Up-regulation of the p75 neurotrophin receptor is an essential mechanism for HIV-gp120 mediated synaptic loss in the striatum.
Up-regulation of the p75 neurotrophin receptor is an essential mechanism for HIV-gp120 mediated synaptic loss in the striatum.
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DOI：
10.1016/j.bbi.2020.07.023
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Mocchetti I
中科院分区：
文献类型：
--
作者：
Speidell A;Asuni GP;Wakulski R;Mocchetti I
突触树突复杂性降低似乎是人类免疫缺陷病毒（HIV）相关神经系统疾病（HAND）的一个关键特征。病毒蛋白，特别是包膜蛋白gp120，在突触的病理学中起作用。Gp120在体外和体内均能增加脑源性神经营养因子，该因子通过激活p75神经营养因子受体（p75NTR）促进突触简化。为了证明p75 NTR在体内gp120介导的突触丢失中起作用，我们将gp120 tg小鼠与p75 NTR缺失小鼠杂交，并使用分子、组织学和行为学分析来建立p75 NTR和gp120介导的突触简化之间的联系。从gp120tg小鼠纹状体获得的突触体表现出p75NTR水平的显著增加，伴随着突触标记物如TrkB和PSD 95的减少。通过高尔基体染色对纹状体树突棘的分析显示，与野生型或缺乏一个或两个p75 NTR等位基因的gp120 tg相比，gp120 tg小鼠除了总体上较少的棘外，还显示蘑菇型棘的比例降低。此外，在gp120转基因小鼠中去除一个p75 NTR等位基因消除了gp120驱动的对纹状体依赖性运动学习任务的损害。这些数据表明，p75NTR可能是一个关键球员在艾滋病毒介导的突触简化纹状体。
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.
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DOI：
10.1016/j.bbi.2016.01.020
发表时间：
2016-05
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
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10.1017/s1355617715000971
发表时间：
2015-10-01
影响因子：
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