HIV-Associated Insults Modulate ADAM10 and Its Regulator Sirtuin1 in an NMDA Receptor-Dependent Manner.
HIV-Associated Insults Modulate ADAM10 and Its Regulator Sirtuin1 in an NMDA Receptor-Dependent Manner.
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DOI：
10.3390/cells11192962
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发表时间：
2022-09-22
期刊：
影响因子：
6
通讯作者：
Jordan-Sciutto, Kelly
中科院分区：
文献类型：
--
作者：
Lloreda, Claudia Lopez;Chowdhury, Sarah;Ghura, Shivesh;Alvarez-Periel, Elena;Jordan-Sciutto, Kelly
与人类免疫缺陷病毒（HIV）感染相关的神经功能缺陷影响了大约50%的HIV感染者（PWH）。这些疾病被称为hiv相关神经认知障碍（HAND），具有与阿尔茨海默病（AD）相似的神经病理学，包括细胞内和细胞外淀粉样蛋白- β (Aβ)肽聚集。β肽是由β分泌酶BACE1裂解淀粉样蛋白前体蛋白（APP）产生的。然而，这被非淀粉样变性α分泌酶ADAM10切割APP所排除。既往研究发现，在PWH伴HAND的中枢神经系统以及HAND动物模型中，BACE1的表达均升高。此外，BACE1导致神经毒性。然而，在体外模型中，ADAM10的作用及其潜在的调节机制尚未得到检验。为了解决这个问题，用HIV感染的人巨噬细胞（HIV/MDMs）的上清液处理大鼠皮层神经元。我们发现HIV/MDMs降低了ADAM10和SIRT1的水平，SIRT1是ADAM10的调节因子，与衰老和阿尔茨海默病有关。NMDA受体拮抗剂阻断了这两种降低，NMDA治疗足以诱导ADAM10和SIRT1蛋白水平的降低。此外，SIRT1蛋白水平的下降比ADAM10蛋白水平的下降在更早的时间点被观察到，SIRT1的下降被蛋白酶体抑制剂MG132逆转。该研究表明，hiv相关的损伤，特别是兴奋性毒性，通过下调ADAM10及其调节因子的水平，有助于APP分泌酶的变化。
Neurologic deficits associated with human immunodeficiency virus (HIV) infection impact about 50% of persons with HIV (PWH). These disorders, termed HIV-associated neurocognitive disorders (HAND), possess neuropathologic similarities to Alzheimer’s disease (AD), including intra- and extracellular amyloid-beta (Aβ) peptide aggregates. Aβ peptide is produced through cleavage of the amyloid precursor protein (APP) by the beta secretase BACE1. However, this is precluded by cleavage of APP by the non-amyloidogenic alpha secretase, ADAM10. Previous studies have found that BACE1 expression was increased in the CNS of PWH with HAND as well as animal models of HAND. Further, BACE1 contributed to neurotoxicity. Yet in in vitro models, the role of ADAM10 and its potential regulatory mechanisms had not been examined. To address this, primary rat cortical neurons were treated with supernatants from HIV-infected human macrophages (HIV/MDMs). We found that HIV/MDMs decreased levels of both ADAM10 and Sirtuin1 (SIRT1), a regulator of ADAM10 that is implicated in aging and in AD. Both decreases were blocked with NMDA receptor antagonists, and treatment with NMDA was sufficient to induce reduction in ADAM10 and SIRT1 protein levels. Furthermore, decreases in SIRT1 protein levels were observed at an earlier time point than the decreases in ADAM10 protein levels, and the reduction in SIRT1 was reversed by proteasome inhibitor MG132. This study indicates that HIV-associated insults, particularly excitotoxicity, contribute to changes of APP secretases by downregulating levels of ADAM10 and its regulator.
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DOI：
10.1016/j.bbadis.2012.10.009
发表时间：
2013-01-01
影响因子：
6.2
作者：
Caldeira, Margarida V.;Curcio, Michele;Duarte, Carlos B.
通讯作者：
Duarte, Carlos B.
影响因子：
4.2
作者：
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通讯作者：
Lahiri, Debomoy K.
影响因子：
4.7
作者：
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通讯作者：
Marcondes, Maria Cecilia Garibaldi
影响因子：
4.8
作者：
Chen, J;Zhou, YG;Li, G
通讯作者：
Li, G
影响因子：
9.9
作者：
Brew, BJ;Pemberton, L;Hagberg, L
通讯作者：
Hagberg, L