p75NTR enhances cognitive dysfunction in a mouse Alzheimer's disease model by inhibiting microRNA-210-3p-mediated PCYT2 through activation of NF-κB
p75NTR enhances cognitive dysfunction in a mouse Alzheimer's disease model by inhibiting microRNA-210-3p-mediated PCYT2 through activation of NF-κB
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p75NTR 通过激活 NF-κB 抑制 microRNA-210-3p 介导的 PCYT2，从而增强小鼠阿尔茨海默病模型中的认知功能障碍
DOI：
10.1016/j.ijbiomac.2022.11.078
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发表时间：
2022
影响因子：
8.2
通讯作者：
Chongdong Jian
中科院分区：
文献类型：
--
作者：
Zhongliang Wei;Chengmin Yang;Keyu Feng;Suchan Guo;Zhenzhen Huang;Yifan Wang;Chongdong Jian
阿尔茨海默病(AD)是痴呆的主要原因之一，表现为认知行为异常。在此，我们探讨p75神经营养因子受体(P75NTR)在AD认知功能障碍中的作用。首先，用淀粉样β1-42(Aβ1-42)处理C57BL/6小鼠和神经母细胞瘤细胞，建立AD的体内和体外模型。通过RNA测序和生物信息学分析预测了p75NTR的下游基因。验证p75NTR、核因子-kappaB(NF-κB)、MicroRNA210-3p(miR-210-3p)和磷酸乙醇胺胞苷转移酶2(PYCT2)之间的相互作用，并分析它们对AD样症状小鼠海马神经元认知行为和生物学特性的影响。P75NTR基因敲除可减轻AD样症状小鼠的认知功能障碍，并减少Aβ1-42诱导的海马神经元损伤和细胞凋亡。P75NTR通过激活NF-κB上调miR210-3p的表达，从而限制PCYT2的表达。P75NTR−/−小鼠中PCYT2的沉默促进了神经元的凋亡，并加重了AD小鼠模型的认知功能障碍。综上所述，p75NTR可能通过调节NF-κB/miR-210-3p/PCYT2轴而加速AD患者的认知功能障碍。
Alzheimer's disease (AD) is a main cause of dementia and exhibits abnormality in cognitive behaviors. Here, we probed into the role of p75 neurotrophin receptor (p75NTR) in cognitive dysfunction in AD. Primarily, C57BL/6 mouse and neuroblastoma cells were treated by amyloid-beta1–42 (Aβ1–42), respectively, to establish thein vivoandin vitromodels of AD. The downstream genes of p75NTR were predicted by RNA-sequencing and bioinformatics analysis. Then the interaction among p75NTR, nuclear factor kappa B (NF-κB), microRNA-210-3p (miR-210-3p) and phosphoethanolamine cytidylyltransferase 2 (PYCT2) was verified, followed by analysis of their effects on cognitive behaviors and biological characteristics of hippocampal neurons of mouse with AD-like symptoms. p75NTR knockout alleviated cognitive dysfunction in mice with AD-like symptoms and reduced Aβ1–42-induced hippocampal neuron damage and apoptosis. p75NTR up-regulated miR-210-3p expression by activating NF-κB, thereby limiting PCYT2 expression. PCYT2 silencing in p75NTR−/−mice promoted neuronal apoptosis and aggravated cognitive dysfunction in AD mouse models. In summary, p75NTR is capable of accelerating cognitive dysfunction in AD by mediating the NF-κB/miR-210-3p/PCYT2 axis.