Phospholipases A2 mediate amyloid-β peptide-induced mitochondrial dysfunction

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 A(2)(PLA(2)s), namely the cytosolic and the calcium-independent PLA(2)s (cPLA(2) and iPLA(2)), are key enzymes mediating oligomeric amyloid-beta peptide (A beta(1-42))-induced loss of mitochondrial membrane potential and increase in production of reactive oxygen species from mitochondria in astrocytes. Whereas the action of iPLA(2) is immediate, the action of cPLA(2) requires a lag time of similar to 12-15 min, probably the time needed for initiating signaling pathways for the phosphorylation and translocation of cPLA(2) to mitochondria. Western blot analysis indicated the ability of oligomeric A beta(1-42) to increase phosphorylation of cPLA(2) in astrocytes through the NADPH oxidase and mitogen-activated protein kinase pathways. The involvement of PLA(2) in A beta(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.