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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.