Pin1 promotes production of Alzheimer's amyloid from β-cleaved amyloid precursor protein
Pin1 promotes production of Alzheimer's amyloid from β-cleaved amyloid precursor protein
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DOI：
10.1016/j.bbrc.2005.08.130
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发表时间：
2005-10-21
影响因子：
3.1
通讯作者：
Uchida, T
中科院分区：
文献类型：
--
作者：
Akiyama, H;Shin, RW;Uchida, T
在这里，我们表明，脯氨酰异构酶Pin I参与了阿尔茨海默病发病机制中的A β生产。Pin 1缺陷小鼠大脑的酶免疫测定显示，A β 40和A β 42的产生低于野生型小鼠，表明Pin 1促进大脑中A β的产生。GST-Pin 1 pull-down和免疫沉淀试验表明Pin 1与C99的Thr 668-Pro磷酸化结合。在用C99转染的Pin 1（-/-）MEF中，与没有Pin 1共转染相比，Pin 1共转染提高了A β 40和A β 42的水平。在转染C99的COS 7细胞中，Pin 1共转染增强了A β 40和A β 42的生成，并降低了C99的表达水平，促进了C99的周转。因此，Pin 1与C99相互作用并促进其γ-裂解，产生A β 40和A β 42。此外，GSK 3抑制剂锂通过降低Thr 668磷酸化和减弱A β生成来阻断Pin 1与C99的结合，解释了锂对A β生成的抑制作用。(c)2005年爱思唯尔公司All rights reserved.
Here we show that prolyl isomerase Pin I is involved in the A beta production central to the pathogenesis of Alzheimer's disease. Enzyme immumoassay of brains of the Pin1-deficient mice revealed that production of A beta 40 and A beta 42 was lower than that of the wild-type mice, indicating that Pin1 promotes A beta production in the brain. GST-Pin1 pull-down and immunoprecipitation assay revealed that Pin1 binds phosphorylated Thr668-Pro of C99. In the Pin1(-/-) MEF transfected with C99, Pin1 co-transfection enhanced the levels of A beta 40 and A beta 42 compared to that without Pin1 co-transfection. In COS7 cells transfected with C99, Pin1 co-transfection enhanced the generation of A beta 40 and A beta 42, and reduced the expression level of C99, facilitating the C99 turnover. Thus, Pin1 interacts with C99 and promotes its gamma-cleavage, generating A beta 40 and A beta 42. Further, GSK3 inhibitor lithium blocked Pin1 binding to C99 by decreasing Thr668 phosphorylation and attenuated A beta generation, explaining the inhibitory effect of lithium on A beta generation. (c) 2005 Elsevier Inc. All rights reserved.