Presenilin 2 deficiency facilitates Abeta-induced neuroinflammation and injury by upregulating P2X7 expression.
Presenilin 2 deficiency facilitates Abeta-induced neuroinflammation and injury by upregulating P2X7 expression.
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早老素 2 缺乏通过上调 P2X7 表达促进 Aβ 诱导的神经炎症和损伤
DOI：
10.1007/s11427-016-0347-4
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Du Bing
中科院分区：
文献类型：
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作者：
Qin Juliang;Zhang Xiaoyu;Wang Ziqiang;Li Jinju;Zhang Zhen;Gao Liangcai;Ren Hua;Qian Min;Du Bing
越来越多的证据表明，β-淀粉样蛋白(Aβ)诱导的神经炎症在阿尔茨海默病(AD)中起着重要的早期作用。在这项研究中，我们证明了早老素2(PS2)缺乏在体内外通过上调P2X7的表达来促进Aβ诱导的神经炎症和损伤。PS2基因敲除小鼠表现出认知障碍和脑损伤的增加。PS2缺乏增加了神经元和小胶质细胞中P2X7的表达。此外，Aβ处理的和未处理的PS2基因敲除的小胶质细胞胞外三磷酸腺苷也增加。值得注意的是，在pS2基因敲除的小胶质细胞中，β诱导的经典致炎细胞因子如IL-1β、IL-1α和肿瘤坏死因子-α增加，提示pS2在神经炎症的调节中可能起作用。在PS2基因敲除的BV2细胞中，P2X7的表达明显增加。与活体数据一致的是，在pS2基因敲除的BV2细胞中，Aβ诱导的IL-1β的产生也明显增强。此外，转录因子Sp1在PS2基因敲除细胞中的表达增加。当我们用特定的Sp1抑制剂MIT处理PS2基因敲除细胞时，我们观察到增强的P2X7表达被显著挽救。综上所述，这些数据表明，PS2在Aβ诱导的神经炎症和损伤中通过下调P2X7的表达而发挥保护作用。
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 bothin vitroandin 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 within vivodata, 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.