proBDNF对老龄鼠空间学习与记忆功能的影响

目的观察外源性proBDNF和内源性proBDNF对老龄鼠认知功能的影响。方法18月龄C57BL/6J鼠30只,随机分为3个组:proBDNF组、抗proBDNF组和对照组,分别采用微量渗透泵连续6d向右侧海马注射proBDNF、羊抗proBDNF或BSA,浓度均为1μg/μL,速度0.2μL/h。采用Morris水迷宫进行航行定位实验测定老龄鼠的平均逃避潜伏期、游泳速度,并进行空间探索实验测定动物在月台所在象限时间的百分比。结果Morris水迷宫实验第3天起,proBDNF注射组平均逃避潜伏期明显长于对照组;而抗proBDNF组平均逃避潜伏期比对照组短。各组之间游泳速度相差不显著。在空间探索实验中,proBDNF组在平台所在象限游泳时间的百分比明显比对照组小,动物入水后无目的游动,而抗proBDNF组在平台所在象限游泳时间的百分比明显比对照组增加,其运动轨迹主要集中于原平台所在位置。结论proBDNF能够降低老龄鼠的学习记忆功能,而阻断内源性proBDNF后能改善老龄鼠的学习记忆能力,提示proBDNF有着与成熟BDNF相反的功能。     

神经营养因子假说与抑郁症发病机制的研究进展

目前关于抑郁症发病机制的神经营养因子假说研究尚不明确,当前研究多聚焦于脑源性神经营养因子(BDNF)及其前体(proBDNF)和成熟体(mBDNF)在抑郁症中的作用。多个研究显示抑郁症患者proBDNF蛋白水平升高,而mBDNF蛋白水平降低。随着对神经营养因子假说研究的深入,有研究发现组织型纤溶酶原激活剂(tPA)可通过促使proBDNF向mBDNF转化而缓解抑郁症状,纤溶酶原激活物抑制剂-1(PAI-1)可抑制tPA的表达,PAI-1在抑郁症患者中的表达增加。本文对BDNF、proBDNF、mBDNF、tPA及PAI-1与抑郁症之间的关系进行综述,以期为抑郁症的发生机制及诊疗提供参考。     

基于生物信息学方法研究脑源性神经营养因子前体蛋白功能

目的 脑源性神经营养因子前体蛋白(proBDNF)分布于中枢神经系统,在情绪障碍和神经退行性病变中起重要作用.为了深入理解proBDNF结构与功能的关系.方法 从NCBI下载了人类proBDNF基因序列,并对基因及其编码的氨基酸序列进行生物信息学分析.结果 序列分析结果显示,该基因编码247个氨基酸序列多肽,预测蛋白质相对分子质量为27.82×103,理论等电点为9.01.信号序列分析结果发现,该蛋白主要定位于细胞的内质网、溶酶体及细胞基质中,提示为细胞内蛋白及分泌性蛋白两种存在形式.结论 结构与功能分析发现,该蛋白含有1个结构域及1个信号肽,推测proBDNF在真核细胞的信号转导、转录调控及胁迫表达等过程中发挥重要功能.     

抑郁症“脑源性神经营养因子假说”的进展

传统的抑郁症“脑源性神经营养因子假说”提出,海马及前额叶皮质脑源性神经营养因子（brain - derived neurotrophic factor, BDNF）信号通路损害参与了抑郁症的病理生理改变,抗抑郁药物通过恢复/增强BDNF信号转导发挥疗效。近年来,新的基础和临床研究证据显示了BDNF信号通路在抑郁症发病和抗抑郁治疗中作用的多样性和复杂性：（1）海马和/或前额叶皮质BDNF-TrkB信号通路的抑制或消除并不诱发抑郁样行为表型,但明显损害各种抑郁治疗反应,提示该信号通路在抑郁情绪障碍发生中缺乏直接或关键性的作用,而完整的、正常的BDNF-TrkB信号通路是目前各种抗抑郁治疗发挥疗效的必要条件;（2）BDNF-TrkB信号通路在海马-前额叶皮质和中脑边缘系统中表现出相反的抑郁行为调节作用,提示BDNF可能通过影响情绪相关神经网络而不是单个脑区的活动发挥情绪调节作用;（3）脑内存在BDNF-TrkB和proBDNF-p75NTR信号通路,分别增强和抑制海马神经可塑性,提示脑内不同BDNF信号通路间可能通过相互制约、相互影响共同参与神经可塑性和情绪行为的调节;（4）BDNF基因多态性可能与抑郁症易感性相关。新的研究证据大大扩展了人们对BDNF信号通路作用途径和作用机理复杂性的认识,促进了对传统的“抑郁症神经营养因子假说”的客观评价和进一步完善。     

Synaptic dysfunction in human immunodeficiency virus type‐1‐positive subjects: inflammation or impaired neuronal plasticity?

Many people infected with the human immunodeficiency virus type‐1 (HIV) exhibit mild or severe neurological problems, termed HIV‐associated neurocognitive disorder (HAND), even when receiving antiretroviral therapy. Thus, novel adjunctive therapies must be developed to overcome the neurotoxic effect of HIV. New therapies require a better understanding of the molecular and cellular mechanisms of HIV‐induced neurotoxicity and the risk factors that, besides inflammation and T‐cell depletion and drugs of abuse, render the central nervous system (CNS) a target of HIV‐induced neurotoxicity. HIV appears to impair neuronal plasticity, which refers to the innate ability of the CNS respond to injury and promote recovery of function. The availability of brain‐derived neurotrophic factor (BDNF), a potent neurotrophic factor that is present in abundance in the adult brain, is essential for neuronal plasticity. BDNF acts through a receptor system composed of Trk and p75NTR. Here, we present experimental evidence that some of the clinical features of HIV‐mediated neurological impairment could result from altered BDNF/TrkB/p75NTR regulation and function.     

脑源性神经营养因子在抑郁症中的研究进展

脑源性神经营养因子（brain-derived neurotrophic factor，BDNF）是参与机体情绪和认知功能至关重要的调节因子，能够促进脑内神经发生和突触发育。在抑郁患者及抑郁动物模型中，BDNF前体（brain-derived neurotrophic factor precursor，proBDNF）和前肽水平升高，BDNF成熟体（mature brain-derived neurotrophic factor，mBDNF）水平降低；抗抑郁药物治疗后，能够抑制proBDNF以及BDNF前肽的表达，促进mBDNF/proBDNF蛋白比值的升高。目前临床常见抗抑郁药的抗抑郁作用多依赖于BDNF及相关蛋白的信号转导。本文通过查阅文献，对BDNF及其相关因子在抑郁症中的作用进行总结。     

ProBDNF and its receptors are upregulated in glioma and inhibit the growth of glioma cells in vitro

Background

High-grade glioma is incurable, with a short survival time and poor prognosis. The increased expression of p75 neurotrophin receptor (NTR) is a characteristic of high-grade glioma, but the potential significance of increased p75NTR in this tumor is not fully understood. Since p75NTR is the receptor for the precursor of brain-derived neurotrophic factor (proBDNF), it is suggested that proBDNF may have an impact on glioma.

Methods

In this study we investigated the expression of proBDNF and its receptors p75NTR and sortilin in 52 cases of human glioma and 13 cases of controls by immunochemistry, quantitative real-time PCR, and Western blot methods. Using C6 glioma cells as a model, we investigated the roles of proBDNF on C6 glioma cell differentiation, growth, apoptosis, and migration in vitro.

Results

We found that the expression levels of proBDNF, p75NTR, and sortilin were significantly increased in high-grade glioma and were positively correlated with the malignancy of the tumor. We also observed that tumors expressed proBDNF, p75NTR, and sortilin in the same cells with different subcellular distributions, suggesting an autocrine or paracrine loop. The ratio of proBDNF to mature BDNF was decreased in high-grade glioma tissues and was negatively correlated with tumor grade. Using C6 glioma cells as a model, we found that proBDNF increased apoptosis and differentiation and decreased cell growth and migration in vitro via p75NTR.

Conclusions

Our data indicate that proBDNF and its receptors are upregulated in high-grade glioma and might play an inhibitory effect on glioma.     

Enhanced protein expression of proBDNF and proNGF in elevated introcular pressure-induced rat retinal ischemia

Purpose Our previous study has shown that expression of p75NTR and sortilin was increased in ischemic retina induced by elevated intraocular pressure (IOP). In this study, we aimed to ascertain the protein expression changes of proNGF and proBDNF in the same situation, since both of them can interact with sortilin and p75NTR. Methods First, expression of proBDNF and proNGF was characterized in normal rat retina by double-labeling immunochemistry. Then, proBDNF and proNGF expression in rat retina with elevated IOP and retinal ischemia was examined by Western blotting and analyzed by statistical methods. Results Immunocytochemistry showed that the proBDNF expressed in the ganglion cell layer (GCL) of normal rat retina while the proNGF primarily existsed in both the nerve fiber layers (NFL) and large ganglion cell bodies. Western blotting analysis demonstrated molecule weights of 32KDa and 28 (proBDNF) /25KDa (proNGF). In case of elevated IOP-induced retinal ischemia, the 28/25KDa band was increased significantly (p<0.05) while the 32KDa band showed little change at day 3, 5 and 7. Conclusion These results suggested that proBDNF protein expressed in the GCL and proNGF primarily presented in NFL and large ganglion cell bodies of normal rat retina and the protein expression forms of 28KDa proBDNF and 25KDa proNGF increased in ischemic retina induced by elevated IOP.     

Up-regulation of the p75 neurotrophin receptor is an essential mechanism for HIV-gp120 mediated synaptic loss in the striatum

Reduced synaptodendritic complexity appears to be a key feature in human immunodeficiency virus (HIV)-associated neurological disorder (HAND). Viral proteins, and in particular the envelope protein gp120, play a role in the pathology of synapses. Gp120 has been shown to increase both in vitro and in vivo the proneurotrophin brain-derived neurotrophic factor, which promotes synaptic simplification through the activation of the p75 neurotrophin receptor (p75NTR). To provide evidence that p75NTR plays a role in gp120-mediated loss of synapses in vivo, we intercrossed gp120tg mice with p75NTR null mice and used molecular, histological and behavioral analyses to establish a link between p75NTR and gp120-mediated synaptic simplification. Synaptosomes obtained from the striatum of gp120tg mice exhibited a significant increase in p75NTR levels concomitantly to a decrease in synaptic markers such as TrkB and PSD95. Analysis of striatal dendritic spines by Golgi staining revealed that gp120tg mice display a reduced proportion of mushroom-type spines in addition to fewer spines overall, when compared to wild type or gp120tg lacking one or two p75NTR alleles. Moreover, removal of one p75NTR allele in gp120 transgenic mice abolished the gp120-driven impairment on a task of striatal-dependent motor learning. These data indicate that p75NTR could be a key player in HIV-mediated synaptic simplification in the striatum.