Genetic deletion of TNFRII gene enhances the Alzheimer-like pathology in an APP transgenic mouse model via reduction of phosphorylated IκBα
Genetic deletion of TNFRII gene enhances the Alzheimer-like pathology in an APP transgenic mouse model via reduction of phosphorylated IκBα
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DOI：
10.1093/hmg/ddu206
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发表时间：
2014-09-15
影响因子：
3.5
通讯作者：
Shen, Yong
中科院分区：
文献类型：
--
作者：
Jiang, Hong;He, Ping;Shen, Yong
肿瘤坏死因子受体II（TNFRII）是TNF受体超家族成员之一，我们最近的病理研究表明，阿尔茨海默病（AD）患者的大脑中缺乏TNFRII。然而，TNFRII在AD发病机制中的作用机制尚不清楚。在本研究中，我们通过基因靶向的方法在AD转基因小鼠模型中删除TNFRII，我们发现，在TNFRII缺失的APP23小鼠（APP23/TNFRII-/-）的大脑中，早在6月龄时就发生了AD样病理，即斑块形成和小胶质细胞激活。为了检验Ab斑块水平的升高是否由于Ab升高，我们测量了Ab，发现A β水平确实在这个年龄段显著升高。由于-分泌酶BACE1是Ab生成的关键酶，我们对BACE1进行了检测，发现早在6个月大时，BACE1的蛋白水平和酶活性都有所增加；在证明BACE1启动子区域含有NF-kappa B结合位点后，我们发现细胞质NF-kappa B升高，而SUMO1与I kappa B α的结合降低。为了进一步验证这些发现，我们过表达TNFRII，并发现过表达TNFRII可以逆转APP23/TNFRII-/-小鼠的研究结果。总之，我们的研究结果证明了TNFRII在调节Ab产生中的新作用，提示通过上调TNFRII水平和通过sumo化提高磷酸化的I κ B α来治疗AD的潜在策略。
Tumor necrosis factor receptor II(TNFRII) is one of the TNF receptor superfamily members and our recent pathological studies show that TNFRII is deficient in the brains of Alzheimer's disease (AD). However, the mechanisms of TNFRII in AD pathogenesis remain unclear. In the present study, by using the gene-targeting approach to delete TNFRII in AD transgenic mouse model, we found that, in the brain of APP23 mice with TNFRII deletion (APP23/TNFRII-/-), AD-like pathology, i.e. plaque formation and microglial activation, occurs as early as 6 months of age. To test whether the increased levels of Ab plaques was due to elevated Ab, we measured Ab and found that A beta levels indeed were significantly increased at this age. Because beta-secretase, BACE1, is critical enzyme for Ab production, we have examined BACE1 and found that BACE1 is increased in both protein levels and enzymatic activity as early as 6 months of age; Having shown that BACE1 promoter region contains NF-kappa B binding sites, we found that cytoplasmic NF-kappa B was elevated and SUMO1 binding to I kappa B alpha was decreased. To further verify these findings, we have overexpressed TNFRII and identified that overexpressing TNFRII can reverse the findings from APP23/TNFRII-/- mice. Altogether, our results demonstrate novel roles of TNFRII in the regulation of Ab production, suggesting a potential therapeutic strategy for AD by up-regulating TNFRII levels and elevating phosphorylated I kappa B alpha by SUMOylation.