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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 A 2  (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, cPLA2 activity and leukotriene B 4  (LTB4) levels were identified in ApoE4 compared to ApoE3 in primary astrocytes, brains of ApoE-targeted replacement (ApoE-TR) mice, and in human brain homogenates from the inferior frontal cortex of patients with AD carrying  APOE3/E4  compared to  APOE3/E3 . Greater cPLA2 phosphorylation was also observed in human postmortem frontal cortical synaptosomes and primary astrocytes after treatment with recombinant ApoE4 ex vivo. In ApoE4 astrocytes, the greater levels of LTB4, reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) were reduced after cPLA2 inhibition.    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.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13024-021-00438-3.

molecular neurodegeneration

RETRACTED ARTICLE: Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4