Irradiation increases brain-derived neurotrophic factor precursor signaling in the mouse hippocampus
Irradiation increases brain-derived neurotrophic factor precursor signaling in the mouse hippocampus
复制标题
辐射增加小鼠海马中的脑源性神经营养因子前体信号传导
DOI：
10.1016/j.nlm.2020.107186
复制
发表时间：
2020-05-01
影响因子：
2.7
通讯作者：
Cao, Wen Yu
中科院分区：
文献类型：
--
作者：
Wang, Zhen;Zhong, Xiao Lin;Cao, Wen Yu
放射性恐怖活动、军事活动或核事故等引起的不受控制的辐射暴露，可能涉及广泛的外照射剂量，并对脑功能产生一系列神经毒性效应。特别地，认知缺陷，其可在照射后几天至一个月发生，限制了其治疗用途（Monje，2008，Padovani等人，2012年）。来自实验动物研究的证据也证明认知障碍与辐射有关（Monje等人，2003年，Rola等人，2004年）。神经营养因子参与神经元的存活、分化、神经发生和突触可塑性（Lu et al.，2005，Park and Poo，2013），以及大脑的结构和功能完整性，特别是与学习和记忆相关的海马体（泰勒，阿隆索，布拉姆，& Pozzo-Miller，2002）。脑源性神经营养因子（BDNF）因其在学习和记忆中的作用而被最好地表征为神经营养因子（Lu等人，2014，Lu等人，2005年，Yoshii和Constantine-Paton，2010年）。辐射诱导的认知能力损伤可能与海马中BDNF信号传导减少有关（Ji等人，2014年，Pius-Sadowska等人，2016年）。增强BDNF信号传导的策略可以改善辐射小鼠的认知行为（Yang et al.，2016年）。BDNF蛋白具有两种蛋白水解形式-原BDNF前体蛋白和成熟BDNF（mBDNF）（Mowla等人，2001年）。proBDNF和mBDNF两者都具有生物活性，但在神经系统中具有相反的功能。mBDNF与TrkB受体结合，并激活ERK信号传导并刺激突触发生、突触强化和神经元存活（Hennigan et al. 2007年，Je等人，2013年）。相反，proBDNF与凋亡受体p75 NTR和共受体分拣蛋白Sorcs 2结合，并诱导神经元死亡、神经突生长抑制、突触抑制（Je等人，2013年，Winnubst等人，2015，Yamashita和Tohyama，2003，Yang等人，2009年）。Sorcs 2是一种proBDNF受体，其在CNS神经元培养物中proBDNF诱导的生长锥塌陷中起关键作用（Deinhardt等人，2011年，Glerup等人，2014年）。海马体中p75 NTR和proBDNF水平升高与啮齿动物的学习和记忆缺陷相关（布胡西，Ethedge，Granholm，&布胡西，2017）。最近的一项研究表明，卵泡抑素样蛋白4（Fslt 4），也称为SPIG 1，与proBDNF结合并在BDNF成熟的调节中起关键作用（Suzuki et al.，2014年）。proBDNF通过细胞外蛋白酶如基质金属蛋白酶-9（MMP-9）和纤溶酶转化为mBDNF（Ethell和Ethell，2007，Hwang等人，2005，Lu等人，2005年）。因此，认为BDNF和proBDNF及其相关蛋白之间的平衡可能在突触可塑性中起重要作用（Deinhardt & Chao，2014）。然而，研究辐射对脑中proBDNF及其受体或将proBDNF转化为mBDNF的酶的影响仍然有限。
Uncontrolled radiation exposure from radiologic terrorism, military activity or nuclear accident will likely involve a wide range of delivered doses, and cause a series of neurotoxic effects on brain function. Particularly, cognitive deficit, which can occur several days to one month after irradiation, limits its therapeutic use (Monje, 2008, Padovani et al., 2012). Evidence from experimental animal studies also proves that cognitive impairment is linked to irradiation (Monje et al., 2003, Rola et al., 2004). However, the mechanism underlying the irradiation induced cognitive impairment remains elusive.Neurotrophins are involved in neuronal survival, differentiation, neurogenesis, and synaptic plasticity (Lu et al., 2005, Park and Poo, 2013), as well as structural and functional integrity of the brain, specifically the hippocampus that links to learning and memory (Tyler, Alonso, Bramham, & Pozzo-Miller, 2002). Brain-derived neurotrophic factor (BDNF) is the best characterized neurotrophin for its role in learning and memory (Lu et al., 2014, Lu et al., 2005, Yoshii and Constantine-Paton, 2010). Irradiation-induced impairment of cognitive performance may be associated with reduced BDNF signaling in the hippocampus (Ji et al., 2014, Pius-Sadowska et al., 2016). The strategies that augment BDNF signaling could improve the cognitive behavior in irradiated mice (Yang et al., 2016). BDNF protein has two proteolytic forms—the proBDNF precursor protein and mature BDNF (mBDNF)(Mowla et al., 2001). Both proBDNF and mBDNF are biologically active but have opposite functions in the nervous system, mBDNF binds with the TrkB receptor, and activates ERK signaling and stimulates synaptogenesis, synapse strengthening and neuronal survival (Hennigan et al., 2007, Je et al., 2013). Instead, proBDNF binds to the apoptotic receptor p75NTR and co-receptor Sortilin, Sorcs2 and induces neuronal death, neurite outgrowth inhibition, synaptic depression (Je et al., 2013, Winnubst et al., 2015, Yamashita and Tohyama, 2003, Yang et al., 2009). Sorcs2 is a proBDNF receptor, which plays key role in proBDNF-induced growth cone collapse in cultures of CNS neurons (Deinhardt et al., 2011, Glerup et al., 2014). And elevated p75NTR and proBDNF levels in the hippocampus are associated with learning and memory deficits in rodents (Buhusi, Etheredge, Granholm, & Buhusi, 2017). And a recent study shows that Follistatin-like protein 4 (Fslt4), also known as SPIG1, bound with proBDNF and plays a key role in the regulation of BDNF maturation (Suzuki et al., 2014). proBDNF is converted to mBDNF by extracellular proteases, such as matrix metalloproteinase-9 (MMP-9) and plasmin (Ethell and Ethell, 2007, Hwang et al., 2005, Lu et al., 2005). Thus it is considered that the balance between BDNF and proBDNF and their associated proteins may play an important role in synaptic plasticity (Deinhardt & Chao, 2014). However, studies investigating the effect of irradiation on proBDNF and its receptors or the enzymes converting proBDNF to mBDNF in the brain are still limited.