Inhibition of RhoA GTPase and the subsequent activation of PTP1B protects cultured hippocampal neurons against amyloid β toxicity.
Inhibition of RhoA GTPase and the subsequent activation of PTP1B protects cultured hippocampal neurons against amyloid β toxicity.
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DOI：
10.1186/1750-1326-6-14
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发表时间：
2011-02-04
影响因子：
15.1
通讯作者：
Rodriguez-Tebar A
中科院分区：
文献类型：
--
作者：
Chacon PJ;Garcia-Mejias R;Rodriguez-Tebar A
淀粉样蛋白β（Aβ）是导致阿尔茨海默病发生和发展的主要因素。这种肽至少可以部分拮抗神经元中的神经生长因子（NGF）信号传导，这可能是Aβ产生的一些效应的原因。因此，更好地了解NGF信号通路可能为如何保护神经元免受Aβ的毒性作用提供线索。我们发现Aβ通过与p75 NTR结合激活RhoA GT3，从而阻止神经元存活所需的蛋白酪氨酸磷酸酶1B（PTP1B）的NGF诱导激活。RhoA GT3的失活和PTP1B的激活对Aβ的损伤有保护作用。事实上，无论是用C3 ADP核糖基转移酶药理学抑制RhoA，还是用RhoA的显性负性形式转染培养的神经元，都能保护培养的海马神经元免受Aβ的影响。此外，PTP1B的过表达还能抑制Aβ对培养海马神经元的损伤作用。我们的研究结果表明，在RhoA失活和PTP1B激活的水平上增强NGF的活性可能代表了对抗Aβ在阿尔茨海默病中的有害作用的新手段。
Amyloid beta (Aβ) is the main agent responsible for the advent and progression of Alzheimer's disease. This peptide can at least partially antagonize nerve growth factor (NGF) signalling in neurons, which may be responsible for some of the effects produced by Aβ. Accordingly, better understanding the NGF signalling pathway may provide clues as to how to protect neurons from the toxic effects of Aβ. We show here that Aβ activates the RhoA GTPase by binding to p75NTR, thereby preventing the NGF-induced activation of protein tyrosine phosphatase 1B (PTP1B) that is required for neuron survival. We also show that the inactivation of RhoA GTPase and the activation of PTP1B protect cultured hippocampal neurons against the noxious effects of Aβ. Indeed, either pharmacological inhibition of RhoA with C3 ADP ribosyl transferase or the transfection of cultured neurons with a dominant negative form of RhoA protects cultured hippocampal neurons from the effects of Aβ. In addition, over-expression of PTP1B also prevents the deleterious effects of Aβ on cultured hippocampal neurons. Our findings indicate that potentiating the activity of NGF at the level of RhoA inactivation and PTP1B activation may represent a new means to combat the noxious effects of Aβ in Alzheimer's disease.
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DOI：
10.1073/pnas.0500195102
发表时间：
2005-03-08
影响因子：
11.1
作者：
De Rosa, R;Garcia, AA;Cattaneo, A
通讯作者：
Cattaneo, A
影响因子：
4
作者：
Capsoni, Simona;Cattaneo, Antonino
通讯作者：
Cattaneo, Antonino
影响因子：
4.8
作者：
De Felice, Fernanda G.;Velasco, Pauline T.;Klein, William L.
通讯作者：
Klein, William L.
影响因子：
7.3
作者：
Liao FF;Xu H
通讯作者：
Xu H
DOI：
10.1073/pnas.0809158106
发表时间：
2009-02-10
影响因子：
11.1
作者：
De Felice, Fernanda G.;Vieira, Marcelo N. N.;Klein, William L.
通讯作者：
Klein, William L.