The p75 neurotrophin receptor promotes amyloid-beta(1-42)-induced neuritic dystrophy in vitro and in vivo.
The p75 neurotrophin receptor promotes amyloid-beta(1-42)-induced neuritic dystrophy in vitro and in vivo.
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DOI：
10.1523/jneurosci.0620-09.2009
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发表时间：
2009-08-26
期刊：
影响因子：
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通讯作者：
Longo FM
中科院分区：
文献类型：
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作者：
Knowles JK;Rajadas J;Nguyen TV;Yang T;LeMieux MC;Vander Griend L;Ishikawa C;Massa SM;Wyss-Coray T;Longo FM
淀粉样蛋白-β(1-42)(Aβ)的寡聚体被认为在阿尔茨海默病(AD)中起致病作用，而p75神经营养素受体(P75NTR)被认为与Aβ诱导的神经变性有关。为了进一步确定p75NTR在AD中的功能，我们研究了寡聚体Aβ与p75NTR的相互作用，以及这种相互作用对神经元培养和慢性AD小鼠模型中神经突起完整性的影响。原子力显微镜观察Aβ的聚集状态，荧光共振能量转移(FRET)分析表明Aβ寡聚体与p75NTR胞外区相互作用。从野生型和p75NTR−/−小鼠分离的神经元细胞培养物中p75NTR胞外区缺失的体外研究表明，突变细胞对Aβ诱导的细胞死亡的敏感性降低。有趣的是，在p75NTRβ神经元培养中，Aβ诱导的神经性营养不良和c-jun的激活是完全防止的，c-jun是已知的A−/−诱导的有害信号的中介。与野生型p75NTR相比，Thy1-hAPPLond/Swe X p75NTR−/−小鼠海马神经性营养不良明显减轻，基底前脑胆碱能神经突起变性完全逆转。Aβ水平未受影响，提示p75NTR胞外区的去除降低了过量Aβ促进神经细胞变性的能力。这些发现表明，虽然p75NTR可能不能介导所有的Aβ效应，但它在体内和体外都能使Aβ诱导的神经变性发挥重要作用，使p75NTR成为AD的重要治疗靶点。
Oligomeric forms of amyloid-β(1–42) (Aβ) are thought to play a causal role in Alzheimer’s disease (AD) and the p75 neurotrophin receptor (p75NTR) has been implicated in Aβ-induced neurodegeneration. To further define the functions of p75NTR in AD, we examined the interaction of oligomeric Aβ with p75NTR, and the effects of that interaction on neurite integrity in neuron cultures and in a chronic AD mouse model. Atomic force microscopy was used to ascertain the aggregated state of Aβ, and fluorescence resonance energy transfer (FRET) analysis revealed that Aβ oligomers interact with the extracellular domain of p75NTR. In vitro studies of Aβ-induced death in neuron cultures isolated from wildtype and p75NTR −/− mice, in which the p75NTR extracellular domain is deleted, showed reduced sensitivity of mutant cells to Aβ-induced cell death. Interestingly, Aβ-induced neuritic dystrophy and activation of c-Jun, a known mediator of Aβ-induced deleterious signaling, were completely prevented in p75NTR −/− neuron cultures. Thy1-hAPPLond/Swe X p75NTR−/− mice exhibited significantly diminished hippocampal neuritic dystrophy and complete reversal of basal forebrain cholinergic neurite degeneration relative to those expressing wild type p75NTR. Aβ levels were not affected, suggesting that removal of p75NTR extracellular domain reduced the ability of excess Aβ to promote neuritic degeneration. These findings indicate that while p75NTR likely does not mediate all Aβ effects, it does play a significant role in enabling Aβ-induced neurodegeneration in vitro and in vivo, establishing p75NTR as an important therapeutic target for AD.