Tiwari Sneham, Atluri Venkata Subba Rao, Yndart Arias Adriana, Jayant Rahul Dev, Kaushik Ajeet, Geiger Jonathan, Nair Madhavan N
Institute of NeuroImmune Pharmacology, Center for Personalized Nanomedicine, Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States.
Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, United States.
Front Aging Neurosci. 2018 Sep 27;10:291. doi: 10.3389/fnagi.2018.00291. eCollection 2018.
Neurological disorders are the biggest concern globally. Out of ~36 million human immunodeficiency virus (HIV) positive people, about 30%-60% exhibit neurological disorders, including dementia and Alzheimer's disease (AD) like pathology. In AD or AD like neurological disorders, the pathogenesis is mainly due to the abnormal accumulation of extracellular amyloid beta (Aβ). In this era of antiretroviral therapy, the life span of the HIV-infected individuals has increased leading towards increased neurocognitive dysfunction in nearly 30% of HIV-infected individuals, specifically older people. Deposition of the Aβ plaques in the CNS is one the major phenomenon happening in aging HIV patients. ART suppresses the viral replication, but the neurotoxic protein (Tat) is still produced and results in increased levels of Aβ. Furthermore, drugs of abuse like cocaine (coc) is known to induce the HIV associated neurocognitive disorders as well as the Aβ secretion. To target the Tat and coc induced Aβ secretion, we propose a potent bifunctional molecule Withaferin A (WA) which may act as a neuro-protectant against Aβ neurotoxicity. In this study, we show that WA reduces secreted Aβ and induced neurotoxicity in amyloid precursor protein (APP)-plasmid transfected SH-SY5Y cells (SH-APP). In this study, we show that in SH-APP cells, Aβ secretion is induced in the presence of HIV-1 Tat (neurotoxic) and drug of abuse coc. Our fluorescent microscopy studies show the increased concentration of Aβ40 in Tat (50 ng/ml) and coc (0.1 μM) treated SH-APP cells as compared to control. Our dose optimization study show, lower concentrations (0.5-2 μM) of WA significantly reduce the Aβ40 levels, without inducing cytotoxicity in the SH-APP cells. Additionally, WA reduces the Tat and cocaine induced Aβ levels. Therefore, we propose that Aβ aggregation is induced by the presence of Tat and coc and WA is potent in reducing the secreted Aβ and induced neurotoxicity. Our study provides new opportunities for exploring the pathophysiology and targeting the neurological disorders.
神经疾病是全球最令人担忧的问题。在约3600万人类免疫缺陷病毒（HIV）阳性人群中，约30%-60%表现出神经疾病，包括痴呆和类似阿尔茨海默病（AD）的病理特征。在AD或类似AD的神经疾病中，发病机制主要是由于细胞外淀粉样蛋白β（Aβ）的异常积累。在这个抗逆转录病毒治疗的时代，HIV感染者的寿命延长，导致近30%的HIV感染者，尤其是老年人，神经认知功能障碍增加。Aβ斑块在中枢神经系统中的沉积是老年HIV患者中发生的主要现象之一。抗逆转录病毒疗法（ART）抑制病毒复制，但神经毒性蛋白（Tat）仍会产生，并导致Aβ水平升高。此外，像可卡因（coc）这样的滥用药物已知会诱发HIV相关神经认知障碍以及Aβ分泌。为了靶向Tat和coc诱导的Aβ分泌，我们提出了一种有效的双功能分子Withaferin A（WA），它可能作为一种针对Aβ神经毒性的神经保护剂。在这项研究中，我们表明WA可减少淀粉样前体蛋白（APP）-质粒转染的SH-SY5Y细胞（SH-APP）中分泌的Aβ并诱导神经毒性。在这项研究中，我们表明在SH-APP细胞中，HIV-1 Tat（神经毒性）和滥用药物coc的存在会诱导Aβ分泌。我们的荧光显微镜研究表明，与对照相比，Tat（50 ng/ml）和coc（0.1 μM）处理的SH-APP细胞中Aβ40的浓度增加。我们的剂量优化研究表明，较低浓度（0.5-2 μM） 的WA可显著降低Aβ40水平，而不会在SH-APP细胞中诱导细胞毒性。此外，WA可降低Tat和可卡因诱导的Aβ水平。因此，我们认为Tat和coc的存在会诱导Aβ聚集，而WA在降低分泌的Aβ和诱导的神经毒性方面具有效力。我们的研究为探索病理生理学和靶向神经疾病提供了新的机会。
