Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4

Background: Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer's disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within the plaques of AD brains. The relation between APOE4 genotype and cPLA2 activity is not known.Methods: Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation, and activity in relation to measures of inflammation and oxidative stress. Results: Greater cPLA2 phosphorylation and activity was identified in ApoE4 compared to ApoE3 in primary astrocytes and brains of ApoE-targeted replacement (ApoE-TR) mice. These differences were also demonstrated in brain homogenates from the inferior frontal cortex from AD patients carrying APOE3/4 compared to APOE3/3. Higher cPLA2 activation with APOE4 was associated with greater activation of the MAPK p38 pathway in human postmortem frontal cortical synaptosomes and astrocytes, as well as with higher levels of leukotriene B4 (LTB4), reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) in astrocytes. Inhibition of cPLA2 reduced LTB4, ROS, and iNOS levels in ApoE4 primary astrocytes to those in ApoE3 astrocytes. Conclusions: Our findings implicate greater activation of cPLA2 signaling system with APOE4, which could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.