Wang Jin Ying, Grabacka Maja, Marcinkiewicz Cezary, Staniszewska Izabella, Peruzzi Francesca, Khalili Kamel, Amini Shohreh, Reiss Krzysztof
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania 19122, USA.
J Neurosci Res. 2006 Jan;83(1):7-18. doi: 10.1002/jnr.20712.
Insulin-like growth factor 1 receptor (IGF-1R) supports neuronal survival against a wide variety of insults. This includes tumor necrosis factor-alpha (TNFalpha)-mediated neuronal damage, which represents one of the factors suspected to play a role in HIV-associated dementia (HAD). PC12 neurons engineered to express human IGF-1R (PC12/IGF-1R) maintain neuronal processes on collagen IV for several weeks. However, prolonged treatment with TNFalpha caused degeneration of neuronal processes, with no apparent signs of apoptosis. In this process, TNFalpha did not affect IGF-1-mediated phosphorylation of IRS-1, IRS-2, Akt, or Erks. In addition, PC12/IGF-1R cells were found to express predominantly alpha1beta1 integrin, which has high affinity to collagen IV. The treatment of PC12/IGF-1R neurons with a specific alpha1beta1 integrin inhibitor, obtustatin, also caused loss of neuronal processes, accompanied by a quick cell detachment and extensive apoptosis. In the presence of IGF-1, both TNFalpha-induced and obtustatin-induced degeneration of neuronal processes were effectively inhibited. Furthermore, TNFalpha-mediated neuronal degeneration correlated with decreased attachment of PC12/IGF-1R cells to collagen IV and with a reduced level of alpha1beta1 integrin, consistent with a role for this surface protein in the maintenance of neuronal processes. Thus the neuroprotective effects of IGF-1 are not restricted to its antiapoptotic properties but also involve an additional neuroprotective mechanism, by which IGF-1 counteracts the negative effect of TNFalpha on alpha1beta1 integrin-mediated attachment to collagen IV.
胰岛素样生长因子1受体（IGF-1R）可支持神经元抵抗多种损伤而存活。这包括肿瘤坏死因子-α（TNFα）介导的神经元损伤，TNFα是怀疑在与HIV相关的痴呆（HAD）中起作用的因素之一。经过基因工程改造以表达人IGF-1R的PC12神经元（PC12/IGF-1R）可在IV型胶原上维持神经元突起数周。然而，用TNFα长期处理会导致神经元突起退化，且无明显的凋亡迹象。在此过程中，TNFα不影响IGF-1介导的IRS-1、IRS-2、Akt或Erks的磷酸化。此外，发现PC12/IGF-1R细胞主要表达对IV型胶原具有高亲和力的α1β1整合素。用特异性α1β1整合素抑制剂obtustatin处理PC12/IGF-1R神经元也会导致神经元突起丧失，并伴有细胞快速脱离和广泛凋亡。在有IGF-1存在的情况下，TNFα诱导的和obtustatin诱导的神经元突起退化均被有效抑制。此外，TNFα介导的神经元退化与PC12/IGF-1R细胞与IV型胶原的附着减少以及α1β1整合素水平降低相关，这与该表面蛋白在维持神经元突起中的作用一致。因此，IGF-1的神经保护作用不仅限于其抗凋亡特性，还涉及一种额外的神经保护机制，通过该机制IGF-1可抵消TNFα对α1β1整合素介导的与IV型胶原附着的负面影响。
