Mitosis-specific phosphorylation of amyloid precursor protein at threonine 668 leads to its altered processing and association with centrosomes.
Mitosis-specific phosphorylation of amyloid precursor protein at threonine 668 leads to its altered processing and association with centrosomes.
复制标题
DOI：
10.1186/1750-1326-6-80
复制
发表时间：
2011-11-23
影响因子：
15.1
通讯作者：
Padmanabhan J
中科院分区：
文献类型：
--
作者：
Judge M;Hornbeck L;Potter H;Padmanabhan J
细胞周期调节蛋白的非典型表达与阿尔茨海默病（AD）有关，但它们诱导神经变性的分子机制尚不清楚。我们检查了表达人淀粉样前体蛋白 (APP) 和早老素 1 (PS1) 的转基因小鼠细胞周期调节蛋白的变化，以确定细胞周期激活与 AD 病理发展之间是否存在相关性。我们对 AD 转基因小鼠的研究表明，在斑块附近的细胞中，细胞周期蛋白 E、细胞周期蛋白 D1、E2F1 和 P-cdc2 的水平显着升高，其中观察到苏氨酸 668 (Thr668)-磷酸化 APP 积累的最高水平。这表明细胞周期调节蛋白可能通过影响 APP 磷酸化来影响斑块病理学。使用过表达 APP 的神经胶质瘤细胞，我们证明 APP 在 Thr668 处的磷酸化是有丝分裂特异性的。正在进行有丝分裂的细胞显示 P-APP 在中心体的细胞分布和定位发生改变。此外，有丝分裂中的 Thr668 磷酸化与 APP 生成 Aβ 和 APP C 末端片段的加工增加相关，而 G1/S 转变的药理学抑制剂可以阻止这种情况。这里提供的数据表明 APP 的细胞周期依赖性磷酸化可能会影响其正常的细胞功能。例如，P-APP 与中心体的关联可能会影响纺锤体组装和细胞周期进展，进一步促进 AD 病理学的发展。 G1/S 抑制剂的实验表明，细胞周期抑制可能通过抑制 βAPP 的修饰来阻碍阿尔茨海默氏病的病理发展，因此可能代表一种新的 AD 治疗方法。最后，细胞周期调节的磷酸化以及 APP 加工成 Aβ 和 C 末端片段表明这些蛋白质在有丝分裂期间可能具有正常功能。
Atypical expression of cell cycle regulatory proteins has been implicated in Alzheimer's disease (AD), but the molecular mechanisms by which they induce neurodegeneration are not well understood. We examined transgenic mice expressing human amyloid precursor protein (APP) and presenilin 1 (PS1) for changes in cell cycle regulatory proteins to determine whether there is a correlation between cell cycle activation and pathology development in AD. Our studies in the AD transgenic mice show significantly higher levels of cyclin E, cyclin D1, E2F1, and P-cdc2 in the cells in the vicinity of the plaques where maximum levels of Threonine 668 (Thr668)-phosphorylated APP accumulation was observed. This suggests that the cell cycle regulatory proteins might be influencing plaque pathology by affecting APP phosphorylation. Using neuroglioma cells overexpressing APP we demonstrate that phosphorylation of APP at Thr668 is mitosis-specific. Cells undergoing mitosis show altered cellular distribution and localization of P-APP at the centrosomes. Also, Thr668 phosphorylation in mitosis correlates with increased processing of APP to generate Aβ and the C-terminal fragment of APP, which is prevented by pharmacological inhibitors of the G1/S transition. The data presented here suggests that cell cycle-dependent phosphorylation of APP may affect its normal cellular function. For example, association of P-APP with the centrosome may affect spindle assembly and cell cycle progression, further contributing to the development of pathology in AD. The experiments with G1/S inhibitors suggest that cell cycle inhibition may impede the development of Alzheimer's pathology by suppressing modification of βAPP, and thus may represent a novel approach to AD treatment. Finally, the cell cycle regulated phosphorylation and processing of APP into Aβ and the C-terminal fragment suggest that these proteins may have a normal function during mitosis.
登录
查看更多内容
DOI：
10.1093/jnen/61.8.678
发表时间：
2002-08-01
影响因子：
3.2
作者：
Hoozemans, JJM;Brückner, MK;Arendt, T
通讯作者：
Arendt, T
影响因子：
6
作者：
Casas, C;Sergeant, N;Pradier, L
通讯作者：
Pradier, L
影响因子：
3.5
作者：
FEDDERSEN, RM;CLARK, HB;ORR, HT
通讯作者：
ORR, HT
影响因子：
3.5
作者：
GLAB, N;LABIDI, B;MEIJER, L
通讯作者：
MEIJER, L
影响因子：
4.8
作者：
Giovanni, A;Wirtz-Brugger, F;Park, DS
通讯作者：
Park, DS