Soliman Mahmoud L, Geiger Jonathan D, Chen Xuesong
Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, 504 Hamline St., Grand Forks, ND, 58203, USA.
J Neuroimmune Pharmacol. 2017 Mar;12(1):163-170. doi: 10.1007/s11481-016-9707-4. Epub 2016 Sep 15.
The increased life expectancy of people living with HIV-1 who are taking effective anti-retroviral therapeutics is now accompanied by increased Alzheimer's disease (AD)-like neurocognitive problems and neuropathological features such as increased levels of amyloid beta (Aβ) and phosphorylated tau proteins. Others and we have shown that HIV-1 Tat promotes the development of AD-like pathology. Indeed, HIV-1 Tat once endocytosed into neurons can alter morphological features and functions of endolysosomes as well as increase Aβ generation. Caffeine has been shown to have protective actions against AD and based on our recent findings that caffeine can inhibit endocytosis in neurons and can prevent neuronal Aβ generation, we tested the hypothesis that caffeine blocks HIV-1 Tat-induced Aβ generation and tau phosphorylation. In SH-SY5Y cells over-expressing wild-type amyloid beta precursor protein (AβPP), we demonstrated that HIV-1 Tat significantly increased secreted levels and intracellular levels of Aβ as well as cellular protein levels of phosphorylated tau. Caffeine significantly decreased levels of secreted and cellular levels of Aβ, and significantly blocked HIV-1 Tat-induced increases in secreted and cellular levels of Aβ. Caffeine also blocked HIV-1 Tat-induced increases in cellular levels of phosphorylated tau. Furthermore, caffeine blocked HIV-1 Tat-induced endolysosome dysfunction as indicated by decreased protein levels of vacuolar-ATPase and increased protein levels of cathepsin D. These results further implicate endolysosome dysfunction in the pathogenesis of AD and HAND, and by virtue of its ability to prevent and/or block neuropathological features associated with AD and HAND caffeine might find use as an effective adjunctive therapeutic agent.
接受有效抗逆转录病毒治疗的HIV-1感染者预期寿命增加，如今随之而来的是阿尔茨海默病（AD）样神经认知问题以及神经病理学特征增多，如β淀粉样蛋白（Aβ）和磷酸化tau蛋白水平升高。我们和其他人已经证明，HIV-1反式激活因子（Tat）会促进AD样病理的发展。事实上，HIV-1 Tat一旦被神经元内吞，就会改变内溶酶体的形态特征和功能，并增加Aβ的生成。已有研究表明咖啡因对AD具有保护作用，基于我们最近的发现，即咖啡因可以抑制神经元的内吞作用并能预防神经元Aβ的生成，我们检验了这样一个假设：咖啡因可以阻断HIV-1 Tat诱导的Aβ生成和tau磷酸化。在过表达野生型淀粉样前体蛋白（AβPP）的SH-SY5Y细胞中，我们证明HIV-1 Tat显著增加了Aβ的分泌水平和细胞内水平以及磷酸化tau的细胞蛋白水平。咖啡因显著降低了Aβ的分泌水平和细胞水平，并显著阻断了HIV-1 Tat诱导的Aβ分泌水平和细胞水平的增加。咖啡因还阻断了HIV-1 Tat诱导的磷酸化tau细胞水平的增加。此外，咖啡因阻断了HIV-1 Tat诱导的内溶酶体功能障碍，这表现为液泡型ATP酶蛋白水平降低和组织蛋白酶D蛋白水平升高。这些结果进一步表明内溶酶体功能障碍与AD和HIV相关神经认知障碍（HAND）的发病机制有关，并且由于咖啡因能够预防和/或阻断与AD和HAND相关的神经病理学特征，它可能会成为一种有效的辅助治疗药物。
