Presenilin 2 is the predominant γ-secretase in microglia and modulates cytokine release.
Presenilin 2 is the predominant γ-secretase in microglia and modulates cytokine release.
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DOI：
10.1371/journal.pone.0015743
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发表时间：
2010-12-29
期刊：
影响因子：
3.7
通讯作者：
Garden GA
中科院分区：
文献类型：
--
作者：
Jayadev S;Case A;Eastman AJ;Nguyen H;Pollak J;Wiley JC;Möller T;Morrison RS;Garden GA
早老素 1 (PS1) 和早老素 2 (PS2) 是 γ-分泌酶复合物的酶成分，可裂解淀粉样前体蛋白 (APP)，释放淀粉样β (Aβ) 肽。小鼠 PS 缺乏会在缺乏 Aβ 积累的情况下导致神经炎症和神经变性。我们假设 PS 通过其在中枢神经系统先天免疫细胞中的 γ 分泌酶作用来影响神经炎症。我们将原代小鼠小胶质细胞暴露于药理学γ-分泌酶抑制剂中，导致对脂多糖的反应导致TNFα和IL-6的过度释放。为了确定这种反应是否由 PS1、PS2 或两者介导，我们使用 shRNA 敲低小鼠小胶质细胞系中的每个 PS。 PS1 的敲低不会导致 γ-分泌酶活性降低，而 PS2 敲低则导致 γ-分泌酶活性显着降低。敲低 PS2 后观察到促炎细胞因子释放增加，但敲除 PS1 后未观察到。体外促炎刺激增加小胶质细胞 PS2 基因转录和蛋白质。这是首次证明 PS2 调节 CNS 先天免疫。综上所述，我们的研究结果表明，PS2 是小胶质细胞中主要的 γ 分泌酶，可调节促炎细胞因子的释放。我们认为 PS2 可能参与调节小胶质细胞炎症行为的负反馈回路。
Presenilin 1 (PS1) and Presenilin 2 (PS2) are the enzymatic component of the γ-secretase complex that cleaves amyloid precursor protein (APP) to release amyloid beta (Aβ) peptide. PS deficiency in mice results in neuroinflammation and neurodegeneration in the absence of accumulated Aβ. We hypothesize that PS influences neuroinflammation through its γ-secretase action in CNS innate immune cells. We exposed primary murine microglia to a pharmacological γ-secretase inhibitor which resulted in exaggerated release of TNFα and IL-6 in response to lipopolysaccharide. To determine if this response was mediated by PS1, PS2 or both we used shRNA to knockdown each PS in a murine microglia cell line. Knockdown of PS1 did not lead to decreased γ-secretase activity while PS2 knockdown caused markedly decreased γ-secretase activity. Augmented proinflammatory cytokine release was observed after knockdown of PS2 but not PS1. Proinflammatory stimuli increased microglial PS2 gene transcription and protein in vitro. This is the first demonstration that PS2 regulates CNS innate immunity. Taken together, our findings suggest that PS2 is the predominant γ-secretase in microglia and modulates release of proinflammatory cytokines. We propose PS2 may participate in a negative feedback loop regulating inflammatory behavior in microglia.
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