Zhang X, Luhrs K J, Ryff K A, Malik W T, Driscoll M J, Culver B
Division of Pharmaceutical Sciences and Graduate Neuroscience Program, University of Wyoming, College of Health Sciences, Department 3375, 1000 East University Avenue, Laramie, WY 82071-3375, USA.
Neuroscience. 2009 Jun 16;161(1):53-8. doi: 10.1016/j.neuroscience.2009.03.010. Epub 2009 Mar 13.
Neuroinflammation has been linked to the pathologies of Alzheimer's disease (AD), however, its effects on beta-amyloid (Abeta) burden are unclear. This study investigated the role of nuclear factor kappa B (NF-kappaB) in regulating neuroinflammation and Abeta deposition in a transgenic mouse model of AD. The APPswe/PS1dE9 mice and their wild-type controls received either the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC, i.p. 50 mg/kg daily) or saline starting at 7 months of age for 5 months. Expression of cyclooxygenase-2 (COX-2), tissue necrosis factor alpha (TNFalpha) precursor protein and microtubule-associated protein 2 was determined, and astrogliosis was assessed. Hippocampal and cortical levels of Abeta(1-40) and Abeta(1-42) were measured using ELISA. PDTC treatment effectively suppressed NF-kappaB signaling in APPswe/PS1dE9 mice as evidenced by the abolishment of COX-2 and TNFalpha induction. Inhibition of NF-kappaB further attenuated astrogliosis in the transgenic AD mice, yet markedly increased cerebral Abeta(1-42) burden. Our findings suggest that NF-kappaB can mediate induction of COX-2, TNFalpha and astrogliosis in APPswe/PS1dE9 mice. Additionally, these results support the idea that neuroinflammation contributes to the clearance of Abeta.
神经炎症已被认为与阿尔茨海默病（AD）的病理过程相关，然而，其对β-淀粉样蛋白（Aβ）负荷的影响尚不清楚。本研究在AD转基因小鼠模型中探究了核因子κB（NF-κB）在调节神经炎症和Aβ沉积中的作用。APPswe/PS1dE9小鼠及其野生型对照从7月龄开始接受NF-κB抑制剂吡咯烷二硫代氨基甲酸盐（PDTC，腹腔注射，每日50 mg/kg）或生理盐水，持续5个月。测定了环氧化酶-2（COX-2）、组织坏死因子α（TNFα）前体蛋白和微管相关蛋白2的表达，并评估了星形胶质细胞增生。使用酶联免疫吸附测定法（ELISA）测量海马体和皮质中Aβ（1-40）和Aβ（1-42）的水平。PDTC处理有效抑制了APPswe/PS1dE9小鼠中的NF-κB信号传导，COX-2和TNFα诱导的消除证明了这一点。抑制NF-κB进一步减轻了转基因AD小鼠中的星形胶质细胞增生，但显著增加了脑中Aβ（1-42）的负荷。我们的研究结果表明，NF-κB可介导APPswe/PS1dE9小鼠中COX-2、TNFα的诱导和星形胶质细胞增生。此外，这些结果支持神经炎症有助于Aβ清除的观点。
