The neurotrophin receptor p75 mediates gp120-induced loss of synaptic spines in aging mice
The neurotrophin receptor p75 mediates gp120-induced loss of synaptic spines in aging mice
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DOI：
10.1016/j.neurobiolaging.2016.07.001
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发表时间：
2016-10-01
影响因子：
4.2
通讯作者：
Mocchetti, Italo
中科院分区：
文献类型：
--
作者：
Bachis, Alessia;Wenzel, Erin;Mocchetti, Italo
人类免疫缺陷病毒 1 及其包膜蛋白 gp120 降低了突触树突的复杂性。然而，造成这种病理特征的机制仍不清楚。前神经营养蛋白脑源性神经营养因子通过激活 p75 神经营养蛋白受体 (p75NTR) 促进突触简化。在这里，我们使用 gp120 转基因 (gp120tg) 小鼠来研究 p75NTR 是否在 gp120 介导的神经毒性中发挥作用。与年龄匹配的野生型小鼠相比，老年（大约 10 个月）的 gp120tg 小鼠表现出海马体中前神经营养蛋白脑源性神经营养因子水平的增加以及树突棘数量的减少。在 3 或 6 个月大的小鼠中没有观察到这些影响。为了测试脊柱密度和形态的减少是否是由 p75NTR 的激活引起的，我们将 gp120tg 小鼠与 p75NTR null 小鼠杂交。我们发现，在 gp120tg 小鼠中，仅删除 1 个 p75NTR 基因拷贝就足以使海马棘的数量正常化，这强烈表明 gp120 的神经毒性作用是由 p75NTR 介导的。这些数据表明，p75NTR 拮抗剂可以为人类免疫缺陷病毒 1 引起的突触简化提供辅助治疗。(C) 2016 Elsevier Inc. 保留所有权利。
Human immunodeficiency virus 1 and its envelope protein gp120 reduce synaptodendritic complexity. However, the mechanisms contributing to this pathological feature are still not understood. The proneurotrophin brain-derived neurotrophic factor promotes synaptic simplification through the activation of the p75 neurotrophin receptor (p75NTR). Here, we have used gp120 transgenic (gp120tg) mice to investigate whether p75NTR has a role in gp120-mediated neurotoxicity. Old (similar to 10 months) gp120tg mice exhibited an increase in proneurotrophin brain-derived neurotrophic factor levels in the hippocampus as well as a decrease in the number of dendritic spines when compared to age-matched wild type. These effects were not observed in 3-or 6-month-old mice. To test if the reduction in spine density and morphology is caused by the activation of p75NTR, we crossed gp120tg mice with p75NTR null mice. We found that deletion of only 1 copy of the p75NTR gene in gp120tg mice is sufficient to normalize the number of hippocampal spines, strongly suggesting that the neurotoxic effect of gp120 is mediated by p75NTR. These data indicate that p75NTR antagonists could provide an adjunct therapy against synaptic simplification caused by human immunodeficiency virus 1. (C) 2016 Elsevier Inc. All rights reserved.