The role of heat shock protein 70 in the protective effect of YC-1 on β-amyloid-induced toxicity in differentiated PC12 cells.
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 Aβ25-35-induced cytotoxicity in differentiated PC12 cells. The results of this study showed that Aβ25-35 (10 µM) significantly increased p25 protein production in a pattern that was consistent with the increase in μ-calpain expression. Moreover, Aβ25-35 significantly increased tau hyperphosphorylation and induced differentiated PC12 cell death. YC-1 (0.5-10 µM) prevented the cell death induced by Aβ25-35. In addition, YC-1 (1, 10 µM) significantly blocked Aβ25-35-induced μ-calpain expression and decreased the formation of p25 and tau hyperphosphorylation. Moreover, YC-1 (5-20 µM) alone or combined with Aβ25-35 (10 µM) 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 µM) or in PC12 cells transfected with an Hsp70 small interfering RNA. However, pretreatment of cells with the GC inhibitor ODQ (10 µM) did not affect the neuroprotective effect of YC-1 against Aβ25-35 in differentiated PC12 cells. These results suggest that the neuroprotective effect of YC-1 against Aβ25-35-induced toxicity is mainly mediated by the induction of Hsp70. Thus, YC-1 is a potential agent against AD.
Department of Obstetrics and Gynecology, Chi-Mei Medical Center, Tainan, Taiwan.
Yung-Chieh
YC
Tsai
Yen-Mei
YM
Lee
Kwok-Keung
KK
Lam
Jui-Fen
JF
Lin
Jhi-Joung
JJ
Wang
Mao-Hsiung
MH
Yen
Pao-Yun
PY
Cheng
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002154:Calpain / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D006162:Guanylate Cyclase / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007191:Indazoles / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D016716:PC12 Cells; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D018840:HSP70 Heat-Shock Proteins; D007191:Indazoles; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D016875:tau Proteins; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D002154:Calpain; C449002:mu-calpain; D006162:Guanylate Cyclase