Study of arachidonic acid metabolism in the aging brain

衰老大脑中花生四烯酸代谢的研究

• 批准号: 7132268
• 负责人: francesca bosetti
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7132268
• 关键词: Macaca mulatta; aging; animal old age; arachidonate; brain; cerebellum; dendrites; developmental neurobiology; eicosanoid metabolism; enzyme activity; enzyme biosynthesis; glial fibrillary acidic protein; hippocampus; immature animal; immunocytochemistry; laboratory rat; mature animal; neural transmission; phospholipase A2; prostaglandin endoperoxide synthase; prostaglandins; synapses

(1) Limited evidence suggests that brain cytosolic phospholipase A2 (cPLA2), which selectively releases arachidonic acid (AA) from membrane phospholipids, and cyclooxygenase-2 (COX-2), the rate-limiting enzyme for AA metabolism to prostanoids, are altered during normal aging. In this study, we examined the protein expression of cPLA2 and COX-2 enzymes in hippocampus, frontal pole and cerebellum from young (2-5 year-old), middle-aged (8-11 year-old) and old (23 year-old) male and female Rhesus monkeys. The cPLA2 protein level was decreased in the cerebellum from both middle-aged and old compared to the young monkeys, whereas the COX-2 protein level was decreased in the frontal pole from both middle-aged and old compared to the young monkeys. Immunohistochemistry in the frontal lobe confirmed fewer COX-2 immunopositive neurons in the old group compared to the young. Based on the localization of cPLA2 and COX-2 at post-synaptic sites in neurons and on evidence of loss of dendritic spines and markers for neurotransmission with aging, these results suggest that the decrease in protein levels of the two enzymes is caused by age-related synaptic dysfunction and that cPLA2 and COX-2 may be considered post-synaptic markers. (2) Only few data are available about COX expression and activity as well as prostaglandin profile during aging. This study aims to determine how these key enzymes in the AA cascade may contribute to the aging process in brain. Our preliminary results indicate an age-related decrease of COX-2 mRNA expression in the hippocampus of 24 and 27 months old rats compared to the young (4 months) and middle aged rats (12 months). However, the upstream enzyme cPLA2 did not show any changes during aging, as the mRNA and protein expression of cPLA2 remained unchanged during aging. Furthermore, we found a significant effect of age on GFAP protein expression in the hippocampus and cerebellum. Further experiments are needed to determine if this age-dependant increase is progressive or not.

（1）有限的证据表明，脑胞质磷脂酶A2（CPLA2）从膜磷脂中有选择地释放蛛网膜酸（AA），以及环氧酶-2（COX-2），在正常情况下，AA代谢剂对AA代谢的速率限制酶改变了AA代谢的速率限制酶。在这项研究中，我们检查了来自年轻（2-5岁），中年（8-11岁）和雄性和女性恒河猴的年轻（2-5岁），中年（2-5岁），中年（8-11岁）和雄性（23岁）的海马，额头和小脑中CPLA2和COX-2酶的蛋白质表达。与年轻的猴子相比，中年和老年的小脑中CPLA2蛋白水平降低，而与年轻的猴子相比，额叶和老年的Cox-2蛋白水平降低。与年轻人相比，额叶中的免疫组织化学证实了旧组的COX-2免疫阳性神经元。基于CPLA2和COX-2在神经元中突触后部位的定位以及在衰老中神经传递的树突状刺和标记的迹象，这些结果表明，两种酶的蛋白质水平的降低是由年龄相关的突触障碍和CPLA2和Cox-cpla2和Cox-2 Mo Chip sy synnapt y Mo cpla2引起的。 （2）在衰老期间，只有很少的有关COX表达和活动以及前列腺素的数据。这项研究旨在确定AA级联反应中的这些关键酶如何有助于大脑的衰老过程。我们的初步结果表明，与年轻大鼠（4个月）和中年大鼠（12个月）相比，海马24和27个月大鼠的COX-2 mRNA表达降低。但是，上游酶CPLA2在衰老过程中没有显示出任何变化，因为在衰老过程中CPLA2的mRNA和蛋白质表达保持不变。此外，我们发现年龄对海马和小脑GFAP蛋白表达的显着影响。需要进一步的实验来确定这种依赖年龄的增加是否进行了进行性。