Phospholipases A2 mediate amyloid-β peptide-induced mitochondrial dysfunction

Abstract

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 (Aβ1-42)-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 Aβ1-42 to increase phosphorylation of cPLA2 in astrocytes through the NADPH oxidase and mitogen-activated protein kinase pathways. The involvement of PLA2 in Aβ1-42-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. Copyright © 2006 Society for Neuroscience.