Endoplasmic Reticulum Stress Induces the Early Appearance of Pro-apoptotic and Anti-apoptotic Proteins in Neurons of Five Familial Alzheimer's Disease Mice.
Endoplasmic Reticulum Stress Induces the Early Appearance of Pro-apoptotic and Anti-apoptotic Proteins in Neurons of Five Familial Alzheimer's Disease Mice.
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内质网应激诱导五只家族性阿尔茨海默病小鼠神经元中促凋亡和抗凋亡蛋白的早期出现。
DOI：
10.4103/0366-6999.194643
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发表时间：
2016-12-05
影响因子：
6.1
通讯作者：
Chen XC
中科院分区：
文献类型：
--
作者：
Shen H;Pan XD;Zhang J;Zeng YQ;Zhou M;Yang LM;Ye B;Dai XM;Zhu YG;Chen XC
β淀粉样蛋白（Aβ）沉积和内质网应激（ERS）在阿尔茨海默病（AD）的发生和发展中均被证实。然而，Aβ诱导的ERS在AD相关病理进展中的机制和作用仍有待阐明。本研究使用了5只2、7和12月龄的家族性AD（5×FAD）小鼠和野生型（WT）小鼠。采用Morris水迷宫测试评价其认知能力。免疫荧光和Western印迹分析用于检测ERS相关未折叠蛋白反应（UPR）途径中促凋亡因子（CCAAT/增强子结合蛋白同源蛋白[CHOP]和裂解的caspase-12）和抗凋亡因子（伴侣葡萄糖调节蛋白[GRP] 78和内质网相关蛋白降解相关泛素连接酶滑膜凋亡抑制因子1 [SYVN 1]）的动态变化。与同龄WT小鼠相比，5×FAD小鼠在12月龄时caspase-3裂解水平较高，神经元阳性染色水平较低，但在7月龄时出现认知功能障碍的时间较早（均P < 0.05）。有趣的是，与年龄匹配的WT小鼠相比，2月龄的5×FAD小鼠中参与ERS相关UPR通路的相关蛋白，包括CHOP，切割的caspase-12，GRP 78和SYVN 1，均显著增加（均P < 0.05）。此外，ERS主要发生在神经元，而不是在星形胶质细胞。这些结果表明，与年龄匹配的WT小鼠相比，2月龄5×FAD小鼠中ERS相关的促凋亡和抗凋亡蛋白上调，与神经元中的细胞内Aβ聚集一致。
Amyloid β (Aβ) deposits and the endoplasmic reticulum stress (ERS) are both well established in the development and progression of Alzheimer's disease (AD). However, the mechanism and role of Aβ-induced ERS in AD-associated pathological progression remain to be elucidated. The five familial AD (5×FAD) mice and wild-type (WT) mice aged 2, 7, and 12 months were used in the present study. Morris water maze test was used to evaluate their cognitive performance. Immunofluorescence and Western blot analyses were used to examine the dynamic changes of pro-apoptotic (CCAAT/enhancer-binding protein homologous protein [CHOP] and cleaved caspase-12) and anti-apoptotic factors (chaperone glucose-regulated protein [GRP] 78 and endoplasmic reticulum-associated protein degradation-associated ubiquitin ligase synovial apoptosis inhibitor 1 [SYVN1]) in the ERS-associated unfolded protein response (UPR) pathway. Compared with age-matched WT mice, 5×FAD mice showed higher cleaved caspase-3, lower neuron-positive staining at the age of 12 months, but earlier cognitive deficit at the age of 7 months (all P < 0.05). Interestingly, for 2-month-old 5×FAD mice, the related proteins involved in the ERS-associated UPR pathway, including CHOP, cleaved caspase-12, GRP 78, and SYVN1, were significantly increased when compared with those in age-matched WT mice (all P < 0.05). Moreover, ERS occurred mainly in neurons, not in astrocytes. These findings suggest that compared with those of age-matched WT mice, ERS-associated pro-apoptotic and anti-apoptotic proteins are upregulated in 2-month-old 5×FAD mice, consistent with intracellular Aβ aggregation in neurons.
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DOI：
10.1074/jbc.m109.014464
发表时间：
2009-10-02
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Zhong N;Ramaswamy G;Weisgraber KH
通讯作者：
Weisgraber KH
DOI：
10.1083/jcb.200303157
发表时间：
2003-08-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kalai M;Lamkanfi M;Denecker G;Boogmans M;Lippens S;Meeus A;Declercq W;Vandenabeele P
通讯作者：
Vandenabeele P
影响因子：
4
作者：
Paschen, W;Mengesdorf, T
通讯作者：
Mengesdorf, T
影响因子：
5.3
作者：
Tomiyama, Takami;Matsuyama, Shogo;Mori, Hiroshi
通讯作者：
Mori, Hiroshi
影响因子：
4.7
作者：
Zeng, Yuqi;Zhang, Jian;Chen, Xiaochun
通讯作者：
Chen, Xiaochun