Objectives:Growing evidence suggested that antiretroviral (ARV) drugs may promote amyloid beta (Aβ) accumulation in HIV-1-infected brain and the persistence of HIV-associated neurocognitive disorders (HANDs). It has also been shown that lipid peroxidation upregulates β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) expression and subsequently promotes Aβ peptide production. In the present study, we examined whether chronic exposure to the anti-HIV drugs tenofovir disoproxil fumarate (TDF) and nevirapine induces lipid peroxidation thereby promoting BACE1 and Aβ generation and consequently impair cognitive function in mice.Methods:TDF or nevirapine was orally administered to female BALB/c mice once a day for 8 weeks. On the 7th week of treatment, spatial learning and memory were assessed using the Morris water maze test. The levels of lipid peroxidation, BACE1, amyloid β 1-42 (Aβ1-42) and Aβ deposits were measured in the hippocampal tissue upon completion of treatment.Results:Chronic administration of nevirapine induced spatial learning and memory impairment in the Morris water maze test, whereas TDF did not have an effect. TDF and nevirapine administration increased hippocampal lipid peroxidation and Aβ1-42 concentration. Nevirapine further upregulated BACE1 expression and Aβ deposits.Conclusion:Our results suggest that chronic exposure to TDF and nevirapine contributes to hippocampal lipid peroxidation and Aβ accumulation, respectively, as well as spatial learning and memory deficits in mice even in the absence of HIV infection. These findings further support a possible link between ARV drug toxicity, Aβ accumulation and the persistence of HANDs.

中文翻译：

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抗 HIV 药物促进 BALB/c 小鼠的 β-淀粉样蛋白沉积并损害学习和记忆

目的：越来越多的证据表明，抗逆转录病毒 (ARV) 药物可能会促进淀粉样蛋白β (Aβ) 在 HIV-1 感染的大脑中的积累和 HIV 相关神经认知障碍 (HANDs) 的持续存在。还显示脂质过氧化上调 β 位点淀粉样前体蛋白 (APP) 裂解酶 1 (BACE1) 的表达并随后促进 Aβ 肽的产生。在本研究中，我们检查了长期暴露于抗 HIV 药物富马酸替诺福韦酯 (TDF) 和奈韦拉平是否会诱导脂质过氧化，从而促进 BACE1 和 Aβ 的生成，从而损害小鼠的认知功能。方法：口服 TDF 或奈韦拉平雌性 BALB/c 小鼠每天一次，持续 8 周。在治疗的第 7 周，使用 Morris 水迷宫测试评估空间学习和记忆。治疗完成后，测量海马组织中脂质过氧化、BACE1、淀粉样蛋白β1-42（Aβ1-42）和Aβ沉积物的水平。结果：长期服用奈韦拉平在Morris水迷宫试验中引起空间学习和记忆障碍，而 TDF 没有效果。TDF 和奈韦拉平给药增加了海马脂质过氧化和 Aβ1-42 浓度。奈韦拉平进一步上调 BACE1 表达和 Aβ 沉积。结论：我们的研究结果表明，即使在没有 HIV 感染的情况下，长期暴露于 TDF 和奈韦拉平也会导致小鼠海马脂质过氧化和 Aβ 积累，以及空间学习和记忆缺陷。这些发现进一步支持了 ARV 药物毒性、Aβ 积累和 HAND 持久性之间可能存在的联系。