Chronic Neuron-Specific Tumor Necrosis Factor-Alpha Expression Enhances the Local Inflammatory Environment Ultimately Leading to Neuronal Death in 3xTg-AD Mice
Chronic Neuron-Specific Tumor Necrosis Factor-Alpha Expression Enhances the Local Inflammatory Environment Ultimately Leading to Neuronal Death in 3xTg-AD Mice
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DOI：
10.2353/ajpath.2008.080528
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发表时间：
2008-12-01
影响因子：
6
通讯作者：
Bowers, William J.
中科院分区：
文献类型：
--
作者：
Janelsins, Michelle C.;Mastrangelo, Michael A.;Bowers, William J.
炎症介质，如肿瘤坏死因子 -α（TNF -α）和白细胞介素 -1β，似乎在引发和/或促进阿尔茨海默病（AD）相关发病机制中不可或缺。我们先前观察到编码促炎细胞因子TNF -α的mRNA转录本数量显著增加，这与在明显的淀粉样病变发生之前三重转基因小鼠（3xTg - AD）大脑中局部增强的小胶质细胞活化相关。在这项研究中，我们揭示在3xTg - AD小鼠中神经元是TNF -α的重要来源。为了进一步明确神经元衍生的TNF -α在早期类似AD病理过程中的作用，将一种表达TNF -α的重组腺相关病毒载体立体定向递送至2月龄的3xTg - AD小鼠和非转基因对照小鼠，以产生持续的局部细胞因子表达。在6月龄时，3xTg - AD小鼠表现出细胞内β - 淀粉样蛋白水平升高和过度磷酸化的tau蛋白水平升高以及小胶质细胞活化的迹象。在12月龄时，TNF受体1和Jun相关的mRNA水平显著升高，并且在3xTg - AD小鼠中观察到外周细胞浸润和神经元死亡，但在非转基因小鼠中未观察到。这些数据表明在3xTg - AD小鼠大脑中TNF -α与AD相关转基因产物之间存在病理相互作用。此处呈现的结果表明，在这种AD小鼠模型中，慢性神经元TNF -α表达促进炎症，并最终导致神经元细胞死亡，这支持开发针对TNF -α的特异性药物来治疗AD。（《美国病理学杂志》2008年，173:1768 - 1782；DOI: 10.2353/ajpath.2008.080528）
Inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta, appear integral in initiating and/or propagating Alzheimer's disease (AD)-associated pathogenesis. We have previously observed a significant increase in the number of mRNA transcripts encoding the pro-inflammatory cytokine TNF-alpha, which correlated to regionally enhanced microglial activation in the brains of triple transgenic mice (3xTg-AD) before the onset of overt amyloid pathology. In this study, we reveal that neurons serve as significant sources of TNF-alpha in 3xTg-AD mice. To further define the role of neuronally derived TNF-alpha during early AD-like pathology, a recombinant adeno-associated virus vector expressing TNF-alpha was stereotactically delivered to 2-month-old 3xTg-AD mice and non-transgenic control mice to produce sustained focal cytokine expression. At 6 months of age, 3xTg-AD mice exhibited evidence of enhanced intracellular levels of amyloid-beta and hyperphosphorylated tau, as well as microglial activation. At 12 months of age, both TNF receptor H and Jun-related mRNA levels were significantly enhanced, and peripheral cell infiltration and neuronal death were observed in 3xTg-AD mice, but not in non-transgenic mice. These data indicate that a pathological interaction exists between TNF-alpha and the AD-related transgene products in the brains of 3xTg-AD mice. Results presented here suggest that chronic neuronal TNF-alpha expression promotes inflammation and, ultimately, neuronal cell death in this AD mouse model, advocating the development of TNF-alpha-specific agents to subvert AD. (Am J Pathol 2008, 173:1768-1782; DOI: 10.2353/ajpath.2008.080528)