oxide (NO) and S-nitrosation, significantly increased in the hippocampus of both aging human and mice. Neuronal specific overexpression of GSNOR leads to cognitive impairment, long-term potentiation (LTP) defect and lower dendrite spine density. While knock out GSNOR rescued the age related cognitive impairment. We then performed quantitative proteomic analysis of protein S-nitrosation and found S-nitrosation of CamKIIα was significantly decreased in the hippocampus of aging mice and GSNOR transgenic mice. In consistent with the change of CamKIIα S-nitrosation, the accumulation of CamKIIα in hippocampal Synaptosomal and its downstream signaling p-GLUR1 and CREB/c-fos were also significantly decreased, which can all be rescued in GSNOR knockout mice. The cognitive impairment in GSNOR transgenic mice can be rescued by up-regulation of the NO signaling pathway or CamKIIα/CREB signaling pathway. In summary, our research demonstrated that GSNOR is a new potential target for treatment of the age related cognitive impairment. NO signaling deficiency may be the main cause to induce age-related cognitive impairment. In addition, we explored the physiological function of S-nitrosation of CamKIIα for the first time.