Inhibition of cPLA2 ameliorates memory deficits and reduces neuroinflammation in ApoE4‐TR mice

Abstract

AbstractBackgroundThe activation of calcium‐dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling by promoting the conversion of arachidonic acid (AA) into eicosanoids, while catabolizing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We previously found higher cPLA2 activation correlated with increased pro‐inflammatory lipid metabolites in APOE4 brains. However, it is not known whether the inhibition cPLA2 will decrease neuroinflammation ApoE4‐mice.MethodFirst, ApoE4 targeted replacement mice (ApoE4‐TR, n = 3, male, 4 months old) were treated daily with vehicle or the specific cPLA2 inhibitor ASB14780 (10 mg/kg, intraperitoneal) for three days. The brains were collected and analyzed using LC‐MS based lipidomics. Second, ApoE2‐TR (n = 14, 8M/6F), ApoE3‐TR (n = 12, 5M/7F) and ApoE4‐TR (n = 17, 8M/9F) mice were fed a low‐DHA diet starting at 6 months old. ApoE4 mice were treated daily for three weeks with vehicle (n = 8, 4M/4F) or 10mg/kg/day ASB14780 IP (n = 9, 5M/4F) starting at 14 months old. Behavioral tests were subsequently conducted on the mice, after which the brains were collected for lipidomic and biochemical analyses.ResultIP ASB14780 was detected in brain tissue corresponding with decreases in pro‐inflammatory metabolites of AA after only 3 days treatment in ApoE4‐TR mice. In addition, long term ASB14780 treatment decreased brain cPLA2 phosphorylation levels and significantly increased brain EPA and DHA levels (p<0.01 for both) but did not change brain AA levels in ApoE4‐TR mice. Compared to ApoE3‐TR mice, untreated ApoE4‐TR mice had higher levels of inflammatory eicosanoids (e.g., prostaglandin E2, PGE2) resulting from AA metabolism. However, ASB14780 treatment decreased inflammatory metabolites in ApoE4‐TR mice. Additionally, ASB14780‐treatment was able to reduce microglia activation in ApoE4‐TR mice (p = 0.04 for hippocampus and p<0.01 for cortex). For behavioral experiments, ApoE4‐TR mice had significantly lower discrimination index compared to ApoE3‐TR mice at 15 months using the novel object recognition test (p = 0.029). Treatment with ASB14780 ameliorated the recognition deficits of ApoE4‐TR mice but the effects did not reach statistical significance (p = 0.15).ConclusionOur findings reveal inhibition of cPLA2 with ASB14780 could ameliorate eicosanoid‐driven neuroinflammation in ApoE4 mice, restoring synaptic dysfunction, and preventing behavioral deficits. cPLA2 represents a potential drug target to mitigate increased neuroinflammation with APOE4 and AD.