Abstract
BackgroundApolipoprotein 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.MethodsMouse 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.ResultsGreater cPLA2 phosphorylation, cPLA2 activity and leukotriene B4 (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.ConclusionsOur 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.
Highlights
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
Results cytosolic phospholipase A2 (cPLA2) and phosphorylated cPLA2 are increased in ApoE4 mouse primary astrocytes We previously found that docosahexaenoic acid (DHA)/arachidonic acid (AA) ratio in cerebrospinal fluid (CSF) is lower in APOE4/E4 carriers compared to APOE3/E3 carriers [21, 22]
To further explore the activities of cPLA2 and iPLA2, the efflux of 3H-AA or 14C-DHA from ApoE3 and ApoE4 primary astrocyte cells to media with or without ATP stimulation for 15 min was examined. 3H-AA efflux was significantly greater in stimulated ApoE4 compared to ApoE3 primary astrocytes (Fig. 1e), whereas 14C-DHA efflux showed no difference between ApoE4 and ApoE3 (Fig. 1f)
Summary
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. CPLA2 and AA metabolic pathways contribute to reactive oxygen species (ROS) and nitric oxide (NO) production during cell activation [8]. CPLA2 activation is one of the pathways that activates microglia and astrocytes in the brain. The activation of cPLA2 by Aβ oligomers contributes to dysregulation of fatty acid metabolism and promotes neurodegeneration [15, 16]. Overexpression of p25 (Protein 25, a cyclin-dependent kinase 5 activator) in neurons increases the expression of cPLA2, leading to lysophosphatidylcholine (LPC) secretion and the activation of astrocytes and production of proinflammatory cytokines [17]. Knocking out cPLA2 in microglia decreases lipopolysaccharide (LPS) induced oxidative stress and inflammatory response [8]
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