HIV-1 reduces Abeta-degrading enzymatic activities in primary human mononuclear phagocytes.
HIV-1 reduces Abeta-degrading enzymatic activities in primary human mononuclear phagocytes.
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DOI：
10.4049/jimmunol.1100211
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发表时间：
2011-06-15
期刊：
影响因子：
--
通讯作者：
Ikezu T
中科院分区：
文献类型：
--
作者：
Lan X;Xu J;Kiyota T;Peng H;Zheng JC;Ikezu T
抗逆转录病毒疗法的出现和广泛采用大大改善了艾滋病毒感染者的生存和寿命。不幸的是，尽管进行了ART治疗，这些患者仍然患有许多并发症，包括认知功能障碍。越来越多的报告表明，HIV感染的大脑中淀粉样蛋白斑块（由淀粉样蛋白-β肽（Aβ）组成）的沉积加速。尽管HIV病毒感染如何加速Aβ积累还知之甚少。这表明病毒感染导致Aβ产生增加和降解受损。在脑中被HIV感染的单核吞噬细胞（巨噬细胞和小胶质细胞）通过表达和执行两种内肽酶：脑啡肽酶（NEP）和胰岛素降解酶（IDE）在Aβ降解中发挥关键作用。本文报道了NEP对巨噬细胞中Aβ具有主要的内肽酶活性。此外，我们证明，单体Aβ降解的原代培养的巨噬细胞和小胶质细胞显着受损的HIV感染。这可能是由于NEP向细胞表面的转运减少以及在内质网和溶酶体中的细胞内积累所致。因此，这些数据表明，感染巨噬细胞中的NEP功能障碍可能导致HIV所致脑中β淀粉样变性加速，并且巨噬细胞的调节可能是HIV感染患者中Aβ相关认知障碍的潜在预防靶点。
The advent and wide introduction of antiretroviral therapy (ART) has greatly improved the survival and longevity of HIV-infected patients. Unfortunately, despite ART treatment, these patients are still afflicted with many complications including cognitive dysfunction. There is a growing body of reports indicating accelerated deposition of amyloid plaques, which are composed of amyloid-β peptide (Aβ), in HIV-infected brains. Though how HIV viral infection precipitates Aβ accumulation is poorly understood. It is suggested that viral infection leads to increased production and impaired degradation of Aβ. Mononuclear phagocytes (macrophages and microglia) that are productively infected by HIV in brains play a pivotal role in Aβ degradation through the expression and execution of two endopeptidases: neprilysin (NEP) and insulin-degrading enzyme (IDE). Here we report that NEP has the dominant endopeptidase activity towards Aβ in macrophages. Further, we demonstrate that monomeric Aβ degradation by primary cultured macrophages and microglia was significantly impaired by HIV infection. This was accompanied with great reduction of NEP endopeptidase activity, which might be due to the diminished transport of NEP to cell surface and intracellular accumulation at the endoplasmic reticulum and lysosomes. Therefore, these data suggest that malfunction of NEP in infected macrophages may contribute to acceleration of beta amyloidosis in HIV-inflicted brains and modulation of macrophages may be a potential preventative target of Aβ-related cognitive disorders in HIV-affected patients.
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