HIV-1 Tat-induced cerebrovascular toxicity is enhanced in mice with amyloid deposits
HIV-1 Tat-induced cerebrovascular toxicity is enhanced in mice with amyloid deposits
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DOI：
10.1016/j.neurobiolaging.2011.06.004
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发表时间：
2012-08-01
影响因子：
4.2
通讯作者：
Toborek, Michal
中科院分区：
文献类型：
--
作者：
Chen, Lei;Choi, Jeong June;Toborek, Michal
HIV-1感染的大脑的特征是淀粉样β蛋白(Aβ)沉积增加；然而，Aβ和HIV-1之间的相互作用尚不清楚。在本研究中，我们将特定的HIV-1蛋白TAT注射到50-52周龄的双转基因(B6C3-TG)小鼠的脑血管中，这些小鼠表达嵌合的鼠/人淀粉样前体蛋白(Mo/HuAPP695swe)和突变的人早老素1(PS1-dE9)，其特征是脑中Aβ沉积增加。与年龄匹配的小鼠相比，暴露于TAT增加了B6C3-TG小鼠大脑毛细血管的通透性，增强了对闭锁带(ZO)-1紧密连接蛋白的破坏，并增加了脑组织基质金属蛋白酶-9(MMP-9)的表达。这些变化与白细胞附着增加和它们的跨毛细血管迁移有关。TAT诱导的大部分效应可通过特定的Rho抑制剂羟基法舒地尔治疗而减弱。动物实验结果在培养的脑内皮细胞中复制，暴露于Aβ和/或TAT。目前的数据表明，脑内Aβ水平的升高可以增强HIV-1蛋白Tat诱导的血管毒性和促炎反应。(C)2012 Elsevier Inc.保留所有权利。
HIV-1-infected brains are characterized by elevated depositions of amyloid beta (A beta); however, the interactions between A beta and HIV-1 are poorly understood. In the present study, we administered specific HIV-1 protein Tat into the cerebral vasculature of 50-52-week-old double transgenic (B6C3-Tg) mice that express a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) and are characterized by increased A beta depositions in the brain. Exposure to Tat increased permeability across cerebral capillaries, enhanced disruption of zonula occludens (ZO)-1 tight junction protein, and elevated brain expression of matrix metalloproteinase-9 (MMP-9) in B6C3-Tg mice as compared with age-matched littermate controls. These changes were associated with increased leukocyte attachment and their transcapillary migration. The majority of Tat-induced effects were attenuated by treatment with a specific Rho inhibitor, hydroxyfasudil. The results of animal experiments were reproduced in cultured brain endothelial cells exposed to A beta and/or Tat. The present data indicate that increased brain levels of A beta can enhance vascular toxicity and proinflammatory responses induced by HIV-1 protein Tat. (C) 2012 Elsevier Inc. All rights reserved.