p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer's disease.
p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer's disease.
复制标题
p75NTR 胞外域是一种生理性神经保护分子，可对抗阿尔茨海默病大脑中的淀粉样蛋白 - β 毒性
DOI：
10.1038/mp.2015.49
复制
发表时间：
2015-11
影响因子：
11
通讯作者：
Wang YJ
中科院分区：
文献类型：
--
作者：
Yao XQ;Jiao SS;Saadipour K;Zeng F;Wang QH;Zhu C;Shen LL;Zeng GH;Liang CR;Wang J;Liu YH;Hou HY;Xu X;Su YP;Fan XT;Xiao HL;Lue LF;Zeng YQ;Giunta B;Zhong JH;Walker DG;Zhou HD;Tan J;Zhou XF;Wang YJ
在阿尔茨海默病（AD）中，神经变性信号如淀粉样蛋白-β（Aβ）和神经营养因子的前体，超过神经营养信号的平衡，导致突触功能障碍和神经变性。神经营养因子受体p75（p75 NTR）是Aβ的一种受体，介导Aβ诱导的神经退行性变信号。其胞外域从细胞表面脱落是生理调节的;然而，脱落后可扩散的p75 NTR胞外域（p75 ECD）的功能在很大程度上仍然未知。在这里，我们发现，由于Aβ抑制了脱落酶-肿瘤坏死因子-α-转化酶，阿尔茨海默病患者和淀粉样β前体蛋白（APP）/PS1转基因小鼠的脑脊液和大脑中的p75 ECD水平显著降低。在APP/PS 1小鼠脑中Aβ沉积之前或之后通过脑递送编码人p75 ECD的基因使p75 ECD恢复到正常水平，逆转了行为缺陷和AD型病理，如Aβ存款、凋亡事件、神经炎症、Tau磷酸化和树突棘、神经元结构和突触蛋白的丢失。此外，p75 ECD还可以通过抑制β-分泌酶的表达和活性来减少淀粉样蛋白的生成。我们的数据表明，p75 ECD是一种生理性神经保护分子，可对抗Aβ毒性，有望成为AD的新治疗靶点和生物标志物。
In Alzheimer's disease (AD), neurodegenerative signals such as amyloid-beta (Aβ) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aβ and mediates Aβ-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer's patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aβ. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aβ deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aβ deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing β-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aβ toxicity and would be a novel therapeutic target and biomarker for AD.