Ait-Ghezala Ghania, Volmar Claude-Henry, Frieling Jeremy, Paris Daniel, Tweed Miles, Bakshi Pancham, Mullan Michael
The Roskamp Institute, Sarasota, FL 34243, USA.
Eur J Neurosci. 2007 Mar;25(6):1685-95. doi: 10.1111/j.1460-9568.2007.05424.x.
The CD40 receptor is a member of the tumor necrosis factor (TNF) super-family of trans-membrane receptors. Interaction of CD40 with its ligand CD40L mediates a broad range of immune and inflammatory responses in the periphery and in the central nervous system. Recently it has been suggested that CD40/CD40L interaction is involved in amyloid precursor protein (APP) processing and Alzheimer's disease (AD)-like pathology in transgenic mouse models of AD. We have previously shown that pharmacologically inhibiting CD40/CD40L interaction improves memory deficits in the PSAPP AD mouse model. We have also recently shown that CD40 deficiency mitigates amyloid deposition in APPsw and PSAPP mouse models. In the present report, using human embryonic kidney cells (HEK293) over-expressing both the APPsw mutation and CD40, we demonstrate that CD40/CD40L interaction directly increases the production of APP metabolites (Abeta 1-40, Abeta 1-42, CTFs, sAPPbeta and sAPPalpha). The results also show that CD40/CD40L interaction affects APP processing via the NF-kappaB pathway. Using NFkappaB inhibitors and SiRNAs to silence diverse elements of the NFkappaB pathway, we observe a reduction in levels of both Abeta 1-40 and Abeta 1-42. Taken together, our results further suggest that CD40L stimulation may be a key component in AD pathology and that elements of the NF-kappaB pathway may be suitable targets for therapeutic approaches against AD.
CD40受体是跨膜受体肿瘤坏死因子(TNF)超家族的成员。CD40与其配体CD40L的相互作用介导外周和中枢神经系统中的多种免疫和炎症反应。最近有研究表明,在转基因阿尔茨海默病(AD)小鼠模型中,CD40/CD40L相互作用参与淀粉样前体蛋白(APP)的加工和AD样病理过程。我们之前已经表明,药理学抑制CD40/CD40L相互作用可改善PSAPP AD小鼠模型中的记忆缺陷。我们最近还表明,CD40缺陷可减轻APPsw和PSAPP小鼠模型中的淀粉样蛋白沉积。在本报告中,我们使用过表达APPsw突变体和CD40的人胚肾细胞(HEK293),证明CD40/CD40L相互作用直接增加APP代谢产物(β-淀粉样蛋白1-40、β-淀粉样蛋白1-42、CTFs、sAPPβ和sAPPα)的产生。结果还表明,CD40/CD40L相互作用通过NF-κB途径影响APP加工。使用NF-κB抑制剂和小干扰RNA(SiRNAs)沉默NF-κB途径的不同元件,我们观察到β-淀粉样蛋白1-40和β-淀粉样蛋白1-42水平降低。综上所述,我们的结果进一步表明,CD40L刺激可能是AD病理的关键组成部分,并且NF-κB途径的元件可能是抗AD治疗方法的合适靶点。