Laboratorio Inmuno-Biología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
J Cell Physiol. 2019 May;234(5):5880-5887. doi: 10.1002/jcp.26462. Epub 2018 Dec 7.
Since the success of combined antiretroviral therapy, HIV-1-infected individuals are now living much longer. This increased life expectancy is accompanied by a higher prevalence of HIV-1 associated neurocognitive disorders. Rising too is the incidence in these patients of pathological hallmarks of Alzheimer's disease such as increased deposition of amyloid beta protein (Aβ). Although neurons are major sources of Aβ in the brain, astrocytes are the most numerous glial cells, therefore, even a small level of astrocytic Aβ metabolism could make a significant contribution to brain pathology. Neprilysin (NEP) is a decisive/crucial regulator of Aβ levels. We evaluated the effects of HIV-1 on Aβ deposition and the expression and activity of NEP in primary human astrocytes. Specifically, no differences in intracellular amyloid deposits were found between infected and control cells. However, primary cultures of infected astrocytes showed more extracellular Aβ levels compared to controls. This was accompanied by reduced expression of NEP and to a significant decrease in its activity. These results indicate that the presence of HIV-1 in the brain could contribute to the increase in the total burden of cerebral Aβ.
自联合抗逆转录病毒疗法取得成功以来，HIV-1 感染者的寿命大大延长。这种预期寿命的延长伴随着 HIV-1 相关神经认知障碍的患病率上升。在这些患者中，阿尔茨海默病的病理标志（如淀粉样β蛋白（Aβ）沉积增加）的发病率也在上升。虽然神经元是大脑中 Aβ的主要来源，但星形胶质细胞是数量最多的神经胶质细胞，因此，即使星形胶质细胞 Aβ代谢水平略有升高，也可能对脑病理学产生重大影响。 Neprilysin (NEP) 是 Aβ 水平的决定性/关键调节因子。我们评估了 HIV-1 对人原代星形胶质细胞中 Aβ 沉积以及 NEP 表达和活性的影响。具体来说，感染细胞和对照细胞之间没有发现细胞内淀粉样沉积物的差异。然而，与对照组相比，感染星形胶质细胞的原代培养物显示出更高的细胞外 Aβ 水平。这伴随着 NEP 表达的减少和其活性的显著下降。这些结果表明，HIV-1 在大脑中的存在可能导致大脑中 Aβ 总负荷的增加。
