TRAF6 和 p62 通过 p75 神经营养因子受体抑制淀粉样β诱导的神经元死亡。
TRAF6 and p62 inhibit amyloid β-induced neuronal death through p75 neurotrophin receptor.
机构信息
Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA.
出版信息
Neurochem Int. 2012 Dec;61(8):1289-93. doi: 10.1016/j.neuint.2012.09.005. Epub 2012 Sep 24.
Abstract
Amyloid β (Aβ) aggregates are the primary component of senile plaques in Alzheimer disease (AD) patient's brain. Aβ is known to bind p75 neurotrophin receptor (p75(NTR)) and mediates Aβ-induced neuronal death. Recently, we showed that NGF leads to p75(NTR) polyubiquitination, which promotes neuronal cell survival. Here, we demonstrate that Aβ stimulation impaired the p75(NTR) polyubiquitination. TRAF6 and p62 are required for polyubiquitination of p75(NTR) on NGF stimulation. Interestingly, we found that overexpression of TRAF6/p62 restored p75(NTR) polyubiquitination upon Aβ/NGF treatment. Aβ significantly reduced NF-κB activity by attenuating the interaction of p75(NTR) with IKKβ. p75(NTR) increased NF-κB activity by recruiting TRAF6/p62, which thereby mediated cell survival. These findings indicate that TRAF6/p62 abrogated the Aβ-mediated inhibition of p75(NTR) polyubiquitination and restored neuronal cell survival.
摘要
淀粉样蛋白β（Aβ）聚集体是阿尔茨海默病（AD）患者大脑中老年斑的主要成分。已知 Aβ 结合 p75 神经营养因子受体（p75（NTR））并介导 Aβ 诱导的神经元死亡。最近，我们表明 NGF 导致 p75（NTR）多泛素化，从而促进神经元细胞存活。在这里，我们证明 Aβ 刺激会损害 p75（NTR）的多泛素化。TRAF6 和 p62 是 NGF 刺激下 p75（NTR）多泛素化所必需的。有趣的是，我们发现 TRAF6/p62 的过表达可在 Aβ/NGF 处理时恢复 p75（NTR）的多泛素化。Aβ 通过减弱 p75（NTR）与 IKKβ 的相互作用，显著降低 NF-κB 活性。p75（NTR）通过招募 TRAF6/p62 增加 NF-κB 活性，从而介导细胞存活。这些发现表明，TRAF6/p62 消除了 Aβ 介导的 p75（NTR）多泛素化抑制，并恢复了神经元细胞存活。
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本文引用的文献
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Amyloid beta serves as an NGF-like neurotrophic factor or acts as a NGF antagonist depending on its concentration.淀粉样蛋白β可以作为一种类似于神经生长因子（NGF）的神经营养因子，也可以根据其浓度充当 NGF 拮抗剂。
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