EFFECT OF GLYCOGEN SYNTHASE KINASE 3 β-MEDIATED PRESENILIN 1 PHOSPHORYLATION ON AMYLOID β PRODUCTION IS NEGATIVELY REGULATED BY INSULIN RECEPTOR CLEAVAGE
EFFECT OF GLYCOGEN SYNTHASE KINASE 3 β-MEDIATED PRESENILIN 1 PHOSPHORYLATION ON AMYLOID β PRODUCTION IS NEGATIVELY REGULATED BY INSULIN RECEPTOR CLEAVAGE
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DOI：
10.1016/j.neuroscience.2010.12.017
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发表时间：
2011-03-17
期刊：
影响因子：
3.3
通讯作者：
Kinoshita, A.
中科院分区：
文献类型：
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作者：
Maesako, M.;Uemura, K.;Kinoshita, A.
早老素1 （PS1）是家族性阿尔茨海默病（AD）的致病分子，已知是糖原合成酶激酶3 β (GSK3 β)的未引物底物[Twomey and McCarthy (2006) FEBS Lett 580:4015-4020]，并在其细胞质环区丝氨酸353,357残基处磷酸化[Kirschenbaum et al. (2001) J Biol Chem 276:7366 7375]。在本报告中，我们研究了PSI磷酸化对AD病理生理的影响，得到了两个重要结果：PSI磷酸化增加了淀粉样蛋白β (A β) 42140比率，PSI磷酸化在人AD大脑中增强。有趣的是，我们发现PS1磷酸化促进了胰岛素受体（IR）的切割，而γ分泌酶产生的IR胞内结构域（IR ICD）导致Akt （PKB）的显著反激活，从而下调了GSK3 β的活性。因此，γ -分泌酶对IR的裂解可以长期抑制PSI的磷酸化。综上所述，我们的研究结果表明，PSI在353、357个丝氨酸残基的磷酸化可能在AD的病理中起关键作用，该机制的失调可能与AD的病理有因果关系。(c) 2011 ibro。Elsevier Ltd.出版。版权所有。
Presenilin 1 (PS1), a causative molecule of familial Alzheimer's disease (AD), is known to be an unprimed substrate of glycogen synthase kinase 3 beta (GSK3 beta) [Twomey and McCarthy (2006) FEBS Lett 580:4015-4020] and is phosphorylated at serine 353, 357 residues in its cytoplasmic loop region [Kirschenbaum et al. (2001) J Biol Chem 276:7366 7375]. In this report, we investigated the effect of PSI phosphorylation on AD pathophysiology and obtained two important results PSI phosphorylation increased amyloid beta (A beta) 42140 ratio, and PSI phosphorylation was enhanced in the human AD brains. Interestingly, we demonstrated that PS1 phosphorylation promoted insulin receptor (IR) cleavage and the IR intracellular domain (IR ICD) generated by gamma-secretase led to a marked transactivation of Akt (PKB), which down-regulated GSK3 beta activity. Thus, the cleavage of IR by gamma-secretase can inhibit PSI phosphorylation in the long run. Taken together, our findings indicate that PSI phosphorylation at serine 353, 357 residues can play a pivotal role in the pathology of AD and that the dysregulation of this mechanism may be causally associated with its pathology. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.