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 A₂ (PLA ₂s), namely the cytosolic and the calcium-independent PLA ₂s (cPLA₂ and iPLA₂), are key enzymes mediating oligomeric amyloid-β peptide (Aβ_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 Aβ_1-42 to increase phosphorylation of cPLA₂ in astrocytes through the NADPH oxidase and mitogen-activated protein kinase pathways. The involvement of PLA₂ in Aβ_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.