Physiological mouse brain Abeta levels are not related to the phosphorylation state of threonine-668 of Alzheimer's APP.
Physiological mouse brain Abeta levels are not related to the phosphorylation state of threonine-668 of Alzheimer's APP.
复制标题
DOI：
10.1371/journal.pone.0000051
复制
发表时间：
2006-12-20
期刊：
影响因子：
3.7
通讯作者：
Suzuki T
中科院分区：
文献类型：
--
作者：
Sano Y;Nakaya T;Pedrini S;Takeda S;Iijima-Ando K;Iijima K;Mathews PM;Itohara S;Gandy S;Suzuki T
位于40和42位（a -β 40， Αβ42）的淀粉样蛋白β肽是由阿尔茨海默病淀粉样前体蛋白（APP）的蛋白水解过程产生的。在阿尔茨海默病（AD）的早期过程中，Aβ肽在大脑中积累，尤其是Aβ42。APP的胞质结构域调节APP及其羧基末端片段（CTFα, CTFβ）的胞内转运和代谢。一般来说，蛋白质磷酸化的作用，特别是APP在苏氨酸-668 （Thr668）处的磷酸化状态，已经被几个实验室（包括我们自己的实验室）详细研究过。一些研究者最近提出Thr668的磷酸化状态在控制大脑a β水平中起着关键作用，这促使了目前的研究。为了评估Thr668的磷酸化状态是否控制了大脑中a β的水平，我们研究了敲入小鼠大脑中holoAPP、sAPPα、sAPPβ、CTFα、CTFβ、a β40和a β42的水平和亚细胞分布，这些敲入小鼠的大脑中，一个不可磷酸化的丙烯基残基被取代了668位，取代了野生型蛋白中存在的苏氨酸残基。Thr668Ala突变小鼠脑内holoAPP、sAPPα、sAPPβ、CTFα、CTFβ、a - β40和a - β42的水平和亚细胞分布与野生型小鼠相同。这些结果表明，APP在Thr668位点的磷酸化状态对体内脑Aβ40或Αβ42的生理水平没有明显的调控作用。
Amyloid-β peptide species ending at positions 40 and 42 (Aβ40, Αβ42) are generated by the proteolytic processing of the Alzheimer's amyloid precursor protein (APP). Aβ peptides accumulate in the brain early in the course of Alzheimer's disease (AD), especially Aβ42. The cytoplasmic domain of APP regulates intracellular trafficking and metabolism of APP and its carboxyl-terminal fragments (CTFα, CTFβ). The role of protein phosphorylation in general, and that of the phosphorylation state of APP at threonine-668 (Thr668) in particular, has been investigated in detail by several laboratories (including our own). Some investigators have recently proposed that the phosphorylation state of Thr668 plays a pivotal role in governing brain Aβ levels, prompting the current study. In order to evaluate whether the phosphorylation state of Thr668 controlled brain Aβ levels, we studied the levels and subcellular distributions of holoAPP, sAPPα, sAPPβ, CTFα, CTFβ, Aβ40 and Aβ42 in brains from “knock-in” mice in which a non-phosphorylatable alanyl residue had been substituted at position 668, replacing the threonyl residue present in the wild-type protein. The levels and subcellular distributions of holoAPP, sAPPα, sAPPβ, CTFα, CTFβ, Aβ40 and Aβ42 in the brains of Thr668Ala mutant mice were identical to those observed in wild-type mice. These results indicate that, despite speculation to the contrary, the phosphorylation state of APP at Thr668 does not play an obvious role in governing the physiological levels of brain Aβ40 or Αβ42 in vivo.
登录
查看更多内容
DOI：
10.1083/jcb.200301115
发表时间：
2003-10-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lee MS;Kao SC;Lemere CA;Xia W;Tseng HC;Zhou Y;Neve R;Ahlijanian MK;Tsai LH
通讯作者：
Tsai LH
影响因子：
56.9
作者：
Cao, XW;Südhof, TC
通讯作者：
Südhof, TC
影响因子：
56.9
作者：
BUSH, AI;PETTINGELL, WH;TANZI, RE
通讯作者：
TANZI, RE
DOI：
10.1016/j.bbrc.2005.08.130
发表时间：
2005-10-21
影响因子：
3.1
作者：
Akiyama, H;Shin, RW;Uchida, T
通讯作者：
Uchida, T
影响因子：
4.8
作者：
Ando, K;Iijima, K;Suzuki, T
通讯作者：
Suzuki, T