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Presenilin 2 deficiency facilitates Aβ-induced neuroinflammation and injury by upregulating P2X7 expression

查看全文 作　　者：Juliang [1]Qin;Xiaoyu [1]Zhang;Ziqiang [1]Wang;Jinju [1]Li;Zhen [1]Zhang;Liangcai [1]Gao;Hua [1]Ren;Min [1]Qian;Bing [1]Du 高影响力作者 机构地区：[1]Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China高影响力机构 出　　处：《Science China(Life Sciences)》索引2017年第60卷第2期,共13页高影响力期刊 基　　金：supported by the National Natural Science Foundation of China (31470040, 31570896, 81172816, 81672811);Doctoral Fund of Ministry of Education of China (20130076110013);Science and Technology Commission of Shanghai Municipality(15JC1401500) 摘　　要：Accumulating evidence suggests that β-amyloid (Aβ)-induced neuroinflammation plays a prominent and early role in Alzheimer’s disease (AD). In this study, we demonstrated that Presenilin 2 (PS2) deficiency facilitates Aβ-induced neuroinflammation and injury by upregulating P2X7 expression both in vitro and in vivo. PS2 knockout mice demonstrated increased cognitive impairments and cerebral injury. PS2 deficiency increased the expression of P2X7 both in neurons and microglial cells.Furthermore, extracellular ATP also increased in both Aβ-treated and untreated PS2 knockout microglial cells. Notably, Aβ-induced classical proinflammatory cytokines such as IL-1β, IL-1α and TNF-α were increased in PS2 knockout microglial cells, suggesting a potential role for PS2 in the regulation of neuroinflammation. The expression of P2X7 clearly increased in PS2 knockdown BV2 cells. Consistent with in vivo data, Aβ-induced IL-1β production was also clearly enhanced in PS2 knockdown BV2 cells. Additionally, expression of the transcription factor Sp1 was increased in PS2 knockdown cells. When we treated PS2 knockdown cells with the specific Sp1 inhibitor MIT, we observed that enhanced P2X7 expression was significantly rescued. Taken together, these data suggests that PS2 plays a protective role during Aβ-induced neuroinflammation and injury through down-regulation of P2X7 expression. 关 键 词：Β-淀粉样蛋白 P2X7 受体表达 炎症反应 脑损伤 诱导 小胶质细胞 IL-1β
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