Neurotoxic and neurotrophic roles of proNGF and the receptor sortilin in the adult and ageing nervous system
Neurotoxic and neurotrophic roles of proNGF and the receptor sortilin in the adult and ageing nervous system
复制标题
DOI：
10.1111/j.1460-9568.2008.06152.x
复制
发表时间：
2008-04-01
影响因子：
3.4
通讯作者：
Cowen, Timothy
中科院分区：
文献类型：
--
作者：
Al-Shawi, Raya;Hafner, Angela;Cowen, Timothy
神经生长因子的前体形式(ProNGF)与受体p75和山梨素形成异源三聚体复合体；该复合体与神经细胞死亡有关。然而，目前尚不清楚proNGF及其受体p75和sortilin是否与年龄和疾病相关的神经退行性变有关。在这里，我们展示了proNGF诱导老年啮齿动物的基底前脑和外周交感神经元亚群的细胞死亡，但对年轻的成年啮齿动物没有。相比之下，proNGF似乎能诱导年轻交感神经元突起生长，而不是细胞死亡。我们研究了proNGF在老年中的神经毒性作用，发现在一些脆弱的中枢和外周神经元的投射区域，proNGF蛋白在衰老过程中升高；热量限制具有已知的神经保护作用，部分阻止了这种增加。山梨素被发现在观察到的与年龄相关的ProNGF介导的神经毒性模式中发挥重要作用。特别是，神经降压素挽救了衰老神经元的存活，神经降压素是一种替代的山梨素配体，可以阻断山梨素介导的proNGF的作用。此外，在老化的啮齿动物的基底前脑和交感神经元中，山梨素的免疫反应性显著增加；相反，p75的水平要么没有变化，要么降低。根据这些数据，我们认为选择性年龄相关性神经元萎缩和神经变性可能是由神经元中sortilin表达增加以及某些靶点proNGF表达水平升高所介导的。
The precursor form of the nerve growth factor (proNGF), forms a heterotrimeric complex with the receptors p75 and sortilin; this complex has been implicated in neuron cell death. However, it is not known whether proNGF and the receptors p75 and sortilin contribute to age- and disease-related neurodegeneration. Here we show that proNGF induces cell death in subpopulations of basal forebrain and peripheral sympathetic neurons of old, but not of young, adult rodents. In contrast, proNGF appears to induce neurite outgrowth rather than cell death of young adult sympathetic neurons. We have examined the neurotoxic role of proNGF in old age, and find that proNGF protein is elevated during ageing in the projection areas of some populations of vulnerable central and peripheral neurons; caloric restriction, which has known neuroprotective effects, partially prevents these increases. Sortilin was found to play a significant part in the observed patterns of age-related proNGF-mediated neurotoxicity. In particular, survival of aged neurons was rescued by neurotensin, an alternative sortilin ligand that blocks the sortilin-mediated effects of proNGF. Furthermore, sortilin immunoreactivity increases markedly in ageing rodent basal forebrain and sympathetic neurons; in contrast, p75 levels are either unchanged or reduced. From these data we propose that selective age-related neuronal atrophy and neurodegeneration may be mediated by increased sortilin expression in neurons, together with elevated levels of proNGF expression in some targets.