Alzheimer's disease-related loss of Pin1 function influences the intracellular localization and the processing of AβPP.
Alzheimer's disease-related loss of Pin1 function influences the intracellular localization and the processing of AβPP.
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DOI：
10.3233/jad-2012-111259
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
L. Pastorino;S. Ma;M. Balastik;Pengyu Huang;D. Pandya;L. Nicholson;K. Lu
中科院分区：
文献类型：
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作者：
L. Pastorino;S. Ma;M. Balastik;Pengyu Huang;D. Pandya;L. Nicholson;K. Lu
淀粉样蛋白前体淀粉样蛋白前体(A-βPP)的淀粉样变性过程增加是阿尔茨海默病(AD)的特征。我们以前观察到在AD中下调的Prolyl异构酶Pin1调节AβPP的构象，加速磷酸化Thr668-Pro669肽键的顺式/反式异构化，并且在小鼠中敲除Pin1增加了AβPP的淀粉样加工，尽管其潜在的机制尚不清楚。由于AβPP的细胞内定位决定了加工是淀粉样变性还是非淀粉样变性，因此我们在这里讨论了PIN1功能的丧失是否会影响AβPP的细胞内定位，从而影响AβPP的加工。利用Pin1基因敲除和Pin1基因敲除的细胞模型，我们证明了降低Pin1水平改变了AβPP的细胞内定位和加工。在此条件下，质膜上残留的AβPP较少，有利于淀粉样蛋白的形成，AβPP内化的动力学增强，AβPP C末端片段的核转运增加。此外，AβPPThr668Ala突变体不能与PIN1结合并保留更多的反式构象，它挽救了PIN1基因敲除细胞质膜上AβPP的水平。因此，PIN1功能的丧失有助于AβPP从主要是非淀粉样变性的间隔室中移除，并内化到更多的淀粉样变性间隔区，从而促进淀粉样变通路的发生。这些数据表明，PIN1的生理水平对于控制Thr668磷酸化的AβPP的细胞内定位和代谢命运是重要的，并且在与AD相关的AβPP过度磷酸化和/或PIN1功能丧失的病理条件下，对AβPP构象的调节尤其重要。
Increased amyloidogenic processing of the amyloid-β protein precursor (AβPP) is a characteristic of Alzheimer's disease (AD). We previously observed that the prolyl isomerase Pin1, which is down-regulated in AD, regulates AβPP conformation accelerating cis/trans isomerization of the phospho-Thr668-Pro669 peptide bond, and that Pin1 knockout in mice increases the amyloidogenic processing of AβPP, although the underlying mechanism is still unknown. Since the intracellular localization of AβPP determines whether the processing will be amyloidogenic or non-amyloidogenic, here we addressed the question whether loss of Pin1 function affects the intracellular localization of AβPP, influencing AβPP processing. Using cellular models of Pin1 knockout and Pin1 knockdown, we have demonstrated that lowering Pin1 levels changed the intracellular localization and the processing of AβPP. Under these conditions, less AβPP was retained at the plasma membrane favoring the amyloidogenic processing, and the kinetics of AβPP internalization increased as well as the nuclear trafficking of AβPP C-terminal fragment AICD. In addition, AβPPThr668Ala mutant, which cannot bind to Pin1 and retains more trans conformation, rescued the levels of AβPP at the plasma membrane in Pin1 knockout cells. Thus, loss of Pin1 function contributes to amyloidogenic pathways, by facilitating both the removal of AβPP from compartments where it is mostly non-amyloidogenic and its internalization to more amyloidogenic compartments. These data suggest that physiological levels of Pin1 are important to control the intracellular localization and metabolic fate of Thr668-phosphorylated AβPP, and regulation of AβPP conformation is especially important in pathologic conditions of AβPP hyperphosphorylation and/or loss of Pin1 function, associated with AD.