Phospholipases A2 mediate amyloid-beta 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 (PLA2s), namely the cytosolic and the calcium-independent PLA2s (cPLA2 and iPLA2), are key enzymes mediating oligomeric amyloid-beta peptide (Abeta(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 approximately 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 Abeta(1-42) to increase phosphorylation of cPLA2 in astrocytes through the NADPH oxidase and mitogen-activated protein kinase pathways. The involvement of PLA2 in Abeta(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.
Zhu
Donghui
D
Department of Biological Engineering, University of Missouri, Columbia, Missouri 65211, USA.
Lai
Yinzhi
Y
Shelat
Phullara B
PB
Hu
Chunhua
C
Sun
Grace Y
GY
Lee
James C-M
JC
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D003600:Cytosol / Q000201:enzymology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity; D010741:Phospholipases A / Q000502:physiology*; D054467:Phospholipases A2; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D010741:Phospholipases A; D054467:Phospholipases A2; D002118:Calcium