Akt/GSK3β serine/threonine kinases:: evidence for a signalling pathway mediated by familial Alzheimer's disease mutations
Akt/GSK3β serine/threonine kinases:: evidence for a signalling pathway mediated by familial Alzheimer's disease mutations
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DOI：
10.1016/j.cellsig.2003.07.004
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发表时间：
2004-02-01
影响因子：
4.8
通讯作者：
Ni, BH
中科院分区：
文献类型：
--
作者：
Ryder, J;Yuan, S;Ni, BH
尽管阿尔茨海默病在病理上影响大脑，但家族性阿尔茨海默病相关的β-淀粉样前体蛋白和早老素突变普遍表达，因此可以预期与大脑分离但相似的异常细胞内信号。在这里，我们报告选择性下调丝氨酸/苏氨酸激酶，Akt/PKB，同时升高内源性GSK 3 β激酶活性在家族性阿尔茨海默病β-淀粉样前体蛋白表达人胚肾（HEK）和家族性阿尔茨海默病早老素淋巴母细胞。此外，人类淋巴母细胞中的家族性阿尔茨海默病早老素与β-连环蛋白不稳定有关。此外，有限的免疫组织化学分析揭示Akt/PKB在神经元缠结的一个子集中，其中GSK 3 β和tau已被报道共定位，表明可能的Akt/GSK 3 β和tau在体内相互作用。我们的数据表明，β-淀粉样前体蛋白和早老素信号的家族性阿尔茨海默病突变体，至少部分地，通过Akt/GSK β途径和Akt/GSK β介导的信号传导可能有助于潜在的阿尔茨海默病的发病机制诱导的家族性阿尔茨海默病突变体。(C)2003年由Elsevier Inc.出版
Although Alzheimer's disease pathologically affects the brain, familial Alzheimer's disease associated mutations of beta-amyloid precursor protein and presenilin are ubiquitously expressed and therefore aberrant intracellular signals, separate from but similar to, the brain may be expected. Here, we report selective down regulation of the serine/threonine kinase, Akt/PKB, concurrent with elevated endogenous GSK3beta kinase activity in familial Alzheimer's disease beta-amyloid precursor protein expressing human embryonic kidney (HEK) and familial Alzheimer's disease presenilin lymphoblast cells. Further, familial Alzheimer's disease presenilin in the human lymphoblast was associated with beta-catenin destabilization. Moreover, limited immunohistochemistry analysis reveals Akt/PKB in a subset of neurofibrillary tangles where GSK3beta and tau have been reported to co-localize, suggesting a possible Akt/GSK3beta and tau interaction in vivo. Our data suggest that familial Alzheimer's disease mutants of beta-amyloid precursor protein and presenilin signal, at least in part, through the Akt/GSKbeta pathway and that Akt/GSKbeta-mediated signalling may contribute to the underlying Alzheimer's disease pathogenesis induced by familial Alzheimer's disease mutants. (C) 2003 Published by Elsevier Inc.