Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer's mice.
Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer's mice.
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DOI：
10.1083/jcb.200705042
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发表时间：
2007-08-27
期刊：
影响因子：
--
通讯作者：
Shen Y
中科院分区：
文献类型：
--
作者：
He P;Zhong Z;Lindholm K;Berning L;Lee W;Lemere C;Staufenbiel M;Li R;Shen Y
1型肿瘤坏死因子死亡受体（TNFR1）促进细胞凋亡。TNFR1是TNFR超家族的一个亚群，包含一个细胞质死亡结构域。我们最近证明，TNFR1级联反应是β淀粉样蛋白（Aβ）诱导的神经元死亡所必需的。然而，TNFR1在阿尔茨海默病（AD）中Aβ斑块病理和淀粉样前体蛋白（APP）加工过程中的作用仍不清楚。我们报道，在APP23转基因小鼠（APP23/TNFR1 - / -）中TNFR1基因的缺失抑制了Aβ的产生，并减少了大脑中Aβ斑块的形成。TNFR1的基因缺失导致β - 分泌酶1（BACE1）水平和活性降低。TNFR1通过核因子 - κB途径调节BACE1启动子活性，并且在APP23转基因小鼠中TNFR1的缺失可防止学习和记忆缺陷。这些发现表明，TNFR1不仅有助于神经退行性变，而且还参与APP加工和Aβ斑块形成。因此，TNFR1是AD的一个新的治疗靶点。
The tumor necrosis factor type 1 death receptor (TNFR1) contributes to apoptosis. TNFR1, a subgroup of the TNFR superfamily, contains a cytoplasmic death domain. We recently demonstrated that the TNFR1 cascade is required for amyloid β protein (Aβ)–induced neuronal death. However, the function of TNFR1 in Aβ plaque pathology and amyloid precursor protein (APP) processing in Alzheimer's disease (AD) remains unclear. We report that the deletion of the TNFR1 gene in APP23 transgenic mice (APP23/TNFR1−/−) inhibits Aβ generation and diminishes Aβ plaque formation in the brain. Genetic deletion of TNFR1 leads to reduced β-secretase 1 (BACE1) levels and activity. TNFR1 regulates BACE1 promoter activity via the nuclear factor-κB pathway, and the deletion of TNFR1 in APP23 transgenic mice prevents learning and memory deficits. These findings suggest that TNFR1 not only contributes to neurodegeneration but also that it is involved in APP processing and Aβ plaque formation. Thus, TNFR1 is a novel therapeutic target for AD.
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DOI：
10.1073/pnas.1834280100
发表时间：
2003-09-02
影响因子：
11.1
作者：
Bourtchouladze, R;Lidge, R;Tully, T
通讯作者：
Tully, T
影响因子：
168.9
作者：
Cagnin, A;Brooks, DJ;Banati, RB
通讯作者：
Banati, RB
DOI：
10.1016/s0006-291x(03)01270-1
发表时间：
2003-08-08
影响因子：
3.1
作者：
Hong, HS;Hwang, EM;Mook-Jung, I
通讯作者：
Mook-Jung, I
影响因子：
6
作者：
Matsuoka, Y;Picciano, M;Duff, K
通讯作者：
Duff, K
影响因子：
6
作者：
Casas, C;Sergeant, N;Pradier, L
通讯作者：
Pradier, L