Overexpression of mitochondrial Hsp75 protects neural stem cells against microglia-derived soluble factor-induced neurotoxicity by regulating mitochondrial permeability transition pore opening in vitro.
Microglia (MG)-induced neurotoxicity, a major determinant of Alzheimer's disease, is closely related to the survival of neural stem cells (NSCs). Heat shock protein 75 (Hsp75) has been reported to exert protective effects against environmental stresses; however, whether or not it protects NSCs against MG-derived soluble factor-induced neurotoxicity remains unclear. In the present study, we constructed NSCs that overexpressed human Hsp75 protein and established a co-culture system in order to elucidate the role of Hsp75 in NSC-MG interactions. The results obtained indicated that Hsp75 expression increased after 12 h of soluble factor induction and continued to increase for up to 36 h of treatment. The overexpression of Hsp75 decreased NSC apoptosis and preserved mitochondrial membrane potential. Further experiments revealed that the overexpression of Hsp75 inhibited the formation of cyclophilin D (CypD)-dependent mitochondrial permeability transition pore (mPTP) involvement in neurotoxicity-mediated mitochondrial dysfunction and suppressed the activation of the mitochondrial apoptotic cascade, as demonstrated by the inhibition of the release of cytochrome c (Cytc) and the activation of caspase-3. The findings of this study demonstrate that Hsp75 overexpression prevents the impairment of NSCs induced by MG-derived soluble factors by regulating the opening of mPTP. Thus, Hsp75 warrants further investigation as a potential candidate for protection against neurotoxicity.
Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China.
Yan
Y
Wang
Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, P.R. China.
Jizong
J
Lin
Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China.
Qing-Zhuang
QZ
Chen
Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China.
Ning
N
Zhu
Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China.
De-Qi
DQ
Jiang
Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China.
Ming-Xing
MX
Li
Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China.
Yong
Y
Wang
D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018920:Coculture Techniques; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility
D016229:Amyloid beta-Peptides; D000081406:Peptidyl-Prolyl Isomerase F; D016207:Cytokines; D018841:HSP90 Heat-Shock Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C092306:TRAP1 protein, human; C075222:amyloid beta-protein (1-42); D045304:Cytochromes c; D053148:Caspase 3; D021983:Cyclophilins