Neurodegenerative brain disorders such as Alzheimer's disease (AD) have been well investigated. However, significant methods for the treatment of the progression of AD are unavailable currently. Heat shock protein 70 (Hsp70) plays important roles in neural protection from stress by assisting cellular protein folding. In this study, we investigated the effect and the molecular mechanism of YC-1, an activator of guanylyl cyclase (GC), on A beta(25-35)-induced cytotoxicity in differentiated PC12 cells. The results of this study showed that A beta(25-35) (10 mu M) significantly increased p25 protein production in a pattern that was consistent with the increase in mu-calpain expression. Moreover, A beta(25-35) significantly increased tau hyperphosphorylation and induced differentiated PC12 cell death. YC-1 (0.5-10 mu M) prevented the cell death induced by A beta(25-35). In addition, YC-1 (1, 10 mu M) significantly blocked A beta(25-35)-induced mu-calpain expression and decreased the formation of p25 and tau hyperphosphorylation. Moreover, YC-1 (5-20 mu M) alone or combined with A beta(25-35) (10 mu M) significantly increased the expression of Hsp70 in differentiated PC12 cells. The neuroprotective effect of YC-1 was significantly attenuated by an Hsp70 inhibitor (quercetin, 50 mu M) or in PC12 cells transfected with an Hsp70 small interfering RNA. However, pretreatment of cells with the GC inhibitor ODQ (10 mu M) did not affect the neuroprotective effect of YC-1 against A beta(25-35) in differentiated PC12 cells. These results suggest that the neuroprotective effect of YC-1 against A beta(25-35)-induced toxicity is mainly mediated by the induction of Hsp70. Thus, YC-1 is a potential agent against AD.
