Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
J Neuroimmune Pharmacol. 2011 Dec;6(4):650-7. doi: 10.1007/s11481-011-9259-6. Epub 2011 Feb 2.
HIV-1 brain infection induces neurodegeneration. While most studies focus on HIV-1-mediated neuronal injury, relatively few have investigated HIV-1-associated white matter damage. Corpus callosum (CC) is one of frequently involved white matter structures in HIV-1-associated white matter damage. Utilizing a model of ex vivo treatment of brain slice containing CC with HIV-1 glycoprotein 120 (gp120), we examined axonal injury by analyzing β-amyloid precursor protein (β-APP) accumulation in the axon. Incubation of CC slice with gp120 produced a significant higher density of β-APP in the CC tissue compared with non-gp120-treated controls, suggesting the presence of axonal damage in the CC. The gp120-induced CC axonal damage was blocked by a chemokine CXCR4 receptor antagonist T140 but not by an NMDA receptor blocker MK801 as demonstrated by Western blot analysis of β-APP, indicating that gp120 evokes the CC axonal injury through CXCR4 receptor. Immunocytochemical studies revealed a surprisingly high density of CXCR4-positive immunoreactivity in the CC. The CXCR4-positive labeling was distributed along the nerve fibers. Moreover, double labeling of anti-CXCR4 with either anti-neuronal nuclei or anti-myelin/oligodendrocyte-specific protein antibody revealed co-localization of CXCR4 and myelin/oligodendrocytes in some fiber-like structures, inferring that some neurons and oligodendrocytes in the CC express CXCR4. Taken together, these results indicate that gp120 induced axonal damage via CXCR4 in the CC.
HIV-1 脑感染会导致神经退行性变。虽然大多数研究都集中在 HIV-1 介导的神经元损伤上，但相对较少的研究调查了 HIV-1 相关的白质损伤。胼胝体（CC）是 HIV-1 相关白质损伤中经常涉及的白质结构之一。利用包含 CC 的脑片离体处理模型，用 HIV-1 糖蛋白 120（gp120）处理，我们通过分析轴突中 β-淀粉样前体蛋白（β-APP）的积累来检查轴突损伤。与未用 gp120 处理的对照相比，CC 切片与 gp120 孵育会导致 CC 组织中 β-APP 的密度显著增加，这表明 CC 中存在轴突损伤。CC 中的 gp120 诱导的 CC 轴突损伤被趋化因子 CXCR4 受体拮抗剂 T140 阻断，但 NMDA 受体阻滞剂 MK801 不能阻断，这通过 β-APP 的 Western blot 分析证实，表明 gp120 通过 CXCR4 受体引发 CC 轴突损伤。免疫细胞化学研究显示 CC 中 CXCR4 阳性免疫反应的密度出人意料地高。CXCR4 阳性标记沿着神经纤维分布。此外，用抗神经元核或抗髓鞘/少突胶质细胞特异性蛋白抗体对抗-CXCR4 进行双重标记显示，CXCR4 与髓鞘/少突胶质细胞在一些纤维样结构中存在共定位，这表明 CC 中的一些神经元和少突胶质细胞表达 CXCR4。总之，这些结果表明，gp120 通过 CC 中的 CXCR4 诱导轴突损伤。
