Amyloid-beta peptide (Aβ) is shown to be toxic to the mitochondria and implicates this organelle in the pathogenesis of Alzheimer's disease. Previous studies suggest that targeting mitochondria for protection may be a useful strategy to reduce Aβ-induced neurotoxicity. Mortalin is the mitochondrial located member of the heat shock protein 70 family, which serves as a major mitochondrial molecular chaperone and plays a key role in mitochondrial import of proteins. Several studies have demonstrated the protective potential of Hsp75 overexpression against apoptosis induced by various forms of stresses. To investigate whether mortalin overexpression could provide protective effects on Aβ toxicity, SH-SY5Y cells were used to transfect human mortalin gene and then treated with Aβ(1-42) for 24h. It is found that overexpression of mortalin efficiently attenuated Aβ(1-42)-induced cell viability damage and apoptosis. Additionally, inhibition of mortalin expression by mortalin-specific siRNA oligonucleotides sensitized SH-SY5Y cells to Aβ(1-42)-induced neurotoxicity. Furthermore, mortalin overexpression significantly inhibited the Aβ(1-42)-induced depolarization of mitochondrial membrane potential, reversed the Aβ(1-42)-induced reduction in cytochrome c oxidase activity and ATP generation, and suppressed the Aβ(1-42)-induced reactive oxygen species accumulation and lipid peroxidation. Together, our results suggest that mortalin can afford protection against Aβ(1-42)-induced neurotoxicity in SH-SY5Y cells. These beneficial effects of mortalin overexpression may be attributable to its roles in maintaining mitochondrial function and reducing oxidative stress.
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