The Role of Heat Shock Protein 70 in the Protective Effect of YC-1 on b-Amyloid-Induced Toxicity in Differentiated

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 Ab25–35-induced cytotoxicity in differentiated PC12 cells. The results of this study showed that Ab25–35 (10 mM) significantly increased p25 protein production in a pattern that was consistent with the increase in m-calpain expression. Moreover, Ab25–35 significantly increased tau hyperphosphorylation and induced differentiated PC12 cell death. YC-1 (0.5–10 mM) prevented the cell death induced by Ab25–35. In addition, YC-1 (1, 10 mM) significantly blocked Ab25–35-induced m-calpain expression and decreased the formation of p25 and tau hyperphosphorylation. Moreover, YC-1 (5–20 mM) alone or combined with Ab25–35 (10 mM) 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 mM) or in PC12 cells transfected with an Hsp70 small interfering RNA. However, pretreatment of cells with the GC inhibitor ODQ (10 mM) did not affect the neuroprotective effect of YC-1 against Ab25–35 in differentiated PC12 cells. These results suggest that the neuroprotective effect of YC-1 against Ab25–35