Elevated expression of p21ras is an early event in Alzheimer's disease and precedes neurofibrillary degeneration
Elevated expression of p21ras is an early event in Alzheimer's disease and precedes neurofibrillary degeneration
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DOI：
10.1016/s0306-4522(99)00059-7
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发表时间：
1999-01-01
期刊：
影响因子：
3.3
通讯作者：
Arendt, T
中科院分区：
文献类型：
--
作者：
Gärtner, U;Holzer, M;Arendt, T
阿尔茨海默病是一种慢性退行性疾病，其特征是由高度磷酸化的tau组成的“成对螺旋细丝”在细胞内积累，以及聚集的a-肽在细胞外沉积。此外，阿尔茨海默病的神经退行性变与神经炎生长谱的出现有关，这些生长谱在其定位、形态外观和细胞骨架元件的组成方面是异常的。(2)在阿尔茨海默病的早期阶段，多种生长因子和有丝分裂化合物（10,12,15,16,18,32）升高。这些因子大多通过激活p21（ras）依赖的有丝分裂原激活的蛋白激酶级联来介导它们的细胞效应，这一途径也参与淀粉样蛋白前体蛋白和tau蛋白的表达调控和翻译后修饰。（7,11,13,14,19,20,22,31）我们之前报道了p21（ras）的表达升高与成对螺旋丝形成和A - β沉积有关。（17）然而，问题是p21（ras）和下游有丝分裂原激活的蛋白激酶级联的诱导是在发病链中具有相当重要的早期事件，还是仅仅作为神经退行性变的细胞反应而发生。（29）目前的研究表明，p21（ras）的表达在疾病的早期阶段明显升高，早于神经原纤维病理和A β的形成。(C) 1999 IBRO, Elsevier Science Ltd.出版
Alzheimer's disease is a chronic degenerative disorder characterized by the intracellular accumulation of "paired helical filaments" consisting of highly phosphorylated tau and by extracellular deposits of aggregated A beta-peptide. Furthermore, neurodegeneration in Alzheimer's disease is associated with the appearance of neuritic growth profiles that are aberrant with respect to their localization, morphological appearance, and composition of cytoskeletal elements.(2) During early stages of Alzheimer's disease, a variety of growth factors and mitogenic compounds(10,12,15,16,18,32) are elevated. Most of these factors mediate their cellular effects through activation of the p21(ras)-dependent mitogen-activated protein kinase cascade, a pathway that is also involved in the regulation of expression and post-translational modification of the amyloid precursor protein and tau protein.(7,11,13,14,19,20,22,31) We previously reported on the elevated expression of p21(ras) associated with paired helical filament formation and A beta-deposits.(17) However, the question arises as to whether induction of p21(ras) and the downstream mitogen-activated protein kinase cascade is an early event with rather primary importance in the pathogenetic chain or simply occurs as a cellular response to neurodegeneration.(29) The present study shows that expression of p21(ras) is clearly elevated in very early stages of the disease, preceding both neurofibrillary pathology and formation of A beta. (C) 1999 IBRO, Published by Elsevier Science Ltd.