Antiretroviral medications disrupt microglial phagocytosis of β-amyloid and increase its production by neurons: implications for HIV-associated neurocognitive disorders.
Antiretroviral medications disrupt microglial phagocytosis of β-amyloid and increase its production by neurons: implications for HIV-associated neurocognitive disorders.
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DOI：
10.1186/1756-6606-4-23
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发表时间：
2011-06-07
期刊：
影响因子：
3.6
通讯作者：
Shytle RD
中科院分区：
文献类型：
--
作者：
Giunta B;Ehrhart J;Obregon DF;Lam L;Le L;Jin J;Fernandez F;Tan J;Shytle RD
高达50%的长期HIV感染患者，包括那些全身控制良好的感染者，通常会出现记忆问题和缓慢，难以集中注意力，计划和多任务处理。Aβ斑块沉积也是HIV感染的常见病理特征。然而，尚不清楚这种蓄积是否是由于AD样过程、HIV相关免疫抑制、达特蛋白诱导的Aβ升高和/或单一高效抗逆转录病毒治疗（ART）的作用。在此，我们评价了几种ART药物（齐多夫定、拉米夫定、茚地那韦和阿巴卡韦）单独和联合使用对以下方面的影响：1）在用人APP“瑞典”突变形式转染的鼠N2 a细胞中Aβ1-40、42生成; 2）在培养的鼠N9小胶质细胞中FITC-Aβ1-42肽的小胶质细胞吞噬作用。我们首次报告，这些抗逆转录病毒化合物（10 μM）通常可增加SweAPP N2 a细胞中的Aβ生成（约50-200%），并显著抑制小鼠小胶质细胞中FITC-Aβ1-42肽的小胶质细胞吞噬作用。在联合ART中观察到最显著的淀粉样蛋白生成作用（p < 0.05）;表明某些ART药物在联合使用时可能具有附加的淀粉样蛋白生成作用。由于这些抗逆转录病毒化合物能够穿透血脑屏障并达到体外研究中使用的浓度，这些发现提出了ART可能在HIV感染者大脑中发现的Aβ升高中发挥偶然作用的可能性。因此，这些化合物可能因此导致在HIV相关神经认知障碍（HAND）中观察到的认知下降。
Up to 50% of long-term HIV infected patients, including those with systemically well-controlled infection, commonly experience memory problems and slowness, difficulties in concentration, planning, and multitasking. Deposition of Aβ plaques is also a common pathological feature of HIV infection. However, it is not clear whether this accumulation is due to AD-like processes, HIV-associated immunosuppression, Tat protein-induced Aβ elevations, and/or the effects of single highly active antiretroviral therapy (ART). Here we evaluated the effects of several ART medications (Zidovudine, Lamivudine, Indinavir, and Abacavir) alone and in combination on: 1) Aβ1-40, 42 generation in murine N2a cells transfected with the human "Swedish" mutant form of APP; 2) microglial phagocytosis of FITC-Aβ1-42 peptides in cultured murine N9 microglia. We report for the first time that these antiretroviral compounds (10 μM) generally increase Aβ generation (~50-200%) in SweAPP N2a cells and markedly inhibit microglial phagocytosis of FITC-Aβ1-42 peptides in murine microglia. The most significant amyloidogenic effects were observed with combined ART (p < 0.05); suggesting certain ART medications may have additive amyloidogenic effects when combined. As these antiretroviral compounds are capable of penetrating the blood brain barrier and reaching the concentrations employed in the in vitro studies, these findings raise the possibility that ART may play a casual role in the elevated Aβ found in the brains of those infected with HIV. Therefore these compounds may consequently contribute to cognitive decline observed in HIV associated neurocognitive disorders (HAND).
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影响因子：
3.1
作者：
Shapshak, P;Duncan, R;Goodkin, K
通讯作者：
Goodkin, K
影响因子：
--
作者：
Readnower RD;Sauerbeck AD;Sullivan PG
通讯作者：
Sullivan PG
影响因子：
9.9
作者：
Robertson, K. R.;Su, Z.;Skiest, D. J.
通讯作者：
Skiest, D. J.
影响因子：
5.4
作者：
Townsend, KP;Town, T;Tan, J
通讯作者：
Tan, J
影响因子：
3.7
作者：
Kiebala, Michelle;Polesskaya, Oksana;Maggirwar, Sanjay B.
通讯作者：
Maggirwar, Sanjay B.