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Published on: October 9, 2010
Mortalin overexpression attenuates beta-amyloid-induced neurotoxicity in SH-SY5Y cells
Mingyue Qu1, Zhou Zhou, Shangcheng Xu
1Department of Occupational Health, The Third Military Medical University, Chongqing 400038, China.
Abstract:
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.
Insights
Mortalin protects against amyloid-beta peptide (Aβ) toxicity in Alzheimer's disease models. Overexpressing mortalin preserves mitochondrial function and reduces neurotoxicity, offering a potential therapeutic strategy.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Amyloid-beta peptide (Aβ) is implicated in Alzheimer's disease pathogenesis due to its mitochondrial toxicity.
- Mitochondrial protection is a potential therapeutic strategy against Aβ-induced neurotoxicity.
- Mortalin, a mitochondrial heat shock protein 70 family member, acts as a molecular chaperone and aids protein import into mitochondria.
Purpose of the Study:
- To investigate the protective effects of mortalin overexpression against Aβ toxicity.
- To determine if mortalin plays a role in mitigating Aβ-induced neurotoxicity in neuronal cells.
Main Methods:
- SH-SY5Y cells were transfected with the human mortalin gene.
- Cells were subsequently treated with Aβ(1-42) to induce toxicity.
- Mortalin expression was inhibited using mortalin-specific siRNA oligonucleotides.
- Mitochondrial function markers, including membrane potential, cytochrome c oxidase activity, ATP generation, reactive oxygen species, and lipid peroxidation, were assessed.
Main Results:
- Overexpression of mortalin significantly attenuated Aβ(1-42)-induced damage to cell viability and apoptosis.
- Inhibition of mortalin expression sensitized cells to Aβ(1-42)-induced neurotoxicity.
- Mortalin overexpression preserved mitochondrial membrane potential, cytochrome c oxidase activity, and ATP generation.
- Mortalin suppressed Aβ(1-42)-induced reactive oxygen species accumulation and lipid peroxidation.
Conclusions:
- Mortalin provides significant protection against Aβ(1-42)-induced neurotoxicity in SH-SY5Y cells.
- The protective effects are linked to mortalin's role in maintaining mitochondrial function and reducing oxidative stress.
- Targeting mortalin may represent a promising therapeutic avenue for Alzheimer's disease.
