HIV-1 increases extracellular amyloid-beta levels through neprilysin regulation in primary cultures of human astrocytes
HIV-1 increases extracellular amyloid-beta levels through neprilysin regulation in primary cultures of human astrocytes
复制标题
DOI：
10.1002/jcp.26462
复制
发表时间：
2019-05-01
影响因子：
5.6
通讯作者：
Alvarez, Susana
中科院分区：
文献类型：
--
作者：
Martinez-Bonet, Marta;Angeles Munoz-Fernandez, M.;Alvarez, Susana
自从联合抗逆转录病毒疗法取得成功以来，HIV-1 感染者的寿命现在更长了。预期寿命的增加伴随着 HIV-1 相关神经认知障碍患病率的升高。这些患者中阿尔茨海默病病理特征的发生率也在上升，例如淀粉样β蛋白（Aβ）沉积增加。尽管神经元是大脑中 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，即使是少量的星形胶质细胞 Aβ 代谢也可能对大脑病理学做出重大贡献。脑啡肽酶 (NEP) 是 Aβ 水平的决定性/关键调节剂。我们评估了 HIV-1 对原代人星形胶质细胞中 Aβ 沉积以及 NEP 表达和活性的影响。具体而言，感染细胞和对照细胞之间的细胞内淀粉样沉积物没有发现差异。然而，与对照相比，受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 表达的减少及其活性的显着降低。这些结果表明，大脑中 HIV-1 的存在可能导致大脑 Aβ 总负荷的增加。
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 (A beta). Although neurons are major sources of A beta in the brain, astrocytes are the most numerous glial cells, therefore, even a small level of astrocytic A beta metabolism could make a significant contribution to brain pathology. Neprilysin (NEP) is a decisive/crucial regulator of A beta levels. We evaluated the effects of HIV-1 on A beta 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 A beta 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 A beta.