Novel Role of CXCR2 in Regulation of γ-Secretase Activity
Novel Role of CXCR2 in Regulation of γ-Secretase Activity
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DOI：
10.1021/cb800167a
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发表时间：
2008-12-01
影响因子：
4
通讯作者：
Mullan, Michael
中科院分区：
文献类型：
--
作者：
Bakshi, Pancham;Margenthaler, Elaina;Mullan, Michael
阿尔茨海默病（AD）是一种导致认知能力下降的进行性慢性疾病。一些研究已经将一些趋化因子和/或其受体的上调与APP加工的改变相关联，导致β-淀粉样蛋白（A β）的产生增加和AD病理变化。然而，迄今为止还没有直接的证据来确定APP的加工改变是否导致这些受体的上调，或者趋化因子受体的上调是否导致APP的加工调节。我们证明，用激动剂处理趋化因子受体CXCR 2可导致A β产生增强，而用拮抗剂处理或免疫耗竭CXCR 2的内源性激动剂导致A β抑制此外，我们发现CXCR 2拮抗剂对A β 40和A β 42的抑制作用是通过γ-分泌酶介导的，特别是通过减少γ-分泌酶组分之一早老素（PS）的表达。此外，体内慢性治疗与CXCR 2拮抗剂阻断A β 40和A β 42的生产。使用CXCR 2的小干扰RNA，我们进一步表明，CXCR 2在体外的敲低积累γ-分泌酶底物C99和C83，同时减少A β 40和A β 42的产生。总之，这些发现首次强烈表明CXCR 2受体的上调可能是A β产生增加的驱动力。我们的研究结果揭示了CXCR 2受体参与AD发病机制的新机制，并将其作为开发新型治疗药物的潜在靶点。此外，我们在这里提出了一个新的化学系列的利益，可以作为药物开发的原型。
Alzheimer's disease (AD) is a progressive chronic disorder that leads to cognitive decline. Several studies have associated up-regulation of some of the chemokines and/or their receptors with altered APP processing leading to increased production of beta-amyloid protein (A beta) and AD pathological changes. However, there is no direct evidence to date to determine whether the altered processing of APP results in up-regulation of these receptors or whether the up-regulation of the chemokine receptors causes modulated processing of APP. In the current study, we demonstrate that treatment of the chemokine receptor CXCR2 with agonists leads to enhancement of A beta production and treatment with antagonists or immunodepletion of CXCR2's endogenous agonists leads to A beta inhibition. Further, we found that the inhibitory effect of the antagonist of CXCR2 on A beta 40 and A beta 42 is mediated via gamma-secretase, specifically through reduction in expression of presenilin (PS), one of the gamma-secretase components. Also, in vivo chronic treatment with a CXCR2 antagonist blocked A beta 40 and A beta 42 production. Using small interfering RNAs for CXCR2, we further showed that knockdown of CXCR2 in vitro accumulates gamma-secretase substrates C99 and C83 with reduced production of both A beta 40 and A beta 42. Taken together, these findings strongly suggest for the first time that up-regulation of the CXCR2 receptor can be the driving force in increased production of A beta. Our findings unravel new mechanisms involving the CXCR2 receptor in the pathogenesis of AD and pose it as a potential target for developing novel therapeutics for intervention in this disease. Also, we propose here a new chemical series of interest that can serve as a prototype for drug development.