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The Journal of Neuroscience, October 25, 2006, 26(43):11111-11119; doi:10.1523/JNEUROSCI.3505-06.2006

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Neurobiology of Disease
Phospholipases A₂ Mediate Amyloid- Peptide-Induced Mitochondrial Dysfunction

Donghui Zhu,¹ Yinzhi Lai,¹ Phullara B. Shelat,² Chunhua Hu,² Grace Y. Sun,² and James C-M. Lee¹

Departments of ¹Biological Engineering and ²Biochemistry, University of Missouri, Columbia, Missouri 65211

Correspondence should be addressed to Dr. James C-M. Lee, Department of Biological Engineering, University of Missouri, Columbia, MO 65211. Email: leejam{at}missouri.edu

Mitochondrial dysfunction has been implicated in the pathophysiology of Alzheimer's disease (AD) brains. To unravel the mechanism(s) underlying this dysfunction, we demonstrate that phospholipases A₂ (PLA₂s), namely the cytosolic and the calcium-independent PLA₂s (cPLA₂ and iPLA₂), are key enzymes mediating oligomeric amyloid- peptide (A_1–42)-induced loss of mitochondrial membrane potential and increase in production of reactive oxygen species from mitochondria in astrocytes. Whereas the action of iPLA₂ is immediate, the action of cPLA₂ requires a lag time of 12–15 min, probably the time needed for initiating signaling pathways for the phosphorylation and translocation of cPLA₂ to mitochondria. Western blot analysis indicated the ability of oligomeric A_1–42 to increase phosphorylation of cPLA₂ in astrocytes through the NADPH oxidase and mitogen-activated protein kinase pathways. The involvement of PLA₂ in A_1–42-mediated perturbations of mitochondrial function provides new insights to the decline in mitochondrial function, leading to impairment in ATP production and increase in oxidative stress in AD brains.

Key words: Alzheimer's disease (AD); amyloid- peptide (A); phospholipase A₂ (PLA₂); mitochondrial membrane potential; reactive oxygen species; oxidative stress

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Received March 10, 2006; revised Sept. 12, 2006; accepted Sept. 17, 2006.

Correspondence should be addressed to Dr. James C-M. Lee, Department of Biological Engineering, University of Missouri, Columbia, MO 65211. Email: leejam{at}missouri.edu

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