Efavirenz promotes β-secretase expression and increased Aβ1-40,42 via oxidative stress and reduced microglial phagocytosis: implications for HIV associated neurocognitive disorders (HAND).
Efavirenz promotes β-secretase expression and increased Aβ1-40,42 via oxidative stress and reduced microglial phagocytosis: implications for HIV associated neurocognitive disorders (HAND).
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DOI：
10.1371/journal.pone.0095500
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Giunta B
中科院分区：
文献类型：
--
作者：
Brown LA;Jin J;Ferrell D;Sadic E;Obregon D;Smith AJ;Tan J;Giunta B
依法韦仑（EFV）是全球最常用的抗逆转录病毒药物之一，可引起干扰依从性和降低耐受性的神经系统症状，并可能对中枢神经系统（CNS）产生影响，部分导致接受联合抗逆转录病毒治疗（cART）的患者出现HIV相关神经认知障碍（HAND）。因此，我们评估了一种常用的含EFV的方案：EFV/齐多夫定（AZT）/拉米夫定（3 TC）在用人淀粉样前体蛋白的“瑞典”突变形式转染的鼠N2 a细胞（SweAPP N2 a细胞）中，以评估促进淀粉样β（Aβ）产生。EFV或含EFV的治疗方案显著增加可溶性淀粉样蛋白β（Aβ），并促进β-分泌酶-1（BACE-1）表达增加，而3 TC、AZT或溶剂对照未显著改变这些终点。此外，与3 TC、AZT或媒介物对照相比，EFV或含有EFV的方案在SweAPP N2 a细胞中促进显著更多的线粒体应激。接下来，我们使用临床相关剂量在Aβ产生Tg 2576小鼠中联合或单独测试了含EFV的方案。EFV或含EFV的方案显着促进更多的BACE-1表达和可溶性Aβ生成，而3 TC、AZT或溶剂对照则没有。最后，EFV或含EFV的治疗方案可显著降低小胶质细胞Aβ吞噬作用，但AZT、3 TC或单独的溶剂对照组则无此作用。这些数据表明，该cART方案的大部分Aβ促进作用依赖于EFV，因为它促进Aβ肽的产生增加和清除减少。
Efavirenz (EFV) is among the most commonly used antiretroviral drugs globally, causes neurological symptoms that interfere with adherence and reduce tolerability, and may have central nervous system (CNS) effects that contribute in part to HIV associated neurocognitive disorders (HAND) in patients on combination antiretroviral therapy (cART). Thus we evaluated a commonly used EFV containing regimen: EFV/zidovudine (AZT)/lamivudine (3TC) in murine N2a cells transfected with the human “Swedish” mutant form of amyloid precursor protein (SweAPP N2a cells) to assess for promotion of amyloid-beta (Aβ) production. Treatment with EFV or the EFV containing regimen generated significantly increased soluble amyloid beta (Aβ), and promoted increased β-secretase-1 (BACE-1) expression while 3TC, AZT, or, vehicle control did not significantly alter these endpoints. Further, EFV or the EFV containing regimen promoted significantly more mitochondrial stress in SweAPP N2a cells as compared to 3TC, AZT, or vehicle control. We next tested the EFV containing regimen in Aβ - producing Tg2576 mice combined or singly using clinically relevant doses. EFV or the EFV containing regimen promoted significantly more BACE-1 expression and soluble Aβ generation while 3TC, AZT, or vehicle control did not. Finally, microglial Aβ phagocytosis was significantly reduced by EFV or the EFV containing regimen but not by AZT, 3TC, or vehicle control alone. These data suggest the majority of Aβ promoting effects of this cART regimen are dependent upon EFV as it promotes both increased production, and decreased clearance of Aβ peptide.
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影响因子：
9.9
作者：
Ances, B. M.;Christensen, J. J.;Clifford, D. B.
通讯作者：
Clifford, D. B.
DOI：
10.1124/jpet.105.098459
发表时间：
2006-05-01
影响因子：
3.5
作者：
Gibbs, JE;Gaffen, Z;Thomas, SA
通讯作者：
Thomas, SA
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影响因子：
10.6
作者：
Craig-Schapiro, Rebecca;Perrin, Richard J.;Roe, Catherine M.;Xiong, Chengjie;Carter, Deborah;Cairns, Nigel J.;Mintun, Mark A.;Peskind, Elaine R.;Li, Ge;Galasko, Douglas R.;Clark, Christopher M.;Quinn, Joseph F.;D'Angelo, Gina;Malone, James P.;Townsend, R. Reid;Morris, John C.;Fagan, Anne M.;Holtzman, David M.
通讯作者：
Holtzman, David M.
影响因子：
9.9
作者：
Brew, BJ;Pemberton, L;Hagberg, L
通讯作者：
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作者：
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