Yao X-Q, Jiao S-S, Saadipour K, Zeng F, Wang Q-H, Zhu C, Shen L-L, Zeng G-H, Liang C-R, Wang J, Liu Y-H, Hou H-Y, Xu X, Su Y-P, Fan X-T, Xiao H-L, Lue L-F, Zeng Y-Q, Giunta B, Zhong J-H, Walker D G, Zhou H-D, Tan J, Zhou X-F, Wang Y-J
Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
Neuroregeneration Laboratory, School of Pharmacy and Medical Sciences and Sansom Institute, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia.
Mol Psychiatry. 2015 Nov;20(11):1301-10. doi: 10.1038/mp.2015.49. Epub 2015 Apr 28.
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.
在阿尔茨海默病（AD）中，诸如β-淀粉样蛋白（Aβ）和神经营养因子前体等神经退行性信号超过了神经营养信号，导致突触功能障碍和神经退行性变。神经营养因子受体p75（p75NTR）是Aβ的受体，并介导Aβ诱导的神经退行性信号。其胞外域从细胞表面的脱落受到生理调节；然而，脱落之后可扩散的p75NTR胞外域（p75ECD）的功能在很大程度上仍不清楚。在此，我们表明，由于Aβ对裂解酶肿瘤坏死因子-α转换酶的抑制作用，阿尔茨海默病患者脑脊液和大脑以及淀粉样前体蛋白（APP）/早老素1（PS1）转基因小鼠大脑中的p75ECD水平显著降低。在APP/PS1小鼠大脑中Aβ沉积之前或之后，通过脑内递送编码人p75ECD的基因将p75ECD恢复到正常水平，可逆转行为缺陷和AD型病理变化，如Aβ沉积、凋亡事件、神经炎症、Tau磷酸化以及树突棘、神经元结构和突触蛋白的丧失。此外，p75ECD还可通过抑制β-分泌酶的表达和活性来减少淀粉样蛋白生成。我们的数据表明，p75ECD是一种针对Aβ毒性的生理性神经保护分子，将成为AD的新型治疗靶点和生物标志物。
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