Distribution of Secretory Phospholipase A2 XIIA in the Brain and its Role in Lipid Metabolism and Cognition

摘要

Phospholipases A2(PLA2) catalyze the hydrolysis of membrane phospholipids to produce free fatty acids and lysophospholipids, which have important functions in cell signaling. The present study elucidated differential expression of PLA2isoforms in the rat cortex by quantitative reverse transcription PCR and demonstrated that sPLA2-XIIA had greater messenger RNA expression than iPLA2-VI or cPLA2-IVA in different brain regions, or compared to other sPLA2isoforms in the prefrontal cortex (PFC) and hippocampus. Western blots identified a 24-kDa band in different regions of the adult brain, and high levels of sPLA2-XIIA protein expression were detected in the PFC, striatum, and thalamus. Electron microscopy showed that sPLA2-XIIA is present in axon terminals and dendrites. Injection of antisense oligonucleotide to sPLA2-XIIA in the PFC and lipidomic analysis showed increase in phospholipid but decrease in lysophospholipid species consistent with decreased catalytic activity of the enzyme, changes in arachidonic acid release, and alterations in sphingolipids. sPLA2-XIIA knockdown also resulted in shorter latency timings in the passive avoidance test, and higher number of errors in the attention set-shifting task, indicating deficits in working memory and attention. Together, the results show an important role of sPLA2-XIIA in lipid metabolism, prefrontal cortical function, and cognition.